Conference Coverage

The investigational gene therapy exagamglogene autotemcel (exa-cel) shows encouraging efficacy, safety, and patient-reported outcomes for transfusion-dependent beta-thalassemia and sickle cell disease (SCD), in findings that could lead to the first-ever approval of a therapy that utilizes CRISPR-Cas9 gene-editing.

Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.

The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.

In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”

“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
 

Burden is high; current curative options have caveats

Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.

The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.

With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.

A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
 

Gene therapy

Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.

The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.

While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.

“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
 

Phase 3 trial interim results

In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.

Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).

Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.

Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.

And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).

All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).

Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
 

Durability, patient-reported outcomes favorable

Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.

In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.

Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.

In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.

For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.

All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
 

Potentially first ever CRISPR-based FDA approval

While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.

The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.

Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.

“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.

“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”

Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.

Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.

The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.

Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.

“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.

“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”

Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.

The investigational gene therapy exagamglogene autotemcel (exa-cel) shows encouraging efficacy, safety, and patient-reported outcomes for transfusion-dependent beta-thalassemia and sickle cell disease (SCD), in findings that could lead to the first-ever approval of a therapy that utilizes CRISPR-Cas9 gene-editing.

Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.

The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.

In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”

“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
 

Burden is high; current curative options have caveats

Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.

The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.

With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.

A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
 

Gene therapy

Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.

The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.

While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.

“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
 

Phase 3 trial interim results

In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.

Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).

Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.

Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.

And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).

All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).

Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
 

Durability, patient-reported outcomes favorable

Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.

In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.

Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.

In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.

For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.

All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
 

Potentially first ever CRISPR-based FDA approval

While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.

The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.

Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.

“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.

“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”

Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.

Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.

The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.

Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.

“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.

“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”

Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.

The investigational gene therapy exagamglogene autotemcel (exa-cel) shows encouraging efficacy, safety, and patient-reported outcomes for transfusion-dependent beta-thalassemia and sickle cell disease (SCD), in findings that could lead to the first-ever approval of a therapy that utilizes CRISPR-Cas9 gene-editing.

Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.

The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.

In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”

“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
 

Burden is high; current curative options have caveats

Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.

The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.

With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.

A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
 

Gene therapy

Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.

The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.

While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.

“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
 

Phase 3 trial interim results

In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.

Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).

Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.

Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.

And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).

All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).

Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
 

Durability, patient-reported outcomes favorable

Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.

In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.

Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.

In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.

For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.

All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
 

Potentially first ever CRISPR-based FDA approval

While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.

The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.

Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.

“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.

“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”

Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.

Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.

The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.

Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.

“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.

“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”

Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.

SAN DIEGO – An assessment of people with diabetes before Ramadan is vital so they can learn whether it is safe for them to fast, and if it is, how to do so without jeopardizing their health.

“With correct advice and support” from knowledgeable health care professionals “most people with type 2 diabetes can fast safely during Ramadan,” Mohamed Hassanein, MBChB, said at the annual scientific sessions of the American Diabetes Association.

One of the most authoritative guidelines on how people with diabetes can safely fast during Ramadan has come from a collaboration between the International Diabetes Federation and the Diabetes & Ramadan International Alliance, an organization chaired by Dr. Hassanein. The groups issued a revised practical guide in 2021 for Ramadan fasting for people with diabetes, an update of the first edition released in 2016. Dr. Hassanein was lead author of the 2016 guidelines and edited the 2021 revision.

The 2021 guidelines also led to an update of a risk stratification app available for free from the DAR. The app provides risk stratification for people with diabetes and helps them access educational material to guide them through their fasts.

Although the latest guidelines address fasting for people with type 1 or type 2 diabetes, far more people with type 2 diabetes are at risk from fasting, and not only because of the higher prevalence of type 2 diabetes.

Results from a global survey of Muslims with diabetes in 2020 showed that 30% of those with type 1 diabetes did not do any fasting during Ramadan, but the percentage of those abstaining from fasting dropped to 16% among Muslims with type 2 diabetes, Dr. Hassanein explained. (Survey results in 2013 from about 38,000 Muslims in 39 countries showed a median of 7% of all adults did no fasting during Ramadan.)
 

Risk assessment by app

Currently, the DAR app is available in Arabic, English, French, and Urdu (the primary language of Pakistan), with more languages being added soon, said Dr. Hassanein, an endocrinologist at Dubai Hospital and professor at Mohammed Bin-Rashid University of Medicine & Health Sciences in Dubai, United Arab Emirates.

The app and screening protocol divides people with diabetes into low-, moderate-, and high-risk subgroups, and those at high risk are advised to refrain from fasting.

But the many other people with diabetes who potentially could fast still face risks for hypoglycemia, hyperglycemia (from overindulgent break-fast meals), diabetic ketoacidosis, dehydration, and thrombosis. Individual risk for these adverse events depends on many factors, including age, duration of diabetes, diabetes type, treatments received, history of hypoglycemia, and diabetes complications.

Dr. Hassanein and colleagues documented the high rate of complications from fasting in a 2020 survey of more than 5,800 Muslims with type 2 diabetes from 20 countries. The results showed that 72% of survey participants had to interrupt their 30 days of daily fasting for at least 1 day because of a diabetes-related event, and an additional 28% had diabetes-triggered interruptions that totaled more than 7 days. About 7% required hospitalization or an emergency department visit, and 16% developed at least one episode of daytime hypoglycemia.
 

Endorsement from Islamic clerics

The recommended risk assessment, and resulting exemptions from fasting, have been endorsed by the Mofty of Egypt, a group of religious scholars who issue legal opinions interpreting Islamic law.

The Mofty agreed that fasting should be interrupted for cases of hypoglycemia with blood glucose less than 70 mg/dL, hyperglycemia with blood glucose greater than 300 mg/dL, symptoms of hypo- or hyperglycemia, or symptoms of acute illness. The Mofty also endorsed that although fasting is obligatory for low-risk adults with diabetes and preferred for those with moderate-risk diabetes, the latter group may consider not fasting out of concern for their safety or to take prescribed medications. People at high risk were deemed by the Mofty as individuals who should not fast because of the potential for harm.

Other notable 2020 survey findings included pre-Ramadan education being received by just 43% of the respondents, and no self-monitoring of blood glucose performed by about a quarter of the respondents.

The 2021 guidelines also include treatment recommendations, such as avoiding older, longer-acting sulfonylurea agents in people with type 2 diabetes. And having people achieve stable, guideline-directed dosages of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide-1 (GLP-1) agonists before Ramadan starts, rather than trying to initiate these agents during Ramadan. The guidelines also recommend reducing usual insulin doses when fasting during Ramadan.

Despite summarizing findings from several observational studies and surveys, research to date on how to optimize the safety of diabetes management during Ramadan fasting “is all very basic,” Dr. Hassanein said in an interview.

“We need more randomized clinical trials. We need more [data and evidence] for every single aspect” of management, he added.

The 2021 Diabetes and Ramadan Practical Guidelines were supported by an educational grant from Sanofi and Servier. Dr. Hassanein has reported being a speaker on behalf of Abbott, AstraZeneca, Boehringer Ingelheim, Lilly, Novo Nordisk, Sanofi, and Servier.

A version of this article first appeared on Medscape.com.

SAN DIEGO – An assessment of people with diabetes before Ramadan is vital so they can learn whether it is safe for them to fast, and if it is, how to do so without jeopardizing their health.

“With correct advice and support” from knowledgeable health care professionals “most people with type 2 diabetes can fast safely during Ramadan,” Mohamed Hassanein, MBChB, said at the annual scientific sessions of the American Diabetes Association.

One of the most authoritative guidelines on how people with diabetes can safely fast during Ramadan has come from a collaboration between the International Diabetes Federation and the Diabetes & Ramadan International Alliance, an organization chaired by Dr. Hassanein. The groups issued a revised practical guide in 2021 for Ramadan fasting for people with diabetes, an update of the first edition released in 2016. Dr. Hassanein was lead author of the 2016 guidelines and edited the 2021 revision.

The 2021 guidelines also led to an update of a risk stratification app available for free from the DAR. The app provides risk stratification for people with diabetes and helps them access educational material to guide them through their fasts.

Although the latest guidelines address fasting for people with type 1 or type 2 diabetes, far more people with type 2 diabetes are at risk from fasting, and not only because of the higher prevalence of type 2 diabetes.

Results from a global survey of Muslims with diabetes in 2020 showed that 30% of those with type 1 diabetes did not do any fasting during Ramadan, but the percentage of those abstaining from fasting dropped to 16% among Muslims with type 2 diabetes, Dr. Hassanein explained. (Survey results in 2013 from about 38,000 Muslims in 39 countries showed a median of 7% of all adults did no fasting during Ramadan.)
 

Risk assessment by app

Currently, the DAR app is available in Arabic, English, French, and Urdu (the primary language of Pakistan), with more languages being added soon, said Dr. Hassanein, an endocrinologist at Dubai Hospital and professor at Mohammed Bin-Rashid University of Medicine & Health Sciences in Dubai, United Arab Emirates.

The app and screening protocol divides people with diabetes into low-, moderate-, and high-risk subgroups, and those at high risk are advised to refrain from fasting.

But the many other people with diabetes who potentially could fast still face risks for hypoglycemia, hyperglycemia (from overindulgent break-fast meals), diabetic ketoacidosis, dehydration, and thrombosis. Individual risk for these adverse events depends on many factors, including age, duration of diabetes, diabetes type, treatments received, history of hypoglycemia, and diabetes complications.

Dr. Hassanein and colleagues documented the high rate of complications from fasting in a 2020 survey of more than 5,800 Muslims with type 2 diabetes from 20 countries. The results showed that 72% of survey participants had to interrupt their 30 days of daily fasting for at least 1 day because of a diabetes-related event, and an additional 28% had diabetes-triggered interruptions that totaled more than 7 days. About 7% required hospitalization or an emergency department visit, and 16% developed at least one episode of daytime hypoglycemia.
 

Endorsement from Islamic clerics

The recommended risk assessment, and resulting exemptions from fasting, have been endorsed by the Mofty of Egypt, a group of religious scholars who issue legal opinions interpreting Islamic law.

The Mofty agreed that fasting should be interrupted for cases of hypoglycemia with blood glucose less than 70 mg/dL, hyperglycemia with blood glucose greater than 300 mg/dL, symptoms of hypo- or hyperglycemia, or symptoms of acute illness. The Mofty also endorsed that although fasting is obligatory for low-risk adults with diabetes and preferred for those with moderate-risk diabetes, the latter group may consider not fasting out of concern for their safety or to take prescribed medications. People at high risk were deemed by the Mofty as individuals who should not fast because of the potential for harm.

Other notable 2020 survey findings included pre-Ramadan education being received by just 43% of the respondents, and no self-monitoring of blood glucose performed by about a quarter of the respondents.

The 2021 guidelines also include treatment recommendations, such as avoiding older, longer-acting sulfonylurea agents in people with type 2 diabetes. And having people achieve stable, guideline-directed dosages of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide-1 (GLP-1) agonists before Ramadan starts, rather than trying to initiate these agents during Ramadan. The guidelines also recommend reducing usual insulin doses when fasting during Ramadan.

Despite summarizing findings from several observational studies and surveys, research to date on how to optimize the safety of diabetes management during Ramadan fasting “is all very basic,” Dr. Hassanein said in an interview.

“We need more randomized clinical trials. We need more [data and evidence] for every single aspect” of management, he added.

The 2021 Diabetes and Ramadan Practical Guidelines were supported by an educational grant from Sanofi and Servier. Dr. Hassanein has reported being a speaker on behalf of Abbott, AstraZeneca, Boehringer Ingelheim, Lilly, Novo Nordisk, Sanofi, and Servier.

A version of this article first appeared on Medscape.com.

SAN DIEGO – An assessment of people with diabetes before Ramadan is vital so they can learn whether it is safe for them to fast, and if it is, how to do so without jeopardizing their health.

“With correct advice and support” from knowledgeable health care professionals “most people with type 2 diabetes can fast safely during Ramadan,” Mohamed Hassanein, MBChB, said at the annual scientific sessions of the American Diabetes Association.

One of the most authoritative guidelines on how people with diabetes can safely fast during Ramadan has come from a collaboration between the International Diabetes Federation and the Diabetes & Ramadan International Alliance, an organization chaired by Dr. Hassanein. The groups issued a revised practical guide in 2021 for Ramadan fasting for people with diabetes, an update of the first edition released in 2016. Dr. Hassanein was lead author of the 2016 guidelines and edited the 2021 revision.

The 2021 guidelines also led to an update of a risk stratification app available for free from the DAR. The app provides risk stratification for people with diabetes and helps them access educational material to guide them through their fasts.

Although the latest guidelines address fasting for people with type 1 or type 2 diabetes, far more people with type 2 diabetes are at risk from fasting, and not only because of the higher prevalence of type 2 diabetes.

Results from a global survey of Muslims with diabetes in 2020 showed that 30% of those with type 1 diabetes did not do any fasting during Ramadan, but the percentage of those abstaining from fasting dropped to 16% among Muslims with type 2 diabetes, Dr. Hassanein explained. (Survey results in 2013 from about 38,000 Muslims in 39 countries showed a median of 7% of all adults did no fasting during Ramadan.)
 

Risk assessment by app

Currently, the DAR app is available in Arabic, English, French, and Urdu (the primary language of Pakistan), with more languages being added soon, said Dr. Hassanein, an endocrinologist at Dubai Hospital and professor at Mohammed Bin-Rashid University of Medicine & Health Sciences in Dubai, United Arab Emirates.

The app and screening protocol divides people with diabetes into low-, moderate-, and high-risk subgroups, and those at high risk are advised to refrain from fasting.

But the many other people with diabetes who potentially could fast still face risks for hypoglycemia, hyperglycemia (from overindulgent break-fast meals), diabetic ketoacidosis, dehydration, and thrombosis. Individual risk for these adverse events depends on many factors, including age, duration of diabetes, diabetes type, treatments received, history of hypoglycemia, and diabetes complications.

Dr. Hassanein and colleagues documented the high rate of complications from fasting in a 2020 survey of more than 5,800 Muslims with type 2 diabetes from 20 countries. The results showed that 72% of survey participants had to interrupt their 30 days of daily fasting for at least 1 day because of a diabetes-related event, and an additional 28% had diabetes-triggered interruptions that totaled more than 7 days. About 7% required hospitalization or an emergency department visit, and 16% developed at least one episode of daytime hypoglycemia.
 

Endorsement from Islamic clerics

The recommended risk assessment, and resulting exemptions from fasting, have been endorsed by the Mofty of Egypt, a group of religious scholars who issue legal opinions interpreting Islamic law.

The Mofty agreed that fasting should be interrupted for cases of hypoglycemia with blood glucose less than 70 mg/dL, hyperglycemia with blood glucose greater than 300 mg/dL, symptoms of hypo- or hyperglycemia, or symptoms of acute illness. The Mofty also endorsed that although fasting is obligatory for low-risk adults with diabetes and preferred for those with moderate-risk diabetes, the latter group may consider not fasting out of concern for their safety or to take prescribed medications. People at high risk were deemed by the Mofty as individuals who should not fast because of the potential for harm.

Other notable 2020 survey findings included pre-Ramadan education being received by just 43% of the respondents, and no self-monitoring of blood glucose performed by about a quarter of the respondents.

The 2021 guidelines also include treatment recommendations, such as avoiding older, longer-acting sulfonylurea agents in people with type 2 diabetes. And having people achieve stable, guideline-directed dosages of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide-1 (GLP-1) agonists before Ramadan starts, rather than trying to initiate these agents during Ramadan. The guidelines also recommend reducing usual insulin doses when fasting during Ramadan.

Despite summarizing findings from several observational studies and surveys, research to date on how to optimize the safety of diabetes management during Ramadan fasting “is all very basic,” Dr. Hassanein said in an interview.

“We need more randomized clinical trials. We need more [data and evidence] for every single aspect” of management, he added.

The 2021 Diabetes and Ramadan Practical Guidelines were supported by an educational grant from Sanofi and Servier. Dr. Hassanein has reported being a speaker on behalf of Abbott, AstraZeneca, Boehringer Ingelheim, Lilly, Novo Nordisk, Sanofi, and Servier.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Prescribing optimal medical therapy for people with both type 2 diabetes and cardiovascular disease can and should improve, speakers urged at the annual scientific sessions of the American Diabetes Association.

A symposium there focused on the recent randomized, controlled COORDINATE-Diabetes trial, which investigated a multipronged educational intervention in 43 U.S. cardiology clinics aimed at improving prescribing of guideline-recommended treatments for people with both type 2 diabetes and cardiovascular disease. Compared with clinics that were randomly assigned to offer usual care, the intervention significantly increased recommended prescribing of high-intensity statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors and/or glucagonlike peptide 1 receptor agonists (GLP-1 agonists).

COORDINATE-Diabetes was aimed at cardiologists, who typically see these patients more often than do endocrinologists. However, the results are relevant to all health care providers involved in the care of those with type 2 diabetes, speakers argued at the ADA symposium.

“This is a cardiology study. I think it’s safe to say that not too many of you in the room are cardiologists. So why would you care about the results of the COORDINATE study?” said Ildiko Lingvay, MD, of the University of Texas Southwestern Medical Center, Dallas.

Dr. Lingvay went on to outline reasons that the COORDINATE findings apply to endocrinologists and primary care clinicians, as well as cardiologists. For one, a study from her institution that was presented at a recent internal medicine meeting showed that, among more than 10,000 patients with type 2 diabetes and cardiovascular disease, heart failure, and/or chronic kidney disease, the proportion of patients who were prescribed the appropriate guideline-indicated medications was 20.1% for those seen in primary care, 24.8% in endocrinology, 20.3% in cardiology, and 18.3% in nephrology.

“So, we [endocrinologists are] not that much better [than other specialties]” at prescribing, she noted.

Mikhail N. Kosiborod, MD, in independent commentary called the COORDINATE trial and other similar initiatives “the beginning of care transformation.”

The COORDINATE-Diabetes results were originally presented in March at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published in JAMA.
 

‘They’ve shown we can do better’

Asked to comment, Robert H. Eckel, MD, said in an interview, “I look at COORDINATE as a wake-up call to the need for multispecialty approaches to people with type 2 diabetes and cardiovascular disease. ... I think it’s a step in the door.”

Dr. Eckel, who has long advocated for a new “cardiometabolic” physician subspecialty, noted that COORDINATE-Diabetes “stopped short of training health care providers in the science and medicine of cardio-renal-metabolic disease.”

Nonetheless, regarding the efforts toward a more coordinated system of care, Dr. Eckel said, “I support the concept, unequivocally.” He is associated with the division of endocrinology, metabolism, and diabetes, University of Colorado at Denver, Aurora.

But the cost-effectiveness of the intervention “requires time to assess,” he added. “We don’t know anything yet other than [that] managing drug administration to meet goals that relate to outcomes in people with diabetes can be accomplished. They’ve shown that we can do better.”
 

Why should you care about a cardiology study?

In COORDINATE-Diabetes, 20 of the centers were randomly assigned to provide five interventions: assess local barriers, develop care pathways, coordinate care, educate clinicians, report data back to the clinics, and provide tools for the 459 participants. The other 23 clinics, with 590 participants, were randomly assigned to provide usual care per practice guidelines.

The primary outcome was the proportion of participants that prescribed all three groups of the recommended therapies at 6-12 months after enrollment; 37.9% prescribed the intervention, and 14.5% provided usual care, a significant 23% difference (P < .001). The rate of prescriptions of each of the three individual drug groups was also significantly higher with the intervention. No differences were seen in cardiovascular risk factors or outcomes.

Dr. Lingvay pointed out that the interventions tested in COORDINATE – such as fact sheets and medication passports for patients, system audits and feedback, and provider grand rounds – can be extrapolated to any specialist setting.

She added that the long-held model of team-based care means that “everyone involved in the care of these patients is responsible for ensuring best practices are followed.” Part of that, she said, is helping other specialists prescribe the same medications and communicate across the team.

For all specialists, she recommends using the resources available on the COORDINATE website.
 

‘It’s not a silver bullet; additional solutions are needed’

In his commentary, Dr. Kosiborod, executive director of the Cardiometabolic Center Alliance, noted, “The treatments studied in COORDINATE represent the biggest advances in a generation when it comes to improving outcomes in this population. ... We’re living in a renaissance age with the number of tools we have available. ... It’s getting better every day.”

Moreover, all the relevant professional society guidelines now recommend GLP-1 agonists and SGLT2 inhibitors. “And yet, when we look, less than 1 in 10 patients with type 2 diabetes and atherosclerotic cardiovascular disease are getting appropriate recommended care. One of the lessons of COORDINATE is that this needs to change if we’re really going to improve our patients’ lives.”

The barriers aren’t simply financial, Dr. Kosiborod said. He pointed to two studies that show that even reducing out-of-pocket costs resulted in only modest increases in adherence.

Educational gaps on the part of both clinicians and patients also factor in, as do misaligned incentives.

“Clinicians get paid for how many things they do, not necessarily how well they do them. Everyone wants to do the right thing, but ultimately, incentives do matter,” he emphasized.

While the COORDINATE-Diabetes interventions addressed several of the barriers, two-thirds of the participants still did not receive optimal therapy.

“It’s not a silver bullet. ... Additional solutions are needed,” Dr. Kosiborod observed.
 

Transformation occurs ‘when the status quo is no longer acceptable’

Enter his institution, the Cardiometabolic Center Alliance, part of Saint Luke’s Mid-America Heart Institute. The nonprofit system, which currently has 16 subscribing clinics around the country, offers patient-centered “team-based, coordinated, comprehensive care” for people with both type 2 diabetes and cardiovascular disease.

The model is led by preventive cardiology in collaboration with endocrinology and primary care. Support staff includes advance practice providers, nurse navigators, certified diabetes educators, dietitians, and pharmacists. Individualized treatment plans aim for “aggressive secondary risk reduction,” Dr. Kosiborod noted.

Six-month data from the Cardiometabolic Center Alliance show an increase from 28.2% at baseline to 67.1% (P < .0001) in prescribing of a four-agent guideline-directed medical therapy “bundle,” including the three from COORDINATE-Diabetes plus an antiplatelet or anticoagulant agent. Dr. Kosiborod presented these data during the ADA meeting in a poster.

Remaining questions involve sustainability, scalability, and system transformation, which require buy-in from multiple stakeholders, he noted.

He contends that it can be done. A prior example of “rapid and lasting care transformation” occurred in November 2006 with the launch of the “Door to Balloon (D2B) Alliance for Quality,” which dramatically increased the proportion of patients who received primary angioplasty within 90 minutes at hospitals around the United States. From January 2005 to September 2010, those proportions rose from 27.3% to 70.4%.

“Patients were coming into the emergency department with myocardial infarctions and waiting for hours before the interventional cardiologist came. The community said we needed a nationwide quality improvement initiative. ... Almost every hospital in the country changed their systems of care. It was a huge national effort. ... When we no longer consider the status quo acceptable, we can actually make something very special happen very quickly.”

After the session, Dr. Kosiborod said in an interview that the Cardiometabolic Center Alliance is now gathering data to make the financial case for the approach.

“We’re trying to develop a model that tells the admins which patients will save money, because, of course, if you can create a financial incentive, it only makes it go faster. ... We want to synchronize it in the best way possible.”

Dr. Lingvay has receiving nonfinancial support and grants from Novo Nordisk, personal fees or nonfinancial support from Sanofi, Lilly, Boehringer Ingelheim, Merck/Pfizer, Mylan, AstraZeneca, Johnson & Johnson, Intercept, Target Pharma, Zealand, Shionogi, Carmot, Structure, Bayer, Mediflix, WebMD, GI Dynamics, Intarcia Therapeutics, Mannkind, Novartis, Structure Therapeutics, and Valeritas. Dr. Kosiborod is a consultant for Alnylam Pharmaceuticals, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, ESPERION Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, Vifor Pharma Management, and Youngene Therapeutics. He also receives research support from AstraZeneca and Boehringer Ingelheim. Dr. Eckel serves on consulting/advisory boards for Amgen, Arrowhead, Better, Ionis, Kowa, Lexicon, Novo Nordisk, Precision BioSciences, The Healthy Aging Company, Tolmar, and Weight Watchers.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Prescribing optimal medical therapy for people with both type 2 diabetes and cardiovascular disease can and should improve, speakers urged at the annual scientific sessions of the American Diabetes Association.

A symposium there focused on the recent randomized, controlled COORDINATE-Diabetes trial, which investigated a multipronged educational intervention in 43 U.S. cardiology clinics aimed at improving prescribing of guideline-recommended treatments for people with both type 2 diabetes and cardiovascular disease. Compared with clinics that were randomly assigned to offer usual care, the intervention significantly increased recommended prescribing of high-intensity statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors and/or glucagonlike peptide 1 receptor agonists (GLP-1 agonists).

COORDINATE-Diabetes was aimed at cardiologists, who typically see these patients more often than do endocrinologists. However, the results are relevant to all health care providers involved in the care of those with type 2 diabetes, speakers argued at the ADA symposium.

“This is a cardiology study. I think it’s safe to say that not too many of you in the room are cardiologists. So why would you care about the results of the COORDINATE study?” said Ildiko Lingvay, MD, of the University of Texas Southwestern Medical Center, Dallas.

Dr. Lingvay went on to outline reasons that the COORDINATE findings apply to endocrinologists and primary care clinicians, as well as cardiologists. For one, a study from her institution that was presented at a recent internal medicine meeting showed that, among more than 10,000 patients with type 2 diabetes and cardiovascular disease, heart failure, and/or chronic kidney disease, the proportion of patients who were prescribed the appropriate guideline-indicated medications was 20.1% for those seen in primary care, 24.8% in endocrinology, 20.3% in cardiology, and 18.3% in nephrology.

“So, we [endocrinologists are] not that much better [than other specialties]” at prescribing, she noted.

Mikhail N. Kosiborod, MD, in independent commentary called the COORDINATE trial and other similar initiatives “the beginning of care transformation.”

The COORDINATE-Diabetes results were originally presented in March at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published in JAMA.
 

‘They’ve shown we can do better’

Asked to comment, Robert H. Eckel, MD, said in an interview, “I look at COORDINATE as a wake-up call to the need for multispecialty approaches to people with type 2 diabetes and cardiovascular disease. ... I think it’s a step in the door.”

Dr. Eckel, who has long advocated for a new “cardiometabolic” physician subspecialty, noted that COORDINATE-Diabetes “stopped short of training health care providers in the science and medicine of cardio-renal-metabolic disease.”

Nonetheless, regarding the efforts toward a more coordinated system of care, Dr. Eckel said, “I support the concept, unequivocally.” He is associated with the division of endocrinology, metabolism, and diabetes, University of Colorado at Denver, Aurora.

But the cost-effectiveness of the intervention “requires time to assess,” he added. “We don’t know anything yet other than [that] managing drug administration to meet goals that relate to outcomes in people with diabetes can be accomplished. They’ve shown that we can do better.”
 

Why should you care about a cardiology study?

In COORDINATE-Diabetes, 20 of the centers were randomly assigned to provide five interventions: assess local barriers, develop care pathways, coordinate care, educate clinicians, report data back to the clinics, and provide tools for the 459 participants. The other 23 clinics, with 590 participants, were randomly assigned to provide usual care per practice guidelines.

The primary outcome was the proportion of participants that prescribed all three groups of the recommended therapies at 6-12 months after enrollment; 37.9% prescribed the intervention, and 14.5% provided usual care, a significant 23% difference (P < .001). The rate of prescriptions of each of the three individual drug groups was also significantly higher with the intervention. No differences were seen in cardiovascular risk factors or outcomes.

Dr. Lingvay pointed out that the interventions tested in COORDINATE – such as fact sheets and medication passports for patients, system audits and feedback, and provider grand rounds – can be extrapolated to any specialist setting.

She added that the long-held model of team-based care means that “everyone involved in the care of these patients is responsible for ensuring best practices are followed.” Part of that, she said, is helping other specialists prescribe the same medications and communicate across the team.

For all specialists, she recommends using the resources available on the COORDINATE website.
 

‘It’s not a silver bullet; additional solutions are needed’

In his commentary, Dr. Kosiborod, executive director of the Cardiometabolic Center Alliance, noted, “The treatments studied in COORDINATE represent the biggest advances in a generation when it comes to improving outcomes in this population. ... We’re living in a renaissance age with the number of tools we have available. ... It’s getting better every day.”

Moreover, all the relevant professional society guidelines now recommend GLP-1 agonists and SGLT2 inhibitors. “And yet, when we look, less than 1 in 10 patients with type 2 diabetes and atherosclerotic cardiovascular disease are getting appropriate recommended care. One of the lessons of COORDINATE is that this needs to change if we’re really going to improve our patients’ lives.”

The barriers aren’t simply financial, Dr. Kosiborod said. He pointed to two studies that show that even reducing out-of-pocket costs resulted in only modest increases in adherence.

Educational gaps on the part of both clinicians and patients also factor in, as do misaligned incentives.

“Clinicians get paid for how many things they do, not necessarily how well they do them. Everyone wants to do the right thing, but ultimately, incentives do matter,” he emphasized.

While the COORDINATE-Diabetes interventions addressed several of the barriers, two-thirds of the participants still did not receive optimal therapy.

“It’s not a silver bullet. ... Additional solutions are needed,” Dr. Kosiborod observed.
 

Transformation occurs ‘when the status quo is no longer acceptable’

Enter his institution, the Cardiometabolic Center Alliance, part of Saint Luke’s Mid-America Heart Institute. The nonprofit system, which currently has 16 subscribing clinics around the country, offers patient-centered “team-based, coordinated, comprehensive care” for people with both type 2 diabetes and cardiovascular disease.

The model is led by preventive cardiology in collaboration with endocrinology and primary care. Support staff includes advance practice providers, nurse navigators, certified diabetes educators, dietitians, and pharmacists. Individualized treatment plans aim for “aggressive secondary risk reduction,” Dr. Kosiborod noted.

Six-month data from the Cardiometabolic Center Alliance show an increase from 28.2% at baseline to 67.1% (P < .0001) in prescribing of a four-agent guideline-directed medical therapy “bundle,” including the three from COORDINATE-Diabetes plus an antiplatelet or anticoagulant agent. Dr. Kosiborod presented these data during the ADA meeting in a poster.

Remaining questions involve sustainability, scalability, and system transformation, which require buy-in from multiple stakeholders, he noted.

He contends that it can be done. A prior example of “rapid and lasting care transformation” occurred in November 2006 with the launch of the “Door to Balloon (D2B) Alliance for Quality,” which dramatically increased the proportion of patients who received primary angioplasty within 90 minutes at hospitals around the United States. From January 2005 to September 2010, those proportions rose from 27.3% to 70.4%.

“Patients were coming into the emergency department with myocardial infarctions and waiting for hours before the interventional cardiologist came. The community said we needed a nationwide quality improvement initiative. ... Almost every hospital in the country changed their systems of care. It was a huge national effort. ... When we no longer consider the status quo acceptable, we can actually make something very special happen very quickly.”

After the session, Dr. Kosiborod said in an interview that the Cardiometabolic Center Alliance is now gathering data to make the financial case for the approach.

“We’re trying to develop a model that tells the admins which patients will save money, because, of course, if you can create a financial incentive, it only makes it go faster. ... We want to synchronize it in the best way possible.”

Dr. Lingvay has receiving nonfinancial support and grants from Novo Nordisk, personal fees or nonfinancial support from Sanofi, Lilly, Boehringer Ingelheim, Merck/Pfizer, Mylan, AstraZeneca, Johnson & Johnson, Intercept, Target Pharma, Zealand, Shionogi, Carmot, Structure, Bayer, Mediflix, WebMD, GI Dynamics, Intarcia Therapeutics, Mannkind, Novartis, Structure Therapeutics, and Valeritas. Dr. Kosiborod is a consultant for Alnylam Pharmaceuticals, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, ESPERION Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, Vifor Pharma Management, and Youngene Therapeutics. He also receives research support from AstraZeneca and Boehringer Ingelheim. Dr. Eckel serves on consulting/advisory boards for Amgen, Arrowhead, Better, Ionis, Kowa, Lexicon, Novo Nordisk, Precision BioSciences, The Healthy Aging Company, Tolmar, and Weight Watchers.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Prescribing optimal medical therapy for people with both type 2 diabetes and cardiovascular disease can and should improve, speakers urged at the annual scientific sessions of the American Diabetes Association.

A symposium there focused on the recent randomized, controlled COORDINATE-Diabetes trial, which investigated a multipronged educational intervention in 43 U.S. cardiology clinics aimed at improving prescribing of guideline-recommended treatments for people with both type 2 diabetes and cardiovascular disease. Compared with clinics that were randomly assigned to offer usual care, the intervention significantly increased recommended prescribing of high-intensity statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors and/or glucagonlike peptide 1 receptor agonists (GLP-1 agonists).

COORDINATE-Diabetes was aimed at cardiologists, who typically see these patients more often than do endocrinologists. However, the results are relevant to all health care providers involved in the care of those with type 2 diabetes, speakers argued at the ADA symposium.

“This is a cardiology study. I think it’s safe to say that not too many of you in the room are cardiologists. So why would you care about the results of the COORDINATE study?” said Ildiko Lingvay, MD, of the University of Texas Southwestern Medical Center, Dallas.

Dr. Lingvay went on to outline reasons that the COORDINATE findings apply to endocrinologists and primary care clinicians, as well as cardiologists. For one, a study from her institution that was presented at a recent internal medicine meeting showed that, among more than 10,000 patients with type 2 diabetes and cardiovascular disease, heart failure, and/or chronic kidney disease, the proportion of patients who were prescribed the appropriate guideline-indicated medications was 20.1% for those seen in primary care, 24.8% in endocrinology, 20.3% in cardiology, and 18.3% in nephrology.

“So, we [endocrinologists are] not that much better [than other specialties]” at prescribing, she noted.

Mikhail N. Kosiborod, MD, in independent commentary called the COORDINATE trial and other similar initiatives “the beginning of care transformation.”

The COORDINATE-Diabetes results were originally presented in March at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published in JAMA.
 

‘They’ve shown we can do better’

Asked to comment, Robert H. Eckel, MD, said in an interview, “I look at COORDINATE as a wake-up call to the need for multispecialty approaches to people with type 2 diabetes and cardiovascular disease. ... I think it’s a step in the door.”

Dr. Eckel, who has long advocated for a new “cardiometabolic” physician subspecialty, noted that COORDINATE-Diabetes “stopped short of training health care providers in the science and medicine of cardio-renal-metabolic disease.”

Nonetheless, regarding the efforts toward a more coordinated system of care, Dr. Eckel said, “I support the concept, unequivocally.” He is associated with the division of endocrinology, metabolism, and diabetes, University of Colorado at Denver, Aurora.

But the cost-effectiveness of the intervention “requires time to assess,” he added. “We don’t know anything yet other than [that] managing drug administration to meet goals that relate to outcomes in people with diabetes can be accomplished. They’ve shown that we can do better.”
 

Why should you care about a cardiology study?

In COORDINATE-Diabetes, 20 of the centers were randomly assigned to provide five interventions: assess local barriers, develop care pathways, coordinate care, educate clinicians, report data back to the clinics, and provide tools for the 459 participants. The other 23 clinics, with 590 participants, were randomly assigned to provide usual care per practice guidelines.

The primary outcome was the proportion of participants that prescribed all three groups of the recommended therapies at 6-12 months after enrollment; 37.9% prescribed the intervention, and 14.5% provided usual care, a significant 23% difference (P < .001). The rate of prescriptions of each of the three individual drug groups was also significantly higher with the intervention. No differences were seen in cardiovascular risk factors or outcomes.

Dr. Lingvay pointed out that the interventions tested in COORDINATE – such as fact sheets and medication passports for patients, system audits and feedback, and provider grand rounds – can be extrapolated to any specialist setting.

She added that the long-held model of team-based care means that “everyone involved in the care of these patients is responsible for ensuring best practices are followed.” Part of that, she said, is helping other specialists prescribe the same medications and communicate across the team.

For all specialists, she recommends using the resources available on the COORDINATE website.
 

‘It’s not a silver bullet; additional solutions are needed’

In his commentary, Dr. Kosiborod, executive director of the Cardiometabolic Center Alliance, noted, “The treatments studied in COORDINATE represent the biggest advances in a generation when it comes to improving outcomes in this population. ... We’re living in a renaissance age with the number of tools we have available. ... It’s getting better every day.”

Moreover, all the relevant professional society guidelines now recommend GLP-1 agonists and SGLT2 inhibitors. “And yet, when we look, less than 1 in 10 patients with type 2 diabetes and atherosclerotic cardiovascular disease are getting appropriate recommended care. One of the lessons of COORDINATE is that this needs to change if we’re really going to improve our patients’ lives.”

The barriers aren’t simply financial, Dr. Kosiborod said. He pointed to two studies that show that even reducing out-of-pocket costs resulted in only modest increases in adherence.

Educational gaps on the part of both clinicians and patients also factor in, as do misaligned incentives.

“Clinicians get paid for how many things they do, not necessarily how well they do them. Everyone wants to do the right thing, but ultimately, incentives do matter,” he emphasized.

While the COORDINATE-Diabetes interventions addressed several of the barriers, two-thirds of the participants still did not receive optimal therapy.

“It’s not a silver bullet. ... Additional solutions are needed,” Dr. Kosiborod observed.
 

Transformation occurs ‘when the status quo is no longer acceptable’

Enter his institution, the Cardiometabolic Center Alliance, part of Saint Luke’s Mid-America Heart Institute. The nonprofit system, which currently has 16 subscribing clinics around the country, offers patient-centered “team-based, coordinated, comprehensive care” for people with both type 2 diabetes and cardiovascular disease.

The model is led by preventive cardiology in collaboration with endocrinology and primary care. Support staff includes advance practice providers, nurse navigators, certified diabetes educators, dietitians, and pharmacists. Individualized treatment plans aim for “aggressive secondary risk reduction,” Dr. Kosiborod noted.

Six-month data from the Cardiometabolic Center Alliance show an increase from 28.2% at baseline to 67.1% (P < .0001) in prescribing of a four-agent guideline-directed medical therapy “bundle,” including the three from COORDINATE-Diabetes plus an antiplatelet or anticoagulant agent. Dr. Kosiborod presented these data during the ADA meeting in a poster.

Remaining questions involve sustainability, scalability, and system transformation, which require buy-in from multiple stakeholders, he noted.

He contends that it can be done. A prior example of “rapid and lasting care transformation” occurred in November 2006 with the launch of the “Door to Balloon (D2B) Alliance for Quality,” which dramatically increased the proportion of patients who received primary angioplasty within 90 minutes at hospitals around the United States. From January 2005 to September 2010, those proportions rose from 27.3% to 70.4%.

“Patients were coming into the emergency department with myocardial infarctions and waiting for hours before the interventional cardiologist came. The community said we needed a nationwide quality improvement initiative. ... Almost every hospital in the country changed their systems of care. It was a huge national effort. ... When we no longer consider the status quo acceptable, we can actually make something very special happen very quickly.”

After the session, Dr. Kosiborod said in an interview that the Cardiometabolic Center Alliance is now gathering data to make the financial case for the approach.

“We’re trying to develop a model that tells the admins which patients will save money, because, of course, if you can create a financial incentive, it only makes it go faster. ... We want to synchronize it in the best way possible.”

Dr. Lingvay has receiving nonfinancial support and grants from Novo Nordisk, personal fees or nonfinancial support from Sanofi, Lilly, Boehringer Ingelheim, Merck/Pfizer, Mylan, AstraZeneca, Johnson & Johnson, Intercept, Target Pharma, Zealand, Shionogi, Carmot, Structure, Bayer, Mediflix, WebMD, GI Dynamics, Intarcia Therapeutics, Mannkind, Novartis, Structure Therapeutics, and Valeritas. Dr. Kosiborod is a consultant for Alnylam Pharmaceuticals, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, ESPERION Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, Vifor Pharma Management, and Youngene Therapeutics. He also receives research support from AstraZeneca and Boehringer Ingelheim. Dr. Eckel serves on consulting/advisory boards for Amgen, Arrowhead, Better, Ionis, Kowa, Lexicon, Novo Nordisk, Precision BioSciences, The Healthy Aging Company, Tolmar, and Weight Watchers.

A version of this article first appeared on Medscape.com.

A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.

Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.

The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
 

Which biomarker?

Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.

A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”

“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.

“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”

He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.

“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.

“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”

Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”

For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
 

Harmonizing clinical practice

In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.

They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.

A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.

The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.

When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.

When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.

Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”

Dr. Frisoni noted that the consensus document has a number of limitations.

“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”

He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.

The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.

“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.

“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”

In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.

This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
 

Pros and cons

Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.

On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.

He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.

On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”

From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”

He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.

Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.

The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”

Achieving uniformity will require a pan-regional collaboration, he noted.

The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.

Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.

The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
 

Which biomarker?

Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.

A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”

“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.

“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”

He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.

“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.

“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”

Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”

For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
 

Harmonizing clinical practice

In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.

They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.

A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.

The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.

When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.

When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.

Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”

Dr. Frisoni noted that the consensus document has a number of limitations.

“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”

He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.

The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.

“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.

“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”

In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.

This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
 

Pros and cons

Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.

On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.

He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.

On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”

From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”

He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.

Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.

The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”

Achieving uniformity will require a pan-regional collaboration, he noted.

The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.

Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.

The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
 

Which biomarker?

Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.

A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”

“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.

“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”

He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.

“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.

“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”

Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”

For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
 

Harmonizing clinical practice

In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.

They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.

A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.

The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.

When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.

When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.

Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”

Dr. Frisoni noted that the consensus document has a number of limitations.

“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”

He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.

The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.

“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.

“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”

In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.

This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
 

Pros and cons

Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.

On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.

He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.

On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”

From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”

He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.

Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.

The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”

Achieving uniformity will require a pan-regional collaboration, he noted.

The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The European Society of Hypertension has released updated and expanded guidelines for the management of hypertension.

The guidelines, which are endorsed by the European Renal Association and the International Society of Hypertension, were presented during the annual European Meeting on Hypertension and Cardiovascular Protection Meeting in Milan, Italy.

The guidelines consensus document was also published online in the Journal of Hypertension. Giuseppe Mancia, MD, professor emeritus of medicine, University Milano-Bicocca, Italy, and Reinhold Kreutz, MD, PhD, Charité–University Medicine Berlin, were cochairs of the task force that created the document.

“We have tried to provide a simplified message to key topics with these new guidelines,” Dr. Kreutz said in an interview.

“We have confirmed the definition of hypertension and provide clear guidance for blood pressure monitoring and a simplified general strategy targeting similar blood pressure goals for most patients, although the treatment algorithms of how you get there may be different for different patient groups.”

Dr. Kreutz added: “Because hypertension is so prevalent and many patients have comorbidities, it is not easy to have one approach for all, but we have tried to simplify the key messages as much as possible, with a target that is more general to the whole population.”

While there are no major surprises in the guidelines, there are multiple advances and added-value changes, including clear advice on how to measure blood pressure, an upgrade for beta-blockers in the treatment algorithms, and a new definition and treatment recommendations for “true resistant hypertension.”
 

Definition remains unchanged

The definition of hypertension remains unchanged from the previous guidelines – repeated office systolic blood pressure values of ≥ 140 mm Hg and/or diastolic blood pressure values of ≥ 90 mm Hg.

“The definition and classification of hypertension has not changed in these new guidelines,” Dr. Kreutz said. “While there have been suggestions that the definition/target should be changed again, particularly about blood pressure lowering being beneficial at the very low pressure range, after reviewing all the evidence we do not agree with this, and we are standing with the definition of hypertension when intervention is beneficial rather than doing nothing or causing harm.”
 

Clear guidance on measurement

Dr. Kreutz points out that the correct measurement of blood pressure is of key importance, and the new guidelines include a detailed algorithm on how to measure blood pressure. The preferred method is automated cuff-based blood pressure measurement.

“There are still many variations in blood pressure measurement in clinical practice, so we now have clear guidance on how to measure blood pressure in the office but also at home,” he commented.

They have upgraded the use of out-of-office blood pressure measurement, particularly home measurement, as useful in long-term management. “In future, there should be more emphasis on follow-up using technology with remote control and virtual care.”
 

Thresholds for starting treatment

On thresholds for initiating antihypertensive therapy, the guidelines recommend that treatment be initiated for most patients when systolic blood pressure is ≥ 140 mm Hg or diastolic blood pressure is ≥ 90 mm Hg.

The same recommendation is given for patients with grade 1 hypertension (systolic, 140-159 mm Hg; and/or diastolic, 90-99 mm Hg) irrespective of cardiovascular risk, although they add that for patients in the lower blood pressure range who have no hypertension-mediated organ damage and who are at low cardiovascular risk, consideration may be given to starting treatment with lifestyle changes only. If, however, blood pressure control is not achieved within a few months of a lifestyle-based approach alone, drug treatment is necessary.

For older patients (aged 80 or older), the task force recommends initiation of drug treatment at 160 mm Hg systolic, although a lower systolic threshold of 140-160 mm Hg may be considered. The authors note that thresholds for the initiation of drug treatment for very frail patients should be individualized.
 

Blood pressure targets

In the new guidelines, the blood pressure target is the same as in the previous guidelines for the general population of patients with hypertension. The goal is < 140/80 mm Hg for most patients. This accounts for the major portion of the protective effect of blood pressure lowering.

However, the consensus document notes that despite the smaller incremental benefit, an effort should be made to reach a range of 120-129/70-79 mm Hg, but only if treatment is well tolerated to avoid the risk of treatment discontinuation because of adverse events, which might offset, in part or completely, the incremental reduction in cardiovascular outcomes.

Elaborating on this, Dr. Kreutz said, “We should aim for the systolic blood pressure to be within the range of below 140 mm Hg down to 120 mm Hg, with a specific target of around 130 mm Hg for most patients and lower in patients in whom drug treatments are well tolerated and who are at high risk.

“The problem is, if we go for a target of lower that 130 mm Hg, the evidence gets weaker, the benefits diminish, and we risk losing patients because of adverse effects from using so many drugs,” he added. “But in younger and fitter patients, we would recommend the lower the better, but not below 120 mm Hg.”

Dr. Kreutz noted that the new guidelines have tried to simplify recommendations on target pressures. “We have tried to simplify guidance to focus on a target of around 130 for almost all patients. Before, it wasn’t so clear. There were different targets for different groups of patients with various comorbidities or older patients. But now we are saying the range of 120 to 139 is suitable for the vast majority of patients.”

The guidelines do allow slightly higher targets for older and very frail patients.
 

Drug treatments

The guidelines advise that blood pressure lowering be prioritized over the selection of specific antihypertensive drug classes. The use of any of the five major drug classes – angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, calcium blockers, and thiazide/thiazidelike diuretics – and their combinations are recommended as the basis of antihypertensive treatment strategies.

They advise starting with a two-drug combination for most patients. The preferred combinations including a renin-angiotensin blocker (either an ACE inhibitor or an ARB) with a calcium blocker or a thiazide/thiazidelike diuretic, preferably in a single-pill combination to reduce pill burden and improve adherence and outcome.

If blood pressure is not controlled with the initial two-drug combination at the maximum recommended and tolerated dose of the respective components, treatment should be increased to a three-drug combination.

“We can control 60% of patients in the general hypertensive population with dual therapy, and up to 90% with triple therapy,” Dr. Kreutz said. “Only a small percentage need a fourth drug.”

A new feature of the guidelines is the upgrading of beta-blockers in the treatment algorithms.

“Beta-blockers may not have previously been considered as a first choice of antihypertensive medication, but we see that in clinical practice, many patients are actually treated with these drugs because there are so many conditions in which beta-blockers have a compelling evidence-based indication or are believed to be favorable,” he said. “So, we are now positioning beta-blockers as drugs that can be used at any step of the treatment algorithm if there is a guideline directed indication or other conditions for which they are thought to be beneficial.”

The guidelines also recommend that all drugs be given as once-daily preparations and that they be taken preferably in the morning.

“The new TIME study has established that there is no difference in outcome with morning or evening dosing, but we know that adherence is often better when drugs are taken in the morning, and it is not advisable to take diuretics in the evening,” Dr. Kreutz said.
 

‘True resistant hypertension’

The guidelines have introduced a new term, “true resistant hypertension,” defined as systolic blood pressure of ≥ 140 mm Hg or diastolic blood pressure of ≥ 90 mm Hg in the presence of the following conditions: the maximum recommended and tolerated doses of a three-drug combination comprising a renin-angiotensin system blocker (either an ACE inhibitor or an ARB), a calcium blocker, and a thiazide/thiazidelike diuretic were used; inadequate blood pressure control has been confirmed by ambulatory (preferable) or home blood pressure measurement; and various causes of pseudo-resistant hypertension (especially poor medication adherence) and secondary hypertension have been excluded.

“There are many patients who may appear to have resistant hypertension, but we need to screen them carefully to ensure they are adherent to treatment, and then most of these patients are found not to be truly resistant,” Dr. Kreutz explained. “We estimate that only about 5% of patients have true resistant hypertension.”

For these patients with true resistant hypertension, two treatment approaches are recommended.

For those who do not have advanced kidney disease (glomerular filtration rate > 40 mL/min), renal denervation can be considered. This is a new II B recommendation.

Dr. Kreutz noted that studies of renal denervation excluded patients with advanced kidney disease, so there are no data for this group. For these patients, the guidelines suggest that a combination diuretic approach (chlorthalidone with a loop diuretic) could be considered in light of the results of the recent CLICK study.
 

Differences from U.S. guidelines?

Commenting on the new European guidelines for this news organization, Paul Whelton, MD, chair of the most recent American College of Cardiology/American Heart Association hypertension guidelines committee, said: “Publication of these guidelines is important. I congratulate the European task force. It is an enormous amount of time and effort.”

Dr. Whelton, who is Show Chwan Chair in Global Public Health at Tulane University, New Orleans, and president of the World Hypertension League, added: “I would say the changes are incremental rather than major, but that is probably appropriate.”

He welcomed the greater emphasis on out-of-office blood pressure measurement, saying, “That’s where we should be headed.”

Asked how the European guidelines differ from the U.S. guidelines, Dr. Whelton commented: “There are differences, but they are not huge. The major hypertension guidelines across the world are much more alike than they are different.”

He pointed out that both the U.S. and European guidelines aim for a target blood pressure of 130/80 mm Hg for most patients but have different ways of issuing that advice.

“The Europeans recommend a minimum goal of 140/90 mm Hg, and if there are no issues, then press on to get to under 130/80 mm Hg. That’s kind of a two-step process,” he said. “In the U.S., we’ve gone for a more direct approach of just recommending less than 130/80 mm Hg.

“My fear with the European approach is that by saying, get to 140/90 mm Hg first, then move on to 130/80 mm Hg, is that you’re likely to lose people. And doctors could feel that 140/90 is fine.”
 

More effort needed on implementation

Dr. Whelton says that where all hypertension guidelines are lacking is in the implementation of the recommendations.

“We are all falling down on implementation,” he said. “We have a huge burden of illness, and it is a very cost-effective area for management, but still, rates of blood pressure control are very bad. Generally speaking, even with a very conservative target of 140/90, the best countries only have control rates of around 30%, and this can be as low as 8% in some low/middle-income countries.”

Dr. Whelton believes the approach to blood pressure management needs to change.

“We know that the current traditional model of care, where blood pressure is managed by your local doctor, is not working. It is hopeless,” he said. “That is not an indictment of these doctors. It’s just that they have more pressing issues to deal with, so we need to look at other models.”

He suggests that the way forward is through convenient, community-based care delivered by a team in which nonphysicians assist in much of the management and in which reliable, affordable medications are given at the point of care, with patients tracked with electronic health records so as to identify those who are not adhering to their medication regimens.

“We know that using simple protocols will work for the vast majority of people. We don’t need to individualize or complicate this too much. That tends to lose people in the process.”

Dr. Whelton makes the point that it is well known how to diagnose and treat hypertension, yet this is not being done well.

“We are doing these things really badly. In routine care, blood pressure is measured horribly. Nobody would accept a pilot of a plane saying he should be doing all these procedures but he’s too busy and it’s probably okay, but that’s the way blood pressure is often measured in clinical practice,” he added. “And we can’t really do a good job if were not measuring the key variable properly that the diagnosis is based on.”

Dr. Whelton also points out that the medical profession is not making enough effort to have patients reach target levels.

“If you’re in a country where very few people are being treated and very high pressures are common, then of course you have to focus on that group first. But in most of the Western world, we are long past that, so we can move on down the chain. We then get to a lot more people with moderately high blood pressure getting exposed to increases in risk, and while this is not quite as dramatic as those with very high pressures at the individual risk level, because there are so many of them, that’s where a lot of events are occurring,” he says.

“If we get everyone to 140/90 mm Hg, we can probably prevent 60% of blood pressure–related events. But if we can get them all down to 130 mm Hg systolic, then we can prevent 75%-80% of events. It’s often quite easy to get to that target, but patients need help and encouragement.”

Going forward, he concluded, guidelines should pivot to focus more on implementation.

“We all try to make the guidelines as approachable as possible, but they are encyclopedic, and many doctors just continue doing what they are doing. That is our big challenge.”

A version of this article first appeared on Medscape.com.

The European Society of Hypertension has released updated and expanded guidelines for the management of hypertension.

The guidelines, which are endorsed by the European Renal Association and the International Society of Hypertension, were presented during the annual European Meeting on Hypertension and Cardiovascular Protection Meeting in Milan, Italy.

The guidelines consensus document was also published online in the Journal of Hypertension. Giuseppe Mancia, MD, professor emeritus of medicine, University Milano-Bicocca, Italy, and Reinhold Kreutz, MD, PhD, Charité–University Medicine Berlin, were cochairs of the task force that created the document.

“We have tried to provide a simplified message to key topics with these new guidelines,” Dr. Kreutz said in an interview.

“We have confirmed the definition of hypertension and provide clear guidance for blood pressure monitoring and a simplified general strategy targeting similar blood pressure goals for most patients, although the treatment algorithms of how you get there may be different for different patient groups.”

Dr. Kreutz added: “Because hypertension is so prevalent and many patients have comorbidities, it is not easy to have one approach for all, but we have tried to simplify the key messages as much as possible, with a target that is more general to the whole population.”

While there are no major surprises in the guidelines, there are multiple advances and added-value changes, including clear advice on how to measure blood pressure, an upgrade for beta-blockers in the treatment algorithms, and a new definition and treatment recommendations for “true resistant hypertension.”
 

Definition remains unchanged

The definition of hypertension remains unchanged from the previous guidelines – repeated office systolic blood pressure values of ≥ 140 mm Hg and/or diastolic blood pressure values of ≥ 90 mm Hg.

“The definition and classification of hypertension has not changed in these new guidelines,” Dr. Kreutz said. “While there have been suggestions that the definition/target should be changed again, particularly about blood pressure lowering being beneficial at the very low pressure range, after reviewing all the evidence we do not agree with this, and we are standing with the definition of hypertension when intervention is beneficial rather than doing nothing or causing harm.”
 

Clear guidance on measurement

Dr. Kreutz points out that the correct measurement of blood pressure is of key importance, and the new guidelines include a detailed algorithm on how to measure blood pressure. The preferred method is automated cuff-based blood pressure measurement.

“There are still many variations in blood pressure measurement in clinical practice, so we now have clear guidance on how to measure blood pressure in the office but also at home,” he commented.

They have upgraded the use of out-of-office blood pressure measurement, particularly home measurement, as useful in long-term management. “In future, there should be more emphasis on follow-up using technology with remote control and virtual care.”
 

Thresholds for starting treatment

On thresholds for initiating antihypertensive therapy, the guidelines recommend that treatment be initiated for most patients when systolic blood pressure is ≥ 140 mm Hg or diastolic blood pressure is ≥ 90 mm Hg.

The same recommendation is given for patients with grade 1 hypertension (systolic, 140-159 mm Hg; and/or diastolic, 90-99 mm Hg) irrespective of cardiovascular risk, although they add that for patients in the lower blood pressure range who have no hypertension-mediated organ damage and who are at low cardiovascular risk, consideration may be given to starting treatment with lifestyle changes only. If, however, blood pressure control is not achieved within a few months of a lifestyle-based approach alone, drug treatment is necessary.

For older patients (aged 80 or older), the task force recommends initiation of drug treatment at 160 mm Hg systolic, although a lower systolic threshold of 140-160 mm Hg may be considered. The authors note that thresholds for the initiation of drug treatment for very frail patients should be individualized.
 

Blood pressure targets

In the new guidelines, the blood pressure target is the same as in the previous guidelines for the general population of patients with hypertension. The goal is < 140/80 mm Hg for most patients. This accounts for the major portion of the protective effect of blood pressure lowering.

However, the consensus document notes that despite the smaller incremental benefit, an effort should be made to reach a range of 120-129/70-79 mm Hg, but only if treatment is well tolerated to avoid the risk of treatment discontinuation because of adverse events, which might offset, in part or completely, the incremental reduction in cardiovascular outcomes.

Elaborating on this, Dr. Kreutz said, “We should aim for the systolic blood pressure to be within the range of below 140 mm Hg down to 120 mm Hg, with a specific target of around 130 mm Hg for most patients and lower in patients in whom drug treatments are well tolerated and who are at high risk.

“The problem is, if we go for a target of lower that 130 mm Hg, the evidence gets weaker, the benefits diminish, and we risk losing patients because of adverse effects from using so many drugs,” he added. “But in younger and fitter patients, we would recommend the lower the better, but not below 120 mm Hg.”

Dr. Kreutz noted that the new guidelines have tried to simplify recommendations on target pressures. “We have tried to simplify guidance to focus on a target of around 130 for almost all patients. Before, it wasn’t so clear. There were different targets for different groups of patients with various comorbidities or older patients. But now we are saying the range of 120 to 139 is suitable for the vast majority of patients.”

The guidelines do allow slightly higher targets for older and very frail patients.
 

Drug treatments

The guidelines advise that blood pressure lowering be prioritized over the selection of specific antihypertensive drug classes. The use of any of the five major drug classes – angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, calcium blockers, and thiazide/thiazidelike diuretics – and their combinations are recommended as the basis of antihypertensive treatment strategies.

They advise starting with a two-drug combination for most patients. The preferred combinations including a renin-angiotensin blocker (either an ACE inhibitor or an ARB) with a calcium blocker or a thiazide/thiazidelike diuretic, preferably in a single-pill combination to reduce pill burden and improve adherence and outcome.

If blood pressure is not controlled with the initial two-drug combination at the maximum recommended and tolerated dose of the respective components, treatment should be increased to a three-drug combination.

“We can control 60% of patients in the general hypertensive population with dual therapy, and up to 90% with triple therapy,” Dr. Kreutz said. “Only a small percentage need a fourth drug.”

A new feature of the guidelines is the upgrading of beta-blockers in the treatment algorithms.

“Beta-blockers may not have previously been considered as a first choice of antihypertensive medication, but we see that in clinical practice, many patients are actually treated with these drugs because there are so many conditions in which beta-blockers have a compelling evidence-based indication or are believed to be favorable,” he said. “So, we are now positioning beta-blockers as drugs that can be used at any step of the treatment algorithm if there is a guideline directed indication or other conditions for which they are thought to be beneficial.”

The guidelines also recommend that all drugs be given as once-daily preparations and that they be taken preferably in the morning.

“The new TIME study has established that there is no difference in outcome with morning or evening dosing, but we know that adherence is often better when drugs are taken in the morning, and it is not advisable to take diuretics in the evening,” Dr. Kreutz said.
 

‘True resistant hypertension’

The guidelines have introduced a new term, “true resistant hypertension,” defined as systolic blood pressure of ≥ 140 mm Hg or diastolic blood pressure of ≥ 90 mm Hg in the presence of the following conditions: the maximum recommended and tolerated doses of a three-drug combination comprising a renin-angiotensin system blocker (either an ACE inhibitor or an ARB), a calcium blocker, and a thiazide/thiazidelike diuretic were used; inadequate blood pressure control has been confirmed by ambulatory (preferable) or home blood pressure measurement; and various causes of pseudo-resistant hypertension (especially poor medication adherence) and secondary hypertension have been excluded.

“There are many patients who may appear to have resistant hypertension, but we need to screen them carefully to ensure they are adherent to treatment, and then most of these patients are found not to be truly resistant,” Dr. Kreutz explained. “We estimate that only about 5% of patients have true resistant hypertension.”

For these patients with true resistant hypertension, two treatment approaches are recommended.

For those who do not have advanced kidney disease (glomerular filtration rate > 40 mL/min), renal denervation can be considered. This is a new II B recommendation.

Dr. Kreutz noted that studies of renal denervation excluded patients with advanced kidney disease, so there are no data for this group. For these patients, the guidelines suggest that a combination diuretic approach (chlorthalidone with a loop diuretic) could be considered in light of the results of the recent CLICK study.
 

Differences from U.S. guidelines?

Commenting on the new European guidelines for this news organization, Paul Whelton, MD, chair of the most recent American College of Cardiology/American Heart Association hypertension guidelines committee, said: “Publication of these guidelines is important. I congratulate the European task force. It is an enormous amount of time and effort.”

Dr. Whelton, who is Show Chwan Chair in Global Public Health at Tulane University, New Orleans, and president of the World Hypertension League, added: “I would say the changes are incremental rather than major, but that is probably appropriate.”

He welcomed the greater emphasis on out-of-office blood pressure measurement, saying, “That’s where we should be headed.”

Asked how the European guidelines differ from the U.S. guidelines, Dr. Whelton commented: “There are differences, but they are not huge. The major hypertension guidelines across the world are much more alike than they are different.”

He pointed out that both the U.S. and European guidelines aim for a target blood pressure of 130/80 mm Hg for most patients but have different ways of issuing that advice.

“The Europeans recommend a minimum goal of 140/90 mm Hg, and if there are no issues, then press on to get to under 130/80 mm Hg. That’s kind of a two-step process,” he said. “In the U.S., we’ve gone for a more direct approach of just recommending less than 130/80 mm Hg.

“My fear with the European approach is that by saying, get to 140/90 mm Hg first, then move on to 130/80 mm Hg, is that you’re likely to lose people. And doctors could feel that 140/90 is fine.”
 

More effort needed on implementation

Dr. Whelton says that where all hypertension guidelines are lacking is in the implementation of the recommendations.

“We are all falling down on implementation,” he said. “We have a huge burden of illness, and it is a very cost-effective area for management, but still, rates of blood pressure control are very bad. Generally speaking, even with a very conservative target of 140/90, the best countries only have control rates of around 30%, and this can be as low as 8% in some low/middle-income countries.”

Dr. Whelton believes the approach to blood pressure management needs to change.

“We know that the current traditional model of care, where blood pressure is managed by your local doctor, is not working. It is hopeless,” he said. “That is not an indictment of these doctors. It’s just that they have more pressing issues to deal with, so we need to look at other models.”

He suggests that the way forward is through convenient, community-based care delivered by a team in which nonphysicians assist in much of the management and in which reliable, affordable medications are given at the point of care, with patients tracked with electronic health records so as to identify those who are not adhering to their medication regimens.

“We know that using simple protocols will work for the vast majority of people. We don’t need to individualize or complicate this too much. That tends to lose people in the process.”

Dr. Whelton makes the point that it is well known how to diagnose and treat hypertension, yet this is not being done well.

“We are doing these things really badly. In routine care, blood pressure is measured horribly. Nobody would accept a pilot of a plane saying he should be doing all these procedures but he’s too busy and it’s probably okay, but that’s the way blood pressure is often measured in clinical practice,” he added. “And we can’t really do a good job if were not measuring the key variable properly that the diagnosis is based on.”

Dr. Whelton also points out that the medical profession is not making enough effort to have patients reach target levels.

“If you’re in a country where very few people are being treated and very high pressures are common, then of course you have to focus on that group first. But in most of the Western world, we are long past that, so we can move on down the chain. We then get to a lot more people with moderately high blood pressure getting exposed to increases in risk, and while this is not quite as dramatic as those with very high pressures at the individual risk level, because there are so many of them, that’s where a lot of events are occurring,” he says.

“If we get everyone to 140/90 mm Hg, we can probably prevent 60% of blood pressure–related events. But if we can get them all down to 130 mm Hg systolic, then we can prevent 75%-80% of events. It’s often quite easy to get to that target, but patients need help and encouragement.”

Going forward, he concluded, guidelines should pivot to focus more on implementation.

“We all try to make the guidelines as approachable as possible, but they are encyclopedic, and many doctors just continue doing what they are doing. That is our big challenge.”

A version of this article first appeared on Medscape.com.

The European Society of Hypertension has released updated and expanded guidelines for the management of hypertension.

The guidelines, which are endorsed by the European Renal Association and the International Society of Hypertension, were presented during the annual European Meeting on Hypertension and Cardiovascular Protection Meeting in Milan, Italy.

The guidelines consensus document was also published online in the Journal of Hypertension. Giuseppe Mancia, MD, professor emeritus of medicine, University Milano-Bicocca, Italy, and Reinhold Kreutz, MD, PhD, Charité–University Medicine Berlin, were cochairs of the task force that created the document.

“We have tried to provide a simplified message to key topics with these new guidelines,” Dr. Kreutz said in an interview.

“We have confirmed the definition of hypertension and provide clear guidance for blood pressure monitoring and a simplified general strategy targeting similar blood pressure goals for most patients, although the treatment algorithms of how you get there may be different for different patient groups.”

Dr. Kreutz added: “Because hypertension is so prevalent and many patients have comorbidities, it is not easy to have one approach for all, but we have tried to simplify the key messages as much as possible, with a target that is more general to the whole population.”

While there are no major surprises in the guidelines, there are multiple advances and added-value changes, including clear advice on how to measure blood pressure, an upgrade for beta-blockers in the treatment algorithms, and a new definition and treatment recommendations for “true resistant hypertension.”
 

Definition remains unchanged

The definition of hypertension remains unchanged from the previous guidelines – repeated office systolic blood pressure values of ≥ 140 mm Hg and/or diastolic blood pressure values of ≥ 90 mm Hg.

“The definition and classification of hypertension has not changed in these new guidelines,” Dr. Kreutz said. “While there have been suggestions that the definition/target should be changed again, particularly about blood pressure lowering being beneficial at the very low pressure range, after reviewing all the evidence we do not agree with this, and we are standing with the definition of hypertension when intervention is beneficial rather than doing nothing or causing harm.”
 

Clear guidance on measurement

Dr. Kreutz points out that the correct measurement of blood pressure is of key importance, and the new guidelines include a detailed algorithm on how to measure blood pressure. The preferred method is automated cuff-based blood pressure measurement.

“There are still many variations in blood pressure measurement in clinical practice, so we now have clear guidance on how to measure blood pressure in the office but also at home,” he commented.

They have upgraded the use of out-of-office blood pressure measurement, particularly home measurement, as useful in long-term management. “In future, there should be more emphasis on follow-up using technology with remote control and virtual care.”
 

Thresholds for starting treatment

On thresholds for initiating antihypertensive therapy, the guidelines recommend that treatment be initiated for most patients when systolic blood pressure is ≥ 140 mm Hg or diastolic blood pressure is ≥ 90 mm Hg.

The same recommendation is given for patients with grade 1 hypertension (systolic, 140-159 mm Hg; and/or diastolic, 90-99 mm Hg) irrespective of cardiovascular risk, although they add that for patients in the lower blood pressure range who have no hypertension-mediated organ damage and who are at low cardiovascular risk, consideration may be given to starting treatment with lifestyle changes only. If, however, blood pressure control is not achieved within a few months of a lifestyle-based approach alone, drug treatment is necessary.

For older patients (aged 80 or older), the task force recommends initiation of drug treatment at 160 mm Hg systolic, although a lower systolic threshold of 140-160 mm Hg may be considered. The authors note that thresholds for the initiation of drug treatment for very frail patients should be individualized.
 

Blood pressure targets

In the new guidelines, the blood pressure target is the same as in the previous guidelines for the general population of patients with hypertension. The goal is < 140/80 mm Hg for most patients. This accounts for the major portion of the protective effect of blood pressure lowering.

However, the consensus document notes that despite the smaller incremental benefit, an effort should be made to reach a range of 120-129/70-79 mm Hg, but only if treatment is well tolerated to avoid the risk of treatment discontinuation because of adverse events, which might offset, in part or completely, the incremental reduction in cardiovascular outcomes.

Elaborating on this, Dr. Kreutz said, “We should aim for the systolic blood pressure to be within the range of below 140 mm Hg down to 120 mm Hg, with a specific target of around 130 mm Hg for most patients and lower in patients in whom drug treatments are well tolerated and who are at high risk.

“The problem is, if we go for a target of lower that 130 mm Hg, the evidence gets weaker, the benefits diminish, and we risk losing patients because of adverse effects from using so many drugs,” he added. “But in younger and fitter patients, we would recommend the lower the better, but not below 120 mm Hg.”

Dr. Kreutz noted that the new guidelines have tried to simplify recommendations on target pressures. “We have tried to simplify guidance to focus on a target of around 130 for almost all patients. Before, it wasn’t so clear. There were different targets for different groups of patients with various comorbidities or older patients. But now we are saying the range of 120 to 139 is suitable for the vast majority of patients.”

The guidelines do allow slightly higher targets for older and very frail patients.
 

Drug treatments

The guidelines advise that blood pressure lowering be prioritized over the selection of specific antihypertensive drug classes. The use of any of the five major drug classes – angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, calcium blockers, and thiazide/thiazidelike diuretics – and their combinations are recommended as the basis of antihypertensive treatment strategies.

They advise starting with a two-drug combination for most patients. The preferred combinations including a renin-angiotensin blocker (either an ACE inhibitor or an ARB) with a calcium blocker or a thiazide/thiazidelike diuretic, preferably in a single-pill combination to reduce pill burden and improve adherence and outcome.

If blood pressure is not controlled with the initial two-drug combination at the maximum recommended and tolerated dose of the respective components, treatment should be increased to a three-drug combination.

“We can control 60% of patients in the general hypertensive population with dual therapy, and up to 90% with triple therapy,” Dr. Kreutz said. “Only a small percentage need a fourth drug.”

A new feature of the guidelines is the upgrading of beta-blockers in the treatment algorithms.

“Beta-blockers may not have previously been considered as a first choice of antihypertensive medication, but we see that in clinical practice, many patients are actually treated with these drugs because there are so many conditions in which beta-blockers have a compelling evidence-based indication or are believed to be favorable,” he said. “So, we are now positioning beta-blockers as drugs that can be used at any step of the treatment algorithm if there is a guideline directed indication or other conditions for which they are thought to be beneficial.”

The guidelines also recommend that all drugs be given as once-daily preparations and that they be taken preferably in the morning.

“The new TIME study has established that there is no difference in outcome with morning or evening dosing, but we know that adherence is often better when drugs are taken in the morning, and it is not advisable to take diuretics in the evening,” Dr. Kreutz said.
 

‘True resistant hypertension’

The guidelines have introduced a new term, “true resistant hypertension,” defined as systolic blood pressure of ≥ 140 mm Hg or diastolic blood pressure of ≥ 90 mm Hg in the presence of the following conditions: the maximum recommended and tolerated doses of a three-drug combination comprising a renin-angiotensin system blocker (either an ACE inhibitor or an ARB), a calcium blocker, and a thiazide/thiazidelike diuretic were used; inadequate blood pressure control has been confirmed by ambulatory (preferable) or home blood pressure measurement; and various causes of pseudo-resistant hypertension (especially poor medication adherence) and secondary hypertension have been excluded.

“There are many patients who may appear to have resistant hypertension, but we need to screen them carefully to ensure they are adherent to treatment, and then most of these patients are found not to be truly resistant,” Dr. Kreutz explained. “We estimate that only about 5% of patients have true resistant hypertension.”

For these patients with true resistant hypertension, two treatment approaches are recommended.

For those who do not have advanced kidney disease (glomerular filtration rate > 40 mL/min), renal denervation can be considered. This is a new II B recommendation.

Dr. Kreutz noted that studies of renal denervation excluded patients with advanced kidney disease, so there are no data for this group. For these patients, the guidelines suggest that a combination diuretic approach (chlorthalidone with a loop diuretic) could be considered in light of the results of the recent CLICK study.
 

Differences from U.S. guidelines?

Commenting on the new European guidelines for this news organization, Paul Whelton, MD, chair of the most recent American College of Cardiology/American Heart Association hypertension guidelines committee, said: “Publication of these guidelines is important. I congratulate the European task force. It is an enormous amount of time and effort.”

Dr. Whelton, who is Show Chwan Chair in Global Public Health at Tulane University, New Orleans, and president of the World Hypertension League, added: “I would say the changes are incremental rather than major, but that is probably appropriate.”

He welcomed the greater emphasis on out-of-office blood pressure measurement, saying, “That’s where we should be headed.”

Asked how the European guidelines differ from the U.S. guidelines, Dr. Whelton commented: “There are differences, but they are not huge. The major hypertension guidelines across the world are much more alike than they are different.”

He pointed out that both the U.S. and European guidelines aim for a target blood pressure of 130/80 mm Hg for most patients but have different ways of issuing that advice.

“The Europeans recommend a minimum goal of 140/90 mm Hg, and if there are no issues, then press on to get to under 130/80 mm Hg. That’s kind of a two-step process,” he said. “In the U.S., we’ve gone for a more direct approach of just recommending less than 130/80 mm Hg.

“My fear with the European approach is that by saying, get to 140/90 mm Hg first, then move on to 130/80 mm Hg, is that you’re likely to lose people. And doctors could feel that 140/90 is fine.”
 

More effort needed on implementation

Dr. Whelton says that where all hypertension guidelines are lacking is in the implementation of the recommendations.

“We are all falling down on implementation,” he said. “We have a huge burden of illness, and it is a very cost-effective area for management, but still, rates of blood pressure control are very bad. Generally speaking, even with a very conservative target of 140/90, the best countries only have control rates of around 30%, and this can be as low as 8% in some low/middle-income countries.”

Dr. Whelton believes the approach to blood pressure management needs to change.

“We know that the current traditional model of care, where blood pressure is managed by your local doctor, is not working. It is hopeless,” he said. “That is not an indictment of these doctors. It’s just that they have more pressing issues to deal with, so we need to look at other models.”

He suggests that the way forward is through convenient, community-based care delivered by a team in which nonphysicians assist in much of the management and in which reliable, affordable medications are given at the point of care, with patients tracked with electronic health records so as to identify those who are not adhering to their medication regimens.

“We know that using simple protocols will work for the vast majority of people. We don’t need to individualize or complicate this too much. That tends to lose people in the process.”

Dr. Whelton makes the point that it is well known how to diagnose and treat hypertension, yet this is not being done well.

“We are doing these things really badly. In routine care, blood pressure is measured horribly. Nobody would accept a pilot of a plane saying he should be doing all these procedures but he’s too busy and it’s probably okay, but that’s the way blood pressure is often measured in clinical practice,” he added. “And we can’t really do a good job if were not measuring the key variable properly that the diagnosis is based on.”

Dr. Whelton also points out that the medical profession is not making enough effort to have patients reach target levels.

“If you’re in a country where very few people are being treated and very high pressures are common, then of course you have to focus on that group first. But in most of the Western world, we are long past that, so we can move on down the chain. We then get to a lot more people with moderately high blood pressure getting exposed to increases in risk, and while this is not quite as dramatic as those with very high pressures at the individual risk level, because there are so many of them, that’s where a lot of events are occurring,” he says.

“If we get everyone to 140/90 mm Hg, we can probably prevent 60% of blood pressure–related events. But if we can get them all down to 130 mm Hg systolic, then we can prevent 75%-80% of events. It’s often quite easy to get to that target, but patients need help and encouragement.”

Going forward, he concluded, guidelines should pivot to focus more on implementation.

“We all try to make the guidelines as approachable as possible, but they are encyclopedic, and many doctors just continue doing what they are doing. That is our big challenge.”

A version of this article first appeared on Medscape.com.

AUSTIN, TEX – Posttraumatic headache presents physicians with a dilemma: Should patients be treated early on with preventatives, or should clinicians delay any preventative treatment to see whether headaches resolve on their own? There are no guidelines available, nor is there much quality evidence to support one decision or another, according to two experts who debated the question at the annual meeting of the American Headache Society.

Early treatment

Frank Conidi, DO, spoke first, and pointed out the need to define both early treatment and the condition being treated. Is it early-treatment abortive, is it preventative, and if the patient has a concussion, is it a mild traumatic brain injury (TBI), or severe TBI?

Florida Center for Headache and Sports Neurology

The majority of patients with posttraumatic headache will meet criteria for migraine or probable migraine. “It can be anywhere from 58% to upwards of 90%. And if you see these patients, it makes sense, because posttraumatic headache patients are disabled by their headaches,” said Dr. Conidi, director of the Florida Center for Headache and Sports Neurology.

He argued for early treatment to reduce chronification. “We know that if headaches are left untreated, they’re going to start to spiral up and become daily. This leads to the development of peripheral and central sensitization and lowers the threshold for further migraine attacks,” said Dr. Conidi.

He noted that patients with posttraumatic headache often have comorbidities such as sleep issues, neck pain, or posttraumatic stress disorder, all of which are risk factors for chronification. Treatment does not necessarily mean medication, however. “The mainstay of posttraumatic headache treatment is actually physical and cognitive activity to tolerance. And what I call the 20/5 rule: 20 minutes of physical activity with 5-minute chill breaks. In addition, we use light sub-aerobic exercise 3 to 5 days out in concussion, [which] has been shown to improve concussion recovery time,” he said.

Dr. Conidi suggested treatment of triggers, such as neck issues and whiplash symptoms. “Probably the best treatment I’ve ever seen, and I published on this, are pericranial nerve blocks. Pericranial nerve blocks work wonderfully. If you’re going to block the pericranial nerves, block them all, not just the occipital. Block the trigeminal branches. I’ve actually been able to locate a little two-and-a-half-inch plastic Luer-lock catheter that I can hook on a 1-cc syringe with viscous lidocaine, and I can do sphenopalatine ganglion blocks on all my patients now for under 25 cents. So we’ve been combining the nerve blocks, and we’ve been using them early. Oftentimes the patients won’t have any further headaches, especially if it’s [after] a concussion,” he said.

With respect to concussion-related posttraumatic headache, he summed up: “We’re aggressive early. We’re using intervention. We’re layering our treatment. We’re using medications: prednisone, NSAIDS, and now we have gepants. We’ve been having good success with using gepants,” he said.

Treatment of TBI patients is broadly similar, with the main difference being that neurologists typically won’t see such patients early on as they may be in rehab facilities or hospitals for extended periods. “You may not be getting [to see] them for 1 or 2 months. In that case, you want to educate your neurosurgery and your [physical medicine and rehabilitation] colleagues on the treatment.

Finally, he described work that his group has done in using stimulants for posttraumatic headache. “Stimulants not only treat the cognitive symptoms, but they give the patient cognitive reserve and we find that it gets the patient through the day so they actually have less headaches. It’s a form of prevention. I know there are shortages nationally of both Adderall and Ritalin, but we have had excellent results in our posttraumatic patients using these types of medications,” said Dr. Conidi.
 

Delayed treatment

Amaal J. Starling, MD, offered a counterargument, but she narrowed the question down to whether preventive treatment should be used within one and a half months of the injury, which she defined as early treatment. Her argument against early preventive treatment centered around the core value of beneficence – to act for the benefit of the patient, and avoid harm.

Mayo Clinic, Scottsdale

She discussed the natural history of posttraumatic headache, which is largely self-limited. For example, an NCAA study that found 88% of concussions had symptom resolution within 1 week, and 86% of posttraumatic headache resolved within 1 week. “If individuals routinely are having a self-limited course, there is no need for early treatment with a preventive treatment option because the majority of posttraumatic headache is resolving within that one-and-a-half-month postinjury threshold. The better recommendation, as provided in evidence from Dr. Conidi’s presentation, is to provide supportive care, including acute medications or acute treatment options like nerve blocks for acute pain relief and symptom relief,” said Dr. Starling, associate professor of neurology at Mayo Clinic in Scottsdale, Ariz.

Dr. Starling expressed concern that preventive medications could lead to worsening of comorbidities. For example, posttraumatic headache is often associated with autonomic dysfunction and visual vestibular dysfunction. The former commonly occurs with concussion and is similar to postural orthostatic tachycardia syndrome (POTS), and the second most common symptom of POTS is headache, according to Dr. Starling. Posttraumatic POTS is treated similarly to idiopathic POTS, with a nonpharmacologic approach. One element of POTS management is to withdraw exacerbating medications such as beta-blockers, tricyclic antidepressants, and SNRIs. “These look strikingly similar to some of the headache preventive medications that we might consider for somebody, and so the concern is early preventive treatment with these medications to treat the posttraumatic headache may actually worsen some of these comorbidities that are present in our posttraumatic headache patients. We have to be careful about potentially exacerbating comorbidities with early preventive treatment,” she said.

Prevention medications for headache can also worsen visual vestibular dysfunction, such as dizziness. There are some data suggesting that vestibular rehabilitation and vision therapy can improve dizziness, but also headache. “We all know that many of our preventive medications for headache could potentially exacerbate visual vestibular symptoms, so we have to be careful about that. So again, first do no harm. Posttraumatic POTS is common and causes headache. Posttraumatic vestibular dysfunction is common and causes headache. Instead of initiating a headache preventive medication early, we recommend to identify these comorbidities and provide targeted treatment. Treatment of these comorbidities may, in and of itself, improve the headache. We also we have to be careful because some preventive medications may worsen the comorbidities,” said Dr. Starling.
 

Areas of agreement

Dr. Conidi agreed that preventative treatment is less likely to be needed for concussion patients, but said that TBI patients are more likely to require it to prevent chronification. Dr. Starling agreed that chronification is an important concern, but she noted that many posttraumatic headache patients are athletes, and preventative medications can also lead to issues that might interfere with return to play, such as decreased sweating, or weight gain or loss. This is complicated by the fact that titration and weaning periods can be long. “We have to be very careful about these medications’ side effects, especially when we don’t have the evidence to demonstrate that it is worth the potential risk of being put on these medications,” she said.

The debate led Catherin Chong, PhD, to ask about the state of the field. “There’s a posttraumatic headache special interest section here [at AHS 2023], and the question that really is coming up at every meeting is, is there some coherence in the field? Is it too early or is it time for a position statement?” asked Dr. Chong, a career scientist at Mayo Clinic (Phoenix). Dr. Chong comoderated the debate and ensuing discussion.

Dr. Starling felt it’s too early for a position statement, but a scoping review could identify research questions that could lead to a position statement. “I’m really excited about the work that’s being done to identify the cohort of individuals with acute posttraumatic headache that may chronify to persistent posttraumatic headache so that we can minimize the risk of exposing the large cohort that’s going to be likely self-limited to a treatment option. Then we can identify those individuals where that risk is worth it because they’re the ones that could lead to chronification. Figuring out if that’s looking at levels of allodynia or other factors that can [help identify those at most risk] would be important,” she said.

Dr. Conidi agreed with the need for more information on the parameters to be studied, but he expressed the belief that any position statement would be a consensus statement. “It’s not going to have any hard evidence behind it, but I do think we need [a position statement]. Even in the general neurology world, there’s a huge lack of understanding of how to treat these patients,” he said.

Dr. Conidi did not make any disclosures. Dr. Starling has consulted for AbbVie, Allergan, Amgen, Axsome Therapeutics, Everyday Health, Lundbeck, Med-IQ, Medscape, Neurolief, Satsuma, and WebMD. Dr. Chong has no relevant financial disclosures.

AUSTIN, TEX – Posttraumatic headache presents physicians with a dilemma: Should patients be treated early on with preventatives, or should clinicians delay any preventative treatment to see whether headaches resolve on their own? There are no guidelines available, nor is there much quality evidence to support one decision or another, according to two experts who debated the question at the annual meeting of the American Headache Society.

Early treatment

Frank Conidi, DO, spoke first, and pointed out the need to define both early treatment and the condition being treated. Is it early-treatment abortive, is it preventative, and if the patient has a concussion, is it a mild traumatic brain injury (TBI), or severe TBI?

Florida Center for Headache and Sports Neurology

The majority of patients with posttraumatic headache will meet criteria for migraine or probable migraine. “It can be anywhere from 58% to upwards of 90%. And if you see these patients, it makes sense, because posttraumatic headache patients are disabled by their headaches,” said Dr. Conidi, director of the Florida Center for Headache and Sports Neurology.

He argued for early treatment to reduce chronification. “We know that if headaches are left untreated, they’re going to start to spiral up and become daily. This leads to the development of peripheral and central sensitization and lowers the threshold for further migraine attacks,” said Dr. Conidi.

He noted that patients with posttraumatic headache often have comorbidities such as sleep issues, neck pain, or posttraumatic stress disorder, all of which are risk factors for chronification. Treatment does not necessarily mean medication, however. “The mainstay of posttraumatic headache treatment is actually physical and cognitive activity to tolerance. And what I call the 20/5 rule: 20 minutes of physical activity with 5-minute chill breaks. In addition, we use light sub-aerobic exercise 3 to 5 days out in concussion, [which] has been shown to improve concussion recovery time,” he said.

Dr. Conidi suggested treatment of triggers, such as neck issues and whiplash symptoms. “Probably the best treatment I’ve ever seen, and I published on this, are pericranial nerve blocks. Pericranial nerve blocks work wonderfully. If you’re going to block the pericranial nerves, block them all, not just the occipital. Block the trigeminal branches. I’ve actually been able to locate a little two-and-a-half-inch plastic Luer-lock catheter that I can hook on a 1-cc syringe with viscous lidocaine, and I can do sphenopalatine ganglion blocks on all my patients now for under 25 cents. So we’ve been combining the nerve blocks, and we’ve been using them early. Oftentimes the patients won’t have any further headaches, especially if it’s [after] a concussion,” he said.

With respect to concussion-related posttraumatic headache, he summed up: “We’re aggressive early. We’re using intervention. We’re layering our treatment. We’re using medications: prednisone, NSAIDS, and now we have gepants. We’ve been having good success with using gepants,” he said.

Treatment of TBI patients is broadly similar, with the main difference being that neurologists typically won’t see such patients early on as they may be in rehab facilities or hospitals for extended periods. “You may not be getting [to see] them for 1 or 2 months. In that case, you want to educate your neurosurgery and your [physical medicine and rehabilitation] colleagues on the treatment.

Finally, he described work that his group has done in using stimulants for posttraumatic headache. “Stimulants not only treat the cognitive symptoms, but they give the patient cognitive reserve and we find that it gets the patient through the day so they actually have less headaches. It’s a form of prevention. I know there are shortages nationally of both Adderall and Ritalin, but we have had excellent results in our posttraumatic patients using these types of medications,” said Dr. Conidi.
 

Delayed treatment

Amaal J. Starling, MD, offered a counterargument, but she narrowed the question down to whether preventive treatment should be used within one and a half months of the injury, which she defined as early treatment. Her argument against early preventive treatment centered around the core value of beneficence – to act for the benefit of the patient, and avoid harm.

Mayo Clinic, Scottsdale

She discussed the natural history of posttraumatic headache, which is largely self-limited. For example, an NCAA study that found 88% of concussions had symptom resolution within 1 week, and 86% of posttraumatic headache resolved within 1 week. “If individuals routinely are having a self-limited course, there is no need for early treatment with a preventive treatment option because the majority of posttraumatic headache is resolving within that one-and-a-half-month postinjury threshold. The better recommendation, as provided in evidence from Dr. Conidi’s presentation, is to provide supportive care, including acute medications or acute treatment options like nerve blocks for acute pain relief and symptom relief,” said Dr. Starling, associate professor of neurology at Mayo Clinic in Scottsdale, Ariz.

Dr. Starling expressed concern that preventive medications could lead to worsening of comorbidities. For example, posttraumatic headache is often associated with autonomic dysfunction and visual vestibular dysfunction. The former commonly occurs with concussion and is similar to postural orthostatic tachycardia syndrome (POTS), and the second most common symptom of POTS is headache, according to Dr. Starling. Posttraumatic POTS is treated similarly to idiopathic POTS, with a nonpharmacologic approach. One element of POTS management is to withdraw exacerbating medications such as beta-blockers, tricyclic antidepressants, and SNRIs. “These look strikingly similar to some of the headache preventive medications that we might consider for somebody, and so the concern is early preventive treatment with these medications to treat the posttraumatic headache may actually worsen some of these comorbidities that are present in our posttraumatic headache patients. We have to be careful about potentially exacerbating comorbidities with early preventive treatment,” she said.

Prevention medications for headache can also worsen visual vestibular dysfunction, such as dizziness. There are some data suggesting that vestibular rehabilitation and vision therapy can improve dizziness, but also headache. “We all know that many of our preventive medications for headache could potentially exacerbate visual vestibular symptoms, so we have to be careful about that. So again, first do no harm. Posttraumatic POTS is common and causes headache. Posttraumatic vestibular dysfunction is common and causes headache. Instead of initiating a headache preventive medication early, we recommend to identify these comorbidities and provide targeted treatment. Treatment of these comorbidities may, in and of itself, improve the headache. We also we have to be careful because some preventive medications may worsen the comorbidities,” said Dr. Starling.
 

Areas of agreement

Dr. Conidi agreed that preventative treatment is less likely to be needed for concussion patients, but said that TBI patients are more likely to require it to prevent chronification. Dr. Starling agreed that chronification is an important concern, but she noted that many posttraumatic headache patients are athletes, and preventative medications can also lead to issues that might interfere with return to play, such as decreased sweating, or weight gain or loss. This is complicated by the fact that titration and weaning periods can be long. “We have to be very careful about these medications’ side effects, especially when we don’t have the evidence to demonstrate that it is worth the potential risk of being put on these medications,” she said.

The debate led Catherin Chong, PhD, to ask about the state of the field. “There’s a posttraumatic headache special interest section here [at AHS 2023], and the question that really is coming up at every meeting is, is there some coherence in the field? Is it too early or is it time for a position statement?” asked Dr. Chong, a career scientist at Mayo Clinic (Phoenix). Dr. Chong comoderated the debate and ensuing discussion.

Dr. Starling felt it’s too early for a position statement, but a scoping review could identify research questions that could lead to a position statement. “I’m really excited about the work that’s being done to identify the cohort of individuals with acute posttraumatic headache that may chronify to persistent posttraumatic headache so that we can minimize the risk of exposing the large cohort that’s going to be likely self-limited to a treatment option. Then we can identify those individuals where that risk is worth it because they’re the ones that could lead to chronification. Figuring out if that’s looking at levels of allodynia or other factors that can [help identify those at most risk] would be important,” she said.

Dr. Conidi agreed with the need for more information on the parameters to be studied, but he expressed the belief that any position statement would be a consensus statement. “It’s not going to have any hard evidence behind it, but I do think we need [a position statement]. Even in the general neurology world, there’s a huge lack of understanding of how to treat these patients,” he said.

Dr. Conidi did not make any disclosures. Dr. Starling has consulted for AbbVie, Allergan, Amgen, Axsome Therapeutics, Everyday Health, Lundbeck, Med-IQ, Medscape, Neurolief, Satsuma, and WebMD. Dr. Chong has no relevant financial disclosures.

AUSTIN, TEX – Posttraumatic headache presents physicians with a dilemma: Should patients be treated early on with preventatives, or should clinicians delay any preventative treatment to see whether headaches resolve on their own? There are no guidelines available, nor is there much quality evidence to support one decision or another, according to two experts who debated the question at the annual meeting of the American Headache Society.

Early treatment

Frank Conidi, DO, spoke first, and pointed out the need to define both early treatment and the condition being treated. Is it early-treatment abortive, is it preventative, and if the patient has a concussion, is it a mild traumatic brain injury (TBI), or severe TBI?

Florida Center for Headache and Sports Neurology

The majority of patients with posttraumatic headache will meet criteria for migraine or probable migraine. “It can be anywhere from 58% to upwards of 90%. And if you see these patients, it makes sense, because posttraumatic headache patients are disabled by their headaches,” said Dr. Conidi, director of the Florida Center for Headache and Sports Neurology.

He argued for early treatment to reduce chronification. “We know that if headaches are left untreated, they’re going to start to spiral up and become daily. This leads to the development of peripheral and central sensitization and lowers the threshold for further migraine attacks,” said Dr. Conidi.

He noted that patients with posttraumatic headache often have comorbidities such as sleep issues, neck pain, or posttraumatic stress disorder, all of which are risk factors for chronification. Treatment does not necessarily mean medication, however. “The mainstay of posttraumatic headache treatment is actually physical and cognitive activity to tolerance. And what I call the 20/5 rule: 20 minutes of physical activity with 5-minute chill breaks. In addition, we use light sub-aerobic exercise 3 to 5 days out in concussion, [which] has been shown to improve concussion recovery time,” he said.

Dr. Conidi suggested treatment of triggers, such as neck issues and whiplash symptoms. “Probably the best treatment I’ve ever seen, and I published on this, are pericranial nerve blocks. Pericranial nerve blocks work wonderfully. If you’re going to block the pericranial nerves, block them all, not just the occipital. Block the trigeminal branches. I’ve actually been able to locate a little two-and-a-half-inch plastic Luer-lock catheter that I can hook on a 1-cc syringe with viscous lidocaine, and I can do sphenopalatine ganglion blocks on all my patients now for under 25 cents. So we’ve been combining the nerve blocks, and we’ve been using them early. Oftentimes the patients won’t have any further headaches, especially if it’s [after] a concussion,” he said.

With respect to concussion-related posttraumatic headache, he summed up: “We’re aggressive early. We’re using intervention. We’re layering our treatment. We’re using medications: prednisone, NSAIDS, and now we have gepants. We’ve been having good success with using gepants,” he said.

Treatment of TBI patients is broadly similar, with the main difference being that neurologists typically won’t see such patients early on as they may be in rehab facilities or hospitals for extended periods. “You may not be getting [to see] them for 1 or 2 months. In that case, you want to educate your neurosurgery and your [physical medicine and rehabilitation] colleagues on the treatment.

Finally, he described work that his group has done in using stimulants for posttraumatic headache. “Stimulants not only treat the cognitive symptoms, but they give the patient cognitive reserve and we find that it gets the patient through the day so they actually have less headaches. It’s a form of prevention. I know there are shortages nationally of both Adderall and Ritalin, but we have had excellent results in our posttraumatic patients using these types of medications,” said Dr. Conidi.
 

Delayed treatment

Amaal J. Starling, MD, offered a counterargument, but she narrowed the question down to whether preventive treatment should be used within one and a half months of the injury, which she defined as early treatment. Her argument against early preventive treatment centered around the core value of beneficence – to act for the benefit of the patient, and avoid harm.

Mayo Clinic, Scottsdale

She discussed the natural history of posttraumatic headache, which is largely self-limited. For example, an NCAA study that found 88% of concussions had symptom resolution within 1 week, and 86% of posttraumatic headache resolved within 1 week. “If individuals routinely are having a self-limited course, there is no need for early treatment with a preventive treatment option because the majority of posttraumatic headache is resolving within that one-and-a-half-month postinjury threshold. The better recommendation, as provided in evidence from Dr. Conidi’s presentation, is to provide supportive care, including acute medications or acute treatment options like nerve blocks for acute pain relief and symptom relief,” said Dr. Starling, associate professor of neurology at Mayo Clinic in Scottsdale, Ariz.

Dr. Starling expressed concern that preventive medications could lead to worsening of comorbidities. For example, posttraumatic headache is often associated with autonomic dysfunction and visual vestibular dysfunction. The former commonly occurs with concussion and is similar to postural orthostatic tachycardia syndrome (POTS), and the second most common symptom of POTS is headache, according to Dr. Starling. Posttraumatic POTS is treated similarly to idiopathic POTS, with a nonpharmacologic approach. One element of POTS management is to withdraw exacerbating medications such as beta-blockers, tricyclic antidepressants, and SNRIs. “These look strikingly similar to some of the headache preventive medications that we might consider for somebody, and so the concern is early preventive treatment with these medications to treat the posttraumatic headache may actually worsen some of these comorbidities that are present in our posttraumatic headache patients. We have to be careful about potentially exacerbating comorbidities with early preventive treatment,” she said.

Prevention medications for headache can also worsen visual vestibular dysfunction, such as dizziness. There are some data suggesting that vestibular rehabilitation and vision therapy can improve dizziness, but also headache. “We all know that many of our preventive medications for headache could potentially exacerbate visual vestibular symptoms, so we have to be careful about that. So again, first do no harm. Posttraumatic POTS is common and causes headache. Posttraumatic vestibular dysfunction is common and causes headache. Instead of initiating a headache preventive medication early, we recommend to identify these comorbidities and provide targeted treatment. Treatment of these comorbidities may, in and of itself, improve the headache. We also we have to be careful because some preventive medications may worsen the comorbidities,” said Dr. Starling.
 

Areas of agreement

Dr. Conidi agreed that preventative treatment is less likely to be needed for concussion patients, but said that TBI patients are more likely to require it to prevent chronification. Dr. Starling agreed that chronification is an important concern, but she noted that many posttraumatic headache patients are athletes, and preventative medications can also lead to issues that might interfere with return to play, such as decreased sweating, or weight gain or loss. This is complicated by the fact that titration and weaning periods can be long. “We have to be very careful about these medications’ side effects, especially when we don’t have the evidence to demonstrate that it is worth the potential risk of being put on these medications,” she said.

The debate led Catherin Chong, PhD, to ask about the state of the field. “There’s a posttraumatic headache special interest section here [at AHS 2023], and the question that really is coming up at every meeting is, is there some coherence in the field? Is it too early or is it time for a position statement?” asked Dr. Chong, a career scientist at Mayo Clinic (Phoenix). Dr. Chong comoderated the debate and ensuing discussion.

Dr. Starling felt it’s too early for a position statement, but a scoping review could identify research questions that could lead to a position statement. “I’m really excited about the work that’s being done to identify the cohort of individuals with acute posttraumatic headache that may chronify to persistent posttraumatic headache so that we can minimize the risk of exposing the large cohort that’s going to be likely self-limited to a treatment option. Then we can identify those individuals where that risk is worth it because they’re the ones that could lead to chronification. Figuring out if that’s looking at levels of allodynia or other factors that can [help identify those at most risk] would be important,” she said.

Dr. Conidi agreed with the need for more information on the parameters to be studied, but he expressed the belief that any position statement would be a consensus statement. “It’s not going to have any hard evidence behind it, but I do think we need [a position statement]. Even in the general neurology world, there’s a huge lack of understanding of how to treat these patients,” he said.

Dr. Conidi did not make any disclosures. Dr. Starling has consulted for AbbVie, Allergan, Amgen, Axsome Therapeutics, Everyday Health, Lundbeck, Med-IQ, Medscape, Neurolief, Satsuma, and WebMD. Dr. Chong has no relevant financial disclosures.

In the largest randomized controlled trial of an automated insulin delivery (AID) system (hybrid closed-loop) versus standard insulin delivery in pregnant women with type 1 diabetes, the automated CamAPS FX system prevailed.

The percentage of time spent in the pregnancy-specific target blood glucose range of 63-140 mg/dL (3.5-7.8 mmol/L) from 16 weeks’ gestation to delivery was significantly higher in women in the AID group.

Helen R. Murphy, MD, presented these topline findings from the Automated Insulin Delivery Amongst Pregnant Women With Type 1 Diabetes (AiDAPT) trial during an e-poster session at the annual scientific sessions of the American Diabetes Association.

The “hybrid closed-loop significantly improved maternal glucose and should be offered to all pregnant women with type 1 diabetes,” concluded Dr. Murphy, professor of medicine at the University of East Anglia and a clinician at Norfolk and Norwich University Hospital in the United Kingdom.

CamAPS FX is the only AID system approved in Europe and the United Kingdom for type 1 diabetes from age 1 and during pregnancy. The hybrid closed-loop system is not available in the United States but other systems are available and sometimes used off label in pregnancy. Such systems are sometimes known colloquially as an “artificial pancreas.”

The researchers said their findings provide evidence for the UK National Institute of Clinical Excellence (NICE) to recommend that all pregnant women with type 1 diabetes should be offered the CamAPS FX system.

Asked by an audience member about type 2 diabetes in pregnancy, Dr. Murphy said: “I don’t think we can necessarily extend these data to women with type 2 diabetes. We just don’t have enough data on glucose profiles in type 2 to train an algorithm yet.”  

However, the data provide support for earlier use of closed-loop therapy in type 1 diabetes, she said. “The ideal time to start closed-loop is not necessarily between 8 and 12 weeks. Half of all pregnancies are unplanned,” she noted, “so start [AID] as early as possible [in patients with type 1 diabetes].”
 

Two experts weigh in

Whether pregnant women with type 1 diabetes should be offered hybrid closed-loop therapy “depends,” said Anne L. Peters, MD, who was not involved with the research.

“It is all about being able to set [blood glucose] targets,” according to Dr. Peters, director of the University of Southern California Westside Center for Diabetes in Los Angeles.

USC Westside Center for Diabetes

Study rationale, method, and findings

Pregnant women with diabetes are advised to aim for very tight glucose targets throughout pregnancy and avoid hyperglycemia, to reduce risk of preterm delivery, neonatal weight > 90th percentile, and neonatal morbidity, according to Dr. Murphy and colleagues.

“However, despite increased use of [CGM], continuous subcutaneous insulin infusion (CSII), and improved insulin analogs, achieving and maintaining the recommended glucose targets remains challenging for most pregnant women with type 1 diabetes,” they wrote in their abstract.

Researchers randomized 124 women who had type 1 diabetes for at least 12 months, were at < 13 weeks’ to 6 days’ gestation, and had an A1c of 6.5% to < 10% who were taking intensive standard insulin therapy at nine antenatal clinics in the United Kingdom. Half of the women were using CSII and half were receiving multiple daily injections of insulin. 

As explained in the published study protocol, the women were randomized to continue their standard insulin delivery or switch to a closed-loop system consisting of the study insulin pump (Dana Diabecare RS), a CGM transmitter, and an app (CamAPS FX) on an Android smartphone that communicates wirelessly with the insulin pump and CGM transmitter.

Participants in both groups used the same CGM system and received support for insulin dose adjustment from their antenatal clinical care team.

They were a mean age of 31 years, had a mean A1c of 7.7%, and had had type 1 diabetes for 17 years on average. Their body mass index varied; 37% had normal weight, 27% had overweight, and 26% had obesity.

A significantly higher percentage of women in the AID group than in the control group had blood glucose in target range more than 70% of the time (46% vs. 10%; P < .001).

Compared with women in the control group, those in the AID group had larger reductions in hyperglycemia (–11%; P < .001), higher overnight time-in-range (13%; P < .001), and lower A1c (–0.34%; P < .001), without additional insulin, weight gain, or hypoglycemia.

The effect was consistent across clinical sites and maternal age and A1c categories.
 

Ongoing studies, off-label use

Hybrid closed-loop systems “including Tandem Control IQ, the Omnipod 5, and the Medtronic 780G give insulin continuously on the basis of values obtained from a sensor,” Dr. Peters explained in a recent commentary. “These aren’t fully closed-loop systems because the individual still has to interact with the system and give doses for meals, and then adjust doses for exercise.”

There are currently three studies using commercially available AID systems without pregnancy-specific glucose targets, in type 1 diabetes pregnancies, Dr. Polsky noted.

The Pregnancy Intervention With a Closed-Loop System (PICLS) trial used the Medtronic 670G system in pregnancy and was conducted in the United States. The Closed-Loop Insulin Delivery in Pregnant Women With Type 1 Diabetes (CRISTAL) study is using the Medtronic 780G system in pregnancy and is being conducted in Belgium and the Netherlands. And the Closed-Loop Insulin Delivery in Type 1 Diabetes Pregnancies (CIRCUIT) study is using the Tandem Control IQ system in pregnancy and is being conducted in Canada, she explained.

“The decision to continue to use or to initiate (off-label) use of any of these systems in pregnancy should be individualized, and pregnant individuals should make these decisions by working with an experienced endocrine/diabetes team,” Dr. Polsky stressed.

“The hope is that the results of these exciting trials will show safe and effective use of these systems throughout gestation with improvements in glucose control and quality of life,” she concluded.

The study was funded by the UK National Institute for Health Research, JDRF, and Diabetes Research and Wellness Foundation. Dr. Murphy has reported being on the advisory panel for Medtronic and receiving research support from Dexcom. Dr. Peters disclosed that she served as a consultant for Blue Circle Health, Vertex, and Abbott Diabetes Care, received a research grant from Abbott Diabetes Care, and received stock options from Teladoc and Omada Health. Dr. Polsky has disclosed that she is a contributing writer for diaTribe, was on a medical advisory board for Medtronic MiniMed, has received research funding from DexCom, Eli Lilly, JDRF, Leona & Harry Helmsley Charitable Trust, NIDDK, and Sanofi, and has received research support from Diasome Pharmaceuticals, LabStyle Innovation, Lexicon, Medtronic MiniMed, and Sanofi.

A version of this article first appeared on Medscape.com.

In the largest randomized controlled trial of an automated insulin delivery (AID) system (hybrid closed-loop) versus standard insulin delivery in pregnant women with type 1 diabetes, the automated CamAPS FX system prevailed.

The percentage of time spent in the pregnancy-specific target blood glucose range of 63-140 mg/dL (3.5-7.8 mmol/L) from 16 weeks’ gestation to delivery was significantly higher in women in the AID group.

Helen R. Murphy, MD, presented these topline findings from the Automated Insulin Delivery Amongst Pregnant Women With Type 1 Diabetes (AiDAPT) trial during an e-poster session at the annual scientific sessions of the American Diabetes Association.

The “hybrid closed-loop significantly improved maternal glucose and should be offered to all pregnant women with type 1 diabetes,” concluded Dr. Murphy, professor of medicine at the University of East Anglia and a clinician at Norfolk and Norwich University Hospital in the United Kingdom.

CamAPS FX is the only AID system approved in Europe and the United Kingdom for type 1 diabetes from age 1 and during pregnancy. The hybrid closed-loop system is not available in the United States but other systems are available and sometimes used off label in pregnancy. Such systems are sometimes known colloquially as an “artificial pancreas.”

The researchers said their findings provide evidence for the UK National Institute of Clinical Excellence (NICE) to recommend that all pregnant women with type 1 diabetes should be offered the CamAPS FX system.

Asked by an audience member about type 2 diabetes in pregnancy, Dr. Murphy said: “I don’t think we can necessarily extend these data to women with type 2 diabetes. We just don’t have enough data on glucose profiles in type 2 to train an algorithm yet.”  

However, the data provide support for earlier use of closed-loop therapy in type 1 diabetes, she said. “The ideal time to start closed-loop is not necessarily between 8 and 12 weeks. Half of all pregnancies are unplanned,” she noted, “so start [AID] as early as possible [in patients with type 1 diabetes].”
 

Two experts weigh in

Whether pregnant women with type 1 diabetes should be offered hybrid closed-loop therapy “depends,” said Anne L. Peters, MD, who was not involved with the research.

“It is all about being able to set [blood glucose] targets,” according to Dr. Peters, director of the University of Southern California Westside Center for Diabetes in Los Angeles.

USC Westside Center for Diabetes

Study rationale, method, and findings

Pregnant women with diabetes are advised to aim for very tight glucose targets throughout pregnancy and avoid hyperglycemia, to reduce risk of preterm delivery, neonatal weight > 90th percentile, and neonatal morbidity, according to Dr. Murphy and colleagues.

“However, despite increased use of [CGM], continuous subcutaneous insulin infusion (CSII), and improved insulin analogs, achieving and maintaining the recommended glucose targets remains challenging for most pregnant women with type 1 diabetes,” they wrote in their abstract.

Researchers randomized 124 women who had type 1 diabetes for at least 12 months, were at < 13 weeks’ to 6 days’ gestation, and had an A1c of 6.5% to < 10% who were taking intensive standard insulin therapy at nine antenatal clinics in the United Kingdom. Half of the women were using CSII and half were receiving multiple daily injections of insulin. 

As explained in the published study protocol, the women were randomized to continue their standard insulin delivery or switch to a closed-loop system consisting of the study insulin pump (Dana Diabecare RS), a CGM transmitter, and an app (CamAPS FX) on an Android smartphone that communicates wirelessly with the insulin pump and CGM transmitter.

Participants in both groups used the same CGM system and received support for insulin dose adjustment from their antenatal clinical care team.

They were a mean age of 31 years, had a mean A1c of 7.7%, and had had type 1 diabetes for 17 years on average. Their body mass index varied; 37% had normal weight, 27% had overweight, and 26% had obesity.

A significantly higher percentage of women in the AID group than in the control group had blood glucose in target range more than 70% of the time (46% vs. 10%; P < .001).

Compared with women in the control group, those in the AID group had larger reductions in hyperglycemia (–11%; P < .001), higher overnight time-in-range (13%; P < .001), and lower A1c (–0.34%; P < .001), without additional insulin, weight gain, or hypoglycemia.

The effect was consistent across clinical sites and maternal age and A1c categories.
 

Ongoing studies, off-label use

Hybrid closed-loop systems “including Tandem Control IQ, the Omnipod 5, and the Medtronic 780G give insulin continuously on the basis of values obtained from a sensor,” Dr. Peters explained in a recent commentary. “These aren’t fully closed-loop systems because the individual still has to interact with the system and give doses for meals, and then adjust doses for exercise.”

There are currently three studies using commercially available AID systems without pregnancy-specific glucose targets, in type 1 diabetes pregnancies, Dr. Polsky noted.

The Pregnancy Intervention With a Closed-Loop System (PICLS) trial used the Medtronic 670G system in pregnancy and was conducted in the United States. The Closed-Loop Insulin Delivery in Pregnant Women With Type 1 Diabetes (CRISTAL) study is using the Medtronic 780G system in pregnancy and is being conducted in Belgium and the Netherlands. And the Closed-Loop Insulin Delivery in Type 1 Diabetes Pregnancies (CIRCUIT) study is using the Tandem Control IQ system in pregnancy and is being conducted in Canada, she explained.

“The decision to continue to use or to initiate (off-label) use of any of these systems in pregnancy should be individualized, and pregnant individuals should make these decisions by working with an experienced endocrine/diabetes team,” Dr. Polsky stressed.

“The hope is that the results of these exciting trials will show safe and effective use of these systems throughout gestation with improvements in glucose control and quality of life,” she concluded.

The study was funded by the UK National Institute for Health Research, JDRF, and Diabetes Research and Wellness Foundation. Dr. Murphy has reported being on the advisory panel for Medtronic and receiving research support from Dexcom. Dr. Peters disclosed that she served as a consultant for Blue Circle Health, Vertex, and Abbott Diabetes Care, received a research grant from Abbott Diabetes Care, and received stock options from Teladoc and Omada Health. Dr. Polsky has disclosed that she is a contributing writer for diaTribe, was on a medical advisory board for Medtronic MiniMed, has received research funding from DexCom, Eli Lilly, JDRF, Leona & Harry Helmsley Charitable Trust, NIDDK, and Sanofi, and has received research support from Diasome Pharmaceuticals, LabStyle Innovation, Lexicon, Medtronic MiniMed, and Sanofi.

A version of this article first appeared on Medscape.com.

In the largest randomized controlled trial of an automated insulin delivery (AID) system (hybrid closed-loop) versus standard insulin delivery in pregnant women with type 1 diabetes, the automated CamAPS FX system prevailed.

The percentage of time spent in the pregnancy-specific target blood glucose range of 63-140 mg/dL (3.5-7.8 mmol/L) from 16 weeks’ gestation to delivery was significantly higher in women in the AID group.

Helen R. Murphy, MD, presented these topline findings from the Automated Insulin Delivery Amongst Pregnant Women With Type 1 Diabetes (AiDAPT) trial during an e-poster session at the annual scientific sessions of the American Diabetes Association.

The “hybrid closed-loop significantly improved maternal glucose and should be offered to all pregnant women with type 1 diabetes,” concluded Dr. Murphy, professor of medicine at the University of East Anglia and a clinician at Norfolk and Norwich University Hospital in the United Kingdom.

CamAPS FX is the only AID system approved in Europe and the United Kingdom for type 1 diabetes from age 1 and during pregnancy. The hybrid closed-loop system is not available in the United States but other systems are available and sometimes used off label in pregnancy. Such systems are sometimes known colloquially as an “artificial pancreas.”

The researchers said their findings provide evidence for the UK National Institute of Clinical Excellence (NICE) to recommend that all pregnant women with type 1 diabetes should be offered the CamAPS FX system.

Asked by an audience member about type 2 diabetes in pregnancy, Dr. Murphy said: “I don’t think we can necessarily extend these data to women with type 2 diabetes. We just don’t have enough data on glucose profiles in type 2 to train an algorithm yet.”  

However, the data provide support for earlier use of closed-loop therapy in type 1 diabetes, she said. “The ideal time to start closed-loop is not necessarily between 8 and 12 weeks. Half of all pregnancies are unplanned,” she noted, “so start [AID] as early as possible [in patients with type 1 diabetes].”
 

Two experts weigh in

Whether pregnant women with type 1 diabetes should be offered hybrid closed-loop therapy “depends,” said Anne L. Peters, MD, who was not involved with the research.

“It is all about being able to set [blood glucose] targets,” according to Dr. Peters, director of the University of Southern California Westside Center for Diabetes in Los Angeles.

USC Westside Center for Diabetes

Study rationale, method, and findings

Pregnant women with diabetes are advised to aim for very tight glucose targets throughout pregnancy and avoid hyperglycemia, to reduce risk of preterm delivery, neonatal weight > 90th percentile, and neonatal morbidity, according to Dr. Murphy and colleagues.

“However, despite increased use of [CGM], continuous subcutaneous insulin infusion (CSII), and improved insulin analogs, achieving and maintaining the recommended glucose targets remains challenging for most pregnant women with type 1 diabetes,” they wrote in their abstract.

Researchers randomized 124 women who had type 1 diabetes for at least 12 months, were at < 13 weeks’ to 6 days’ gestation, and had an A1c of 6.5% to < 10% who were taking intensive standard insulin therapy at nine antenatal clinics in the United Kingdom. Half of the women were using CSII and half were receiving multiple daily injections of insulin. 

As explained in the published study protocol, the women were randomized to continue their standard insulin delivery or switch to a closed-loop system consisting of the study insulin pump (Dana Diabecare RS), a CGM transmitter, and an app (CamAPS FX) on an Android smartphone that communicates wirelessly with the insulin pump and CGM transmitter.

Participants in both groups used the same CGM system and received support for insulin dose adjustment from their antenatal clinical care team.

They were a mean age of 31 years, had a mean A1c of 7.7%, and had had type 1 diabetes for 17 years on average. Their body mass index varied; 37% had normal weight, 27% had overweight, and 26% had obesity.

A significantly higher percentage of women in the AID group than in the control group had blood glucose in target range more than 70% of the time (46% vs. 10%; P < .001).

Compared with women in the control group, those in the AID group had larger reductions in hyperglycemia (–11%; P < .001), higher overnight time-in-range (13%; P < .001), and lower A1c (–0.34%; P < .001), without additional insulin, weight gain, or hypoglycemia.

The effect was consistent across clinical sites and maternal age and A1c categories.
 

Ongoing studies, off-label use

Hybrid closed-loop systems “including Tandem Control IQ, the Omnipod 5, and the Medtronic 780G give insulin continuously on the basis of values obtained from a sensor,” Dr. Peters explained in a recent commentary. “These aren’t fully closed-loop systems because the individual still has to interact with the system and give doses for meals, and then adjust doses for exercise.”

There are currently three studies using commercially available AID systems without pregnancy-specific glucose targets, in type 1 diabetes pregnancies, Dr. Polsky noted.

The Pregnancy Intervention With a Closed-Loop System (PICLS) trial used the Medtronic 670G system in pregnancy and was conducted in the United States. The Closed-Loop Insulin Delivery in Pregnant Women With Type 1 Diabetes (CRISTAL) study is using the Medtronic 780G system in pregnancy and is being conducted in Belgium and the Netherlands. And the Closed-Loop Insulin Delivery in Type 1 Diabetes Pregnancies (CIRCUIT) study is using the Tandem Control IQ system in pregnancy and is being conducted in Canada, she explained.

“The decision to continue to use or to initiate (off-label) use of any of these systems in pregnancy should be individualized, and pregnant individuals should make these decisions by working with an experienced endocrine/diabetes team,” Dr. Polsky stressed.

“The hope is that the results of these exciting trials will show safe and effective use of these systems throughout gestation with improvements in glucose control and quality of life,” she concluded.

The study was funded by the UK National Institute for Health Research, JDRF, and Diabetes Research and Wellness Foundation. Dr. Murphy has reported being on the advisory panel for Medtronic and receiving research support from Dexcom. Dr. Peters disclosed that she served as a consultant for Blue Circle Health, Vertex, and Abbott Diabetes Care, received a research grant from Abbott Diabetes Care, and received stock options from Teladoc and Omada Health. Dr. Polsky has disclosed that she is a contributing writer for diaTribe, was on a medical advisory board for Medtronic MiniMed, has received research funding from DexCom, Eli Lilly, JDRF, Leona & Harry Helmsley Charitable Trust, NIDDK, and Sanofi, and has received research support from Diasome Pharmaceuticals, LabStyle Innovation, Lexicon, Medtronic MiniMed, and Sanofi.

A version of this article first appeared on Medscape.com.

AUSTIN, TEX – Treatment with ubrogepant (Ubrelvy, Abbvie) during the prodromal phase of a migraine led to a reduction in both prodromal symptoms and ensuing migraine frequency, according to results from a new randomized, crossover study. Researchers took pains to identify migraineurs who could predict an ensuing headache 75% of the time based on prodromal symptoms. Those who could make such predictions were allowed into the randomized study.

Patients are quite good at predicting ensuing headaches when encouraged to do so, according to Peter J. Goadsby, MBBS, MD, PhD, who presented the study findings at the annual meeting of the American Headache Society.

“I find it quite useful to ask patients about these [symptoms]: Have you got cognitive clouding? Do you pass more urine? Have you got mood change? Do you feel fatigue? Associated with the attack, is how I phrase it. Get them first into the idea of thinking about the symptoms, and then get them to think about when they’re occurring. Certainly with things like brain fog, many patients will tell you that it happens. If you ask them whether they’re 100% [certain] when that’s happening, they will tell you [they’re] not. This is part of taking a history and building a relationship with the patient,” Dr. Goadsby, professor of neurology at the University of California, Los Angeles, said during the Q&A after his presentation.
 

‘Significant’ finding

“This is a significant finding because what patients really want is not to develop their headache and no medication has been shown to prevent a headache during the prodrome,” said Alan M. Rapoport, MD, a board certified neurologist and headache expert, as well as clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. Successful treatment during the prodrome treatment could eliminate the need for use of preventive medication, which might decrease the patient’s adverse effects, he said.

Session comoderator Jason J. Sico, MD, took note of the patient experience during the prodrome period. “One of many noteworthy things is the large percentage of people that reported disability during prodrome before the headache. I just find that staggering, though not surprising to many of us,” he said during the session. Dr. Sico is associate professor of neurology and internal medicine at Yale University, New Haven, Conn.

Dr. Rapoport and Dr. Sico were not involved in the study.
 

Probing the prodrome

The study included a 60-day screening period, which had to include between 3 and 16 recorded prodrome events. Headaches had to occur within 1-6 hours in at least 75% of prodrome events. Study subjects were then randomized to 100 mg ubrogepant or placebo for up to 60 days. After their first prodrome event, they entered a 7-day washout period, and then crossed over to the other group until they experienced a second prodrome event.

During the screening period, 81.5% of prodromal events identified by patients were followed by a headache within 1-6 hours of onset. Nearly 10% of the time headache occurred in 1 hour or less, 81.5% between 1 and 6 hours, and 4.5% between 6 and 24 hours after prodrome. Commonly reported prodromal symptoms included sensitivity to light (57.2%), fatigue (50.1%), neck pain (41.9%), sensitivity to sound (33.9%), and dizziness (27.8%).

The study included 247 patients in the first sequence, and 233 in the second sequence. Patient characteristics were similar in both. Ubrogepant treatment led to a greater absence of moderate- or severe-intensity headache within 24 hours of the dose (45.5% vs. 28.6% headache-free; odds ratio [OR], 2.09; P < .0001). They were also more likely to report normal functioning over 24 hours (OR, 1.66; P < .0001) and to have absence of headache within 24 hours (23.7% vs. 13.9%; OR, 1.93; P < .0001).

Between 73% and 75% of participants reported at least mild functional disability before taking medication. Two hours after a dose, ubrogepant led to a higher rate of normal functioning (37.0% vs. 26.1%; P < .001). Ubrogepant had a similar positive effect on sensitivity to light, fatigue, neck pain, sensitivity to sound, and dizziness. Adverse events were higher during ubrogepant treatment (13.2% vs. 9.1%), and included nausea, dizziness, fatigue, and somnolence, all of which were mild. “One is really scraping the barrel [to identify adverse events]. There were no serious adverse events,” said Dr. Goadsby.
 

A unique result?

One questioner asked if other medications used during the prodrome might yield similar results. Dr. Goadsby expressed doubt. “I think the evidence for other treatments is not terribly good. The triptan evidence is really poor. There is no randomized, placebo-controlled trial of a triptan explicitly in promontory symptomatology. There are randomized placebo controlled trials of triptans during the aura phase. The best one was the injected sumatriptan study, and it failed. So, as far as I can see from the randomized-controlled data, triptans don’t do this, and we don’t have good data for nonsteroidals and other therapies,” said Dr. Goadsby.

The researchers showed that you could treat a patient in advance of the headache to actually prevent the headache a significant number of times; it also reduced the prodromal events and it got patients back to normal functioning to a greater extent.

Dr. Goadsby was asked how many patients are typically able to identify prodrome periods on their own. He estimated that about one in three can do it initially. “I think if you teach people how to do this, it becomes very common. I would say four out of five people in my practice are able to talk about this, but you have to introduce the topic. They’ve had [prodrome symptoms], but they haven’t thought about it for a while. This is one of the things where headache doctors can offer real benefit in helping educate patients,” said Dr. Goadsby.

Dr. Sico did not disclose any conflicts of interest. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureau of AbbVie, Dr. Reddy’s, Impel, Pfizer and Teva Pharmaceutical Industries. He is editor-in-chief of Neurology Reviews and on the Editorial Board of CNS Drugs. Dr. Goadsby has financial ties to Amgen, Eli Lilly, Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc., Biohaven Pharmaceuticals Inc., Dr. Reddy’s Laboratories, Electrocore, eNeura, Massachusetts Medical Society, MedicoLegal work, Novartis, Oxford University Press, Teva Pharmaceuticals, Trigemina, Up-to-Date, and Wolters Kluwer. He has a patent for headache assigned to eNeura without fee.

AUSTIN, TEX – Treatment with ubrogepant (Ubrelvy, Abbvie) during the prodromal phase of a migraine led to a reduction in both prodromal symptoms and ensuing migraine frequency, according to results from a new randomized, crossover study. Researchers took pains to identify migraineurs who could predict an ensuing headache 75% of the time based on prodromal symptoms. Those who could make such predictions were allowed into the randomized study.

Patients are quite good at predicting ensuing headaches when encouraged to do so, according to Peter J. Goadsby, MBBS, MD, PhD, who presented the study findings at the annual meeting of the American Headache Society.

“I find it quite useful to ask patients about these [symptoms]: Have you got cognitive clouding? Do you pass more urine? Have you got mood change? Do you feel fatigue? Associated with the attack, is how I phrase it. Get them first into the idea of thinking about the symptoms, and then get them to think about when they’re occurring. Certainly with things like brain fog, many patients will tell you that it happens. If you ask them whether they’re 100% [certain] when that’s happening, they will tell you [they’re] not. This is part of taking a history and building a relationship with the patient,” Dr. Goadsby, professor of neurology at the University of California, Los Angeles, said during the Q&A after his presentation.
 

‘Significant’ finding

“This is a significant finding because what patients really want is not to develop their headache and no medication has been shown to prevent a headache during the prodrome,” said Alan M. Rapoport, MD, a board certified neurologist and headache expert, as well as clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. Successful treatment during the prodrome treatment could eliminate the need for use of preventive medication, which might decrease the patient’s adverse effects, he said.

Session comoderator Jason J. Sico, MD, took note of the patient experience during the prodrome period. “One of many noteworthy things is the large percentage of people that reported disability during prodrome before the headache. I just find that staggering, though not surprising to many of us,” he said during the session. Dr. Sico is associate professor of neurology and internal medicine at Yale University, New Haven, Conn.

Dr. Rapoport and Dr. Sico were not involved in the study.
 

Probing the prodrome

The study included a 60-day screening period, which had to include between 3 and 16 recorded prodrome events. Headaches had to occur within 1-6 hours in at least 75% of prodrome events. Study subjects were then randomized to 100 mg ubrogepant or placebo for up to 60 days. After their first prodrome event, they entered a 7-day washout period, and then crossed over to the other group until they experienced a second prodrome event.

During the screening period, 81.5% of prodromal events identified by patients were followed by a headache within 1-6 hours of onset. Nearly 10% of the time headache occurred in 1 hour or less, 81.5% between 1 and 6 hours, and 4.5% between 6 and 24 hours after prodrome. Commonly reported prodromal symptoms included sensitivity to light (57.2%), fatigue (50.1%), neck pain (41.9%), sensitivity to sound (33.9%), and dizziness (27.8%).

The study included 247 patients in the first sequence, and 233 in the second sequence. Patient characteristics were similar in both. Ubrogepant treatment led to a greater absence of moderate- or severe-intensity headache within 24 hours of the dose (45.5% vs. 28.6% headache-free; odds ratio [OR], 2.09; P < .0001). They were also more likely to report normal functioning over 24 hours (OR, 1.66; P < .0001) and to have absence of headache within 24 hours (23.7% vs. 13.9%; OR, 1.93; P < .0001).

Between 73% and 75% of participants reported at least mild functional disability before taking medication. Two hours after a dose, ubrogepant led to a higher rate of normal functioning (37.0% vs. 26.1%; P < .001). Ubrogepant had a similar positive effect on sensitivity to light, fatigue, neck pain, sensitivity to sound, and dizziness. Adverse events were higher during ubrogepant treatment (13.2% vs. 9.1%), and included nausea, dizziness, fatigue, and somnolence, all of which were mild. “One is really scraping the barrel [to identify adverse events]. There were no serious adverse events,” said Dr. Goadsby.
 

A unique result?

One questioner asked if other medications used during the prodrome might yield similar results. Dr. Goadsby expressed doubt. “I think the evidence for other treatments is not terribly good. The triptan evidence is really poor. There is no randomized, placebo-controlled trial of a triptan explicitly in promontory symptomatology. There are randomized placebo controlled trials of triptans during the aura phase. The best one was the injected sumatriptan study, and it failed. So, as far as I can see from the randomized-controlled data, triptans don’t do this, and we don’t have good data for nonsteroidals and other therapies,” said Dr. Goadsby.

The researchers showed that you could treat a patient in advance of the headache to actually prevent the headache a significant number of times; it also reduced the prodromal events and it got patients back to normal functioning to a greater extent.

Dr. Goadsby was asked how many patients are typically able to identify prodrome periods on their own. He estimated that about one in three can do it initially. “I think if you teach people how to do this, it becomes very common. I would say four out of five people in my practice are able to talk about this, but you have to introduce the topic. They’ve had [prodrome symptoms], but they haven’t thought about it for a while. This is one of the things where headache doctors can offer real benefit in helping educate patients,” said Dr. Goadsby.

Dr. Sico did not disclose any conflicts of interest. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureau of AbbVie, Dr. Reddy’s, Impel, Pfizer and Teva Pharmaceutical Industries. He is editor-in-chief of Neurology Reviews and on the Editorial Board of CNS Drugs. Dr. Goadsby has financial ties to Amgen, Eli Lilly, Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc., Biohaven Pharmaceuticals Inc., Dr. Reddy’s Laboratories, Electrocore, eNeura, Massachusetts Medical Society, MedicoLegal work, Novartis, Oxford University Press, Teva Pharmaceuticals, Trigemina, Up-to-Date, and Wolters Kluwer. He has a patent for headache assigned to eNeura without fee.

AUSTIN, TEX – Treatment with ubrogepant (Ubrelvy, Abbvie) during the prodromal phase of a migraine led to a reduction in both prodromal symptoms and ensuing migraine frequency, according to results from a new randomized, crossover study. Researchers took pains to identify migraineurs who could predict an ensuing headache 75% of the time based on prodromal symptoms. Those who could make such predictions were allowed into the randomized study.

Patients are quite good at predicting ensuing headaches when encouraged to do so, according to Peter J. Goadsby, MBBS, MD, PhD, who presented the study findings at the annual meeting of the American Headache Society.

“I find it quite useful to ask patients about these [symptoms]: Have you got cognitive clouding? Do you pass more urine? Have you got mood change? Do you feel fatigue? Associated with the attack, is how I phrase it. Get them first into the idea of thinking about the symptoms, and then get them to think about when they’re occurring. Certainly with things like brain fog, many patients will tell you that it happens. If you ask them whether they’re 100% [certain] when that’s happening, they will tell you [they’re] not. This is part of taking a history and building a relationship with the patient,” Dr. Goadsby, professor of neurology at the University of California, Los Angeles, said during the Q&A after his presentation.
 

‘Significant’ finding

“This is a significant finding because what patients really want is not to develop their headache and no medication has been shown to prevent a headache during the prodrome,” said Alan M. Rapoport, MD, a board certified neurologist and headache expert, as well as clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. Successful treatment during the prodrome treatment could eliminate the need for use of preventive medication, which might decrease the patient’s adverse effects, he said.

Session comoderator Jason J. Sico, MD, took note of the patient experience during the prodrome period. “One of many noteworthy things is the large percentage of people that reported disability during prodrome before the headache. I just find that staggering, though not surprising to many of us,” he said during the session. Dr. Sico is associate professor of neurology and internal medicine at Yale University, New Haven, Conn.

Dr. Rapoport and Dr. Sico were not involved in the study.
 

Probing the prodrome

The study included a 60-day screening period, which had to include between 3 and 16 recorded prodrome events. Headaches had to occur within 1-6 hours in at least 75% of prodrome events. Study subjects were then randomized to 100 mg ubrogepant or placebo for up to 60 days. After their first prodrome event, they entered a 7-day washout period, and then crossed over to the other group until they experienced a second prodrome event.

During the screening period, 81.5% of prodromal events identified by patients were followed by a headache within 1-6 hours of onset. Nearly 10% of the time headache occurred in 1 hour or less, 81.5% between 1 and 6 hours, and 4.5% between 6 and 24 hours after prodrome. Commonly reported prodromal symptoms included sensitivity to light (57.2%), fatigue (50.1%), neck pain (41.9%), sensitivity to sound (33.9%), and dizziness (27.8%).

The study included 247 patients in the first sequence, and 233 in the second sequence. Patient characteristics were similar in both. Ubrogepant treatment led to a greater absence of moderate- or severe-intensity headache within 24 hours of the dose (45.5% vs. 28.6% headache-free; odds ratio [OR], 2.09; P < .0001). They were also more likely to report normal functioning over 24 hours (OR, 1.66; P < .0001) and to have absence of headache within 24 hours (23.7% vs. 13.9%; OR, 1.93; P < .0001).

Between 73% and 75% of participants reported at least mild functional disability before taking medication. Two hours after a dose, ubrogepant led to a higher rate of normal functioning (37.0% vs. 26.1%; P < .001). Ubrogepant had a similar positive effect on sensitivity to light, fatigue, neck pain, sensitivity to sound, and dizziness. Adverse events were higher during ubrogepant treatment (13.2% vs. 9.1%), and included nausea, dizziness, fatigue, and somnolence, all of which were mild. “One is really scraping the barrel [to identify adverse events]. There were no serious adverse events,” said Dr. Goadsby.
 

A unique result?

One questioner asked if other medications used during the prodrome might yield similar results. Dr. Goadsby expressed doubt. “I think the evidence for other treatments is not terribly good. The triptan evidence is really poor. There is no randomized, placebo-controlled trial of a triptan explicitly in promontory symptomatology. There are randomized placebo controlled trials of triptans during the aura phase. The best one was the injected sumatriptan study, and it failed. So, as far as I can see from the randomized-controlled data, triptans don’t do this, and we don’t have good data for nonsteroidals and other therapies,” said Dr. Goadsby.

The researchers showed that you could treat a patient in advance of the headache to actually prevent the headache a significant number of times; it also reduced the prodromal events and it got patients back to normal functioning to a greater extent.

Dr. Goadsby was asked how many patients are typically able to identify prodrome periods on their own. He estimated that about one in three can do it initially. “I think if you teach people how to do this, it becomes very common. I would say four out of five people in my practice are able to talk about this, but you have to introduce the topic. They’ve had [prodrome symptoms], but they haven’t thought about it for a while. This is one of the things where headache doctors can offer real benefit in helping educate patients,” said Dr. Goadsby.

Dr. Sico did not disclose any conflicts of interest. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureau of AbbVie, Dr. Reddy’s, Impel, Pfizer and Teva Pharmaceutical Industries. He is editor-in-chief of Neurology Reviews and on the Editorial Board of CNS Drugs. Dr. Goadsby has financial ties to Amgen, Eli Lilly, Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc., Biohaven Pharmaceuticals Inc., Dr. Reddy’s Laboratories, Electrocore, eNeura, Massachusetts Medical Society, MedicoLegal work, Novartis, Oxford University Press, Teva Pharmaceuticals, Trigemina, Up-to-Date, and Wolters Kluwer. He has a patent for headache assigned to eNeura without fee.

SAN DIEGO – Survodutide, a dual glucagonlike peptide–1 (GLP-1) and glucagon receptor agonist, led to “striking” weight loss in a phase 2 dosing trial in people with overweight/obesity but without type 2 diabetes.

Close to 40% of people who were taking the highest dose lost 20% or more of their starting weight at 46 weeks, Carel Le Roux, MBChB, PhD, reported at the annual scientific sessions of the American Diabetes Association.

Boehringer Ingelheim and Zealand Pharma are developing survodutide (formerly BI 456906) to treat obesity and nonalcoholic fatty liver disease (NAFLD), according to a company press release.

Glucagon receptor agonism increases energy expenditure, and GLP-1 receptor agonism inhibits appetite, both part of the mechanism of action, Dr. Le Roux, a professor at University College in Dublin, explained.

The trial showed a “striking” and clear dose-response in terms of weight loss, with no new unexpected safety signals, he reported.

Invited to comment, session moderator Elisabetta Patorno, MD, DrPH, noted that “Obesity is one of the main risk factors for [type 2] diabetes.”

“It’s very stimulating to see this new medication class make such a big impact on weight loss in such a short amount of time,” Dr. Patorno, associate professor of medicine at Harvard Medical School, Boston, said in an interview. However, whether the weight loss can be maintained over time remains to be determined in further research, she said.

Head-to-head weight-loss studies of the dual agonist survodutide versus the mono GLP-1 agonist semaglutide (Ozempic, Wegovy, Novo Nordisk) have not been conducted, Dr. Le Roux said during a press briefing.

“What we don’t know is if somebody doesn’t respond to [weight-loss drug] product A, will they respond to product B?” he said. Because survodutide acts on two types of receptors, “you could argue that you would not only increase the absolute amount of weight but you might also increase the number of patients who would respond, but that’s theoretical at the moment,” he explained.
 

Close to 400 patients, five doses, 46-week endpoint

The researchers randomized 387 adults aged 18-75 who had a body mass index (BMI) ≥ 27 kg/m² (overweight or obesity) without type 2 diabetes at sites in North America, Europe, Australia/New Zealand, and Asia.

On average, patients were 49 years old with a body weight of 106 kg (234 lb) and a BMI of 37 kg/m², and 68% were women.

They were randomized to receive a planned weekly subcutaneous maintenance survodutide dose of 0.6 mg (76 patients), 2.4 mg (78 patients), 3.6 mg (76 patients), or 4.8 mg (76 patients), or placebo (77 patients).

The dose was escalated rapidly (monthly) during a 20-week dose-escalation phase, followed by a 26-week maintenance phase.

Patients who did not reach the planned dose remained on a lower dose during the maintenance phase.

In terms of actual treatment, during the maintenance phase, 76 patients were taking placebo, 88 patients were taking 0.6 mg survodutide, 92 were taking 2.4 mg survodutide, 71 were taking 3.6 mg survodutide, and 54 were taking 4.8 mg survodutide, all given as weekly subcutaneous injections.

Primary outcome was the percentage change in body weight from baseline to week 46.

Secondary outcomes included the percentage of patients who reached a body weight reduction of ≥ 5%, ≥ 10%, and ≥ 15% from baseline to week 46.

Mean weight loss at 46 weeks in the planned treatment analysis (where some patients in each group were taking a lower than planned dose during maintenance) was 6.2% in the 0.6-mg survodutide group, 12.5% in the 2.4-mg group, 13.2% in the 3.6-mg group, 14.9% in the 4.8-mg group, and 2.8% in the placebo group.

Among participants who did reach and stay on their assigned dose during the maintenance phase, average weight loss was 6.8% in the 0.6-mg survodutide group,13.6% with 2.4 mg survodutide,16.7% with 3.6 mg survodutide, 18.6% with 4.8 mg survodutide, and 2.0% with placebo.

That is, patients reaching and staying on a weekly subcutaneous dose of 4.8 mg survodutide lost 18.6% of their body weight at 46 weeks, Dr. Le Roux emphasized.

In terms of secondary outcomes, in the group of patients with a planned weekly dose of 4.8 mg survodutide, 83%, 69%, and 55% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

In the group of patients with an actual weekly dose of 4.8 mg survodutide, 98%, 82%, and 67% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

Moreover, 33% of patients in the group with a planned weekly dose of 4.8 mg survodutide and 38% of patients with an actual weekly dose of 4.8 mg survodutide lost ≥ 20% of their baseline body weight by week 46.

Adverse events occurred in 91% of patients in the survodutide groups and 75% in the placebo group. The most common side effects were nausea, vomiting, diarrhea, and constipation, which were mostly mild to moderate and mainly occurred during dose escalation. These effects may potentially be mitigated by more gradual dose escalation, Dr. Le Roux said.

There were no unexpected safety or tolerability concerns, and no serious drug-related adverse events.

These “encouraging data” support further study of survodutide for weight loss in larger phase 3 trials, Dr. Le Roux and colleagues conclude.
 

Survodutide has FDA fast track designation for NASH

Survodutide has received U.S. Food and Drug Administration Fast Track Designation for adults with NASH. The drug is currently being evaluated in a phase 2 study in adults with NASH and stages F1/F2/F3 liver fibrosis, with trial completion expected in the last quarter of 2023.

The current trial was funded by Boehringer Ingelheim. Dr. Le Roux has reported being on an advisory panel for Boehringer Ingelheim and being on advisory panels and receiving research funding from multiple other pharmaceutical companies. Two study authors are Boehringer Ingelheim employees.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Survodutide, a dual glucagonlike peptide–1 (GLP-1) and glucagon receptor agonist, led to “striking” weight loss in a phase 2 dosing trial in people with overweight/obesity but without type 2 diabetes.

Close to 40% of people who were taking the highest dose lost 20% or more of their starting weight at 46 weeks, Carel Le Roux, MBChB, PhD, reported at the annual scientific sessions of the American Diabetes Association.

Boehringer Ingelheim and Zealand Pharma are developing survodutide (formerly BI 456906) to treat obesity and nonalcoholic fatty liver disease (NAFLD), according to a company press release.

Glucagon receptor agonism increases energy expenditure, and GLP-1 receptor agonism inhibits appetite, both part of the mechanism of action, Dr. Le Roux, a professor at University College in Dublin, explained.

The trial showed a “striking” and clear dose-response in terms of weight loss, with no new unexpected safety signals, he reported.

Invited to comment, session moderator Elisabetta Patorno, MD, DrPH, noted that “Obesity is one of the main risk factors for [type 2] diabetes.”

“It’s very stimulating to see this new medication class make such a big impact on weight loss in such a short amount of time,” Dr. Patorno, associate professor of medicine at Harvard Medical School, Boston, said in an interview. However, whether the weight loss can be maintained over time remains to be determined in further research, she said.

Head-to-head weight-loss studies of the dual agonist survodutide versus the mono GLP-1 agonist semaglutide (Ozempic, Wegovy, Novo Nordisk) have not been conducted, Dr. Le Roux said during a press briefing.

“What we don’t know is if somebody doesn’t respond to [weight-loss drug] product A, will they respond to product B?” he said. Because survodutide acts on two types of receptors, “you could argue that you would not only increase the absolute amount of weight but you might also increase the number of patients who would respond, but that’s theoretical at the moment,” he explained.
 

Close to 400 patients, five doses, 46-week endpoint

The researchers randomized 387 adults aged 18-75 who had a body mass index (BMI) ≥ 27 kg/m² (overweight or obesity) without type 2 diabetes at sites in North America, Europe, Australia/New Zealand, and Asia.

On average, patients were 49 years old with a body weight of 106 kg (234 lb) and a BMI of 37 kg/m², and 68% were women.

They were randomized to receive a planned weekly subcutaneous maintenance survodutide dose of 0.6 mg (76 patients), 2.4 mg (78 patients), 3.6 mg (76 patients), or 4.8 mg (76 patients), or placebo (77 patients).

The dose was escalated rapidly (monthly) during a 20-week dose-escalation phase, followed by a 26-week maintenance phase.

Patients who did not reach the planned dose remained on a lower dose during the maintenance phase.

In terms of actual treatment, during the maintenance phase, 76 patients were taking placebo, 88 patients were taking 0.6 mg survodutide, 92 were taking 2.4 mg survodutide, 71 were taking 3.6 mg survodutide, and 54 were taking 4.8 mg survodutide, all given as weekly subcutaneous injections.

Primary outcome was the percentage change in body weight from baseline to week 46.

Secondary outcomes included the percentage of patients who reached a body weight reduction of ≥ 5%, ≥ 10%, and ≥ 15% from baseline to week 46.

Mean weight loss at 46 weeks in the planned treatment analysis (where some patients in each group were taking a lower than planned dose during maintenance) was 6.2% in the 0.6-mg survodutide group, 12.5% in the 2.4-mg group, 13.2% in the 3.6-mg group, 14.9% in the 4.8-mg group, and 2.8% in the placebo group.

Among participants who did reach and stay on their assigned dose during the maintenance phase, average weight loss was 6.8% in the 0.6-mg survodutide group,13.6% with 2.4 mg survodutide,16.7% with 3.6 mg survodutide, 18.6% with 4.8 mg survodutide, and 2.0% with placebo.

That is, patients reaching and staying on a weekly subcutaneous dose of 4.8 mg survodutide lost 18.6% of their body weight at 46 weeks, Dr. Le Roux emphasized.

In terms of secondary outcomes, in the group of patients with a planned weekly dose of 4.8 mg survodutide, 83%, 69%, and 55% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

In the group of patients with an actual weekly dose of 4.8 mg survodutide, 98%, 82%, and 67% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

Moreover, 33% of patients in the group with a planned weekly dose of 4.8 mg survodutide and 38% of patients with an actual weekly dose of 4.8 mg survodutide lost ≥ 20% of their baseline body weight by week 46.

Adverse events occurred in 91% of patients in the survodutide groups and 75% in the placebo group. The most common side effects were nausea, vomiting, diarrhea, and constipation, which were mostly mild to moderate and mainly occurred during dose escalation. These effects may potentially be mitigated by more gradual dose escalation, Dr. Le Roux said.

There were no unexpected safety or tolerability concerns, and no serious drug-related adverse events.

These “encouraging data” support further study of survodutide for weight loss in larger phase 3 trials, Dr. Le Roux and colleagues conclude.
 

Survodutide has FDA fast track designation for NASH

Survodutide has received U.S. Food and Drug Administration Fast Track Designation for adults with NASH. The drug is currently being evaluated in a phase 2 study in adults with NASH and stages F1/F2/F3 liver fibrosis, with trial completion expected in the last quarter of 2023.

The current trial was funded by Boehringer Ingelheim. Dr. Le Roux has reported being on an advisory panel for Boehringer Ingelheim and being on advisory panels and receiving research funding from multiple other pharmaceutical companies. Two study authors are Boehringer Ingelheim employees.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Survodutide, a dual glucagonlike peptide–1 (GLP-1) and glucagon receptor agonist, led to “striking” weight loss in a phase 2 dosing trial in people with overweight/obesity but without type 2 diabetes.

Close to 40% of people who were taking the highest dose lost 20% or more of their starting weight at 46 weeks, Carel Le Roux, MBChB, PhD, reported at the annual scientific sessions of the American Diabetes Association.

Boehringer Ingelheim and Zealand Pharma are developing survodutide (formerly BI 456906) to treat obesity and nonalcoholic fatty liver disease (NAFLD), according to a company press release.

Glucagon receptor agonism increases energy expenditure, and GLP-1 receptor agonism inhibits appetite, both part of the mechanism of action, Dr. Le Roux, a professor at University College in Dublin, explained.

The trial showed a “striking” and clear dose-response in terms of weight loss, with no new unexpected safety signals, he reported.

Invited to comment, session moderator Elisabetta Patorno, MD, DrPH, noted that “Obesity is one of the main risk factors for [type 2] diabetes.”

“It’s very stimulating to see this new medication class make such a big impact on weight loss in such a short amount of time,” Dr. Patorno, associate professor of medicine at Harvard Medical School, Boston, said in an interview. However, whether the weight loss can be maintained over time remains to be determined in further research, she said.

Head-to-head weight-loss studies of the dual agonist survodutide versus the mono GLP-1 agonist semaglutide (Ozempic, Wegovy, Novo Nordisk) have not been conducted, Dr. Le Roux said during a press briefing.

“What we don’t know is if somebody doesn’t respond to [weight-loss drug] product A, will they respond to product B?” he said. Because survodutide acts on two types of receptors, “you could argue that you would not only increase the absolute amount of weight but you might also increase the number of patients who would respond, but that’s theoretical at the moment,” he explained.
 

Close to 400 patients, five doses, 46-week endpoint

The researchers randomized 387 adults aged 18-75 who had a body mass index (BMI) ≥ 27 kg/m² (overweight or obesity) without type 2 diabetes at sites in North America, Europe, Australia/New Zealand, and Asia.

On average, patients were 49 years old with a body weight of 106 kg (234 lb) and a BMI of 37 kg/m², and 68% were women.

They were randomized to receive a planned weekly subcutaneous maintenance survodutide dose of 0.6 mg (76 patients), 2.4 mg (78 patients), 3.6 mg (76 patients), or 4.8 mg (76 patients), or placebo (77 patients).

The dose was escalated rapidly (monthly) during a 20-week dose-escalation phase, followed by a 26-week maintenance phase.

Patients who did not reach the planned dose remained on a lower dose during the maintenance phase.

In terms of actual treatment, during the maintenance phase, 76 patients were taking placebo, 88 patients were taking 0.6 mg survodutide, 92 were taking 2.4 mg survodutide, 71 were taking 3.6 mg survodutide, and 54 were taking 4.8 mg survodutide, all given as weekly subcutaneous injections.

Primary outcome was the percentage change in body weight from baseline to week 46.

Secondary outcomes included the percentage of patients who reached a body weight reduction of ≥ 5%, ≥ 10%, and ≥ 15% from baseline to week 46.

Mean weight loss at 46 weeks in the planned treatment analysis (where some patients in each group were taking a lower than planned dose during maintenance) was 6.2% in the 0.6-mg survodutide group, 12.5% in the 2.4-mg group, 13.2% in the 3.6-mg group, 14.9% in the 4.8-mg group, and 2.8% in the placebo group.

Among participants who did reach and stay on their assigned dose during the maintenance phase, average weight loss was 6.8% in the 0.6-mg survodutide group,13.6% with 2.4 mg survodutide,16.7% with 3.6 mg survodutide, 18.6% with 4.8 mg survodutide, and 2.0% with placebo.

That is, patients reaching and staying on a weekly subcutaneous dose of 4.8 mg survodutide lost 18.6% of their body weight at 46 weeks, Dr. Le Roux emphasized.

In terms of secondary outcomes, in the group of patients with a planned weekly dose of 4.8 mg survodutide, 83%, 69%, and 55% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

In the group of patients with an actual weekly dose of 4.8 mg survodutide, 98%, 82%, and 67% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

Moreover, 33% of patients in the group with a planned weekly dose of 4.8 mg survodutide and 38% of patients with an actual weekly dose of 4.8 mg survodutide lost ≥ 20% of their baseline body weight by week 46.

Adverse events occurred in 91% of patients in the survodutide groups and 75% in the placebo group. The most common side effects were nausea, vomiting, diarrhea, and constipation, which were mostly mild to moderate and mainly occurred during dose escalation. These effects may potentially be mitigated by more gradual dose escalation, Dr. Le Roux said.

There were no unexpected safety or tolerability concerns, and no serious drug-related adverse events.

These “encouraging data” support further study of survodutide for weight loss in larger phase 3 trials, Dr. Le Roux and colleagues conclude.
 

Survodutide has FDA fast track designation for NASH

Survodutide has received U.S. Food and Drug Administration Fast Track Designation for adults with NASH. The drug is currently being evaluated in a phase 2 study in adults with NASH and stages F1/F2/F3 liver fibrosis, with trial completion expected in the last quarter of 2023.

The current trial was funded by Boehringer Ingelheim. Dr. Le Roux has reported being on an advisory panel for Boehringer Ingelheim and being on advisory panels and receiving research funding from multiple other pharmaceutical companies. Two study authors are Boehringer Ingelheim employees.

A version of this article first appeared on Medscape.com.

SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.

Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.

“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.

Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.

Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”  
 

Two meet primary endpoint, three more on the right path

The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.

The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.

Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.

Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.  
 

Safety: No major concerns thus far

Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.

Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”

However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”

Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”

In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.” 

Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands. 

The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.

A version of this article originally appeared on Medscape.com.

SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.

Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.

“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.

Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.

Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”  
 

Two meet primary endpoint, three more on the right path

The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.

The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.

Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.

Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.  
 

Safety: No major concerns thus far

Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.

Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”

However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”

Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”

In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.” 

Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands. 

The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.

A version of this article originally appeared on Medscape.com.

SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.

Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.

“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.

Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.

Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”  
 

Two meet primary endpoint, three more on the right path

The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.

The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.

Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.

Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.  
 

Safety: No major concerns thus far

Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.

Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”

However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”

Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”

In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.” 

Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands. 

The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.

A version of this article originally appeared on Medscape.com.