Endocrinology

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Mortality is two to three times higher in patients with adrenal incidentalomas who have autonomous cortisol secretion levels of 83 nmol/L (3 µg/dL) or more after a 1 mg dexamethasone suppression test (DST), compared with those with levels below this, new research finds.

Autonomous cortisol secretion (ACS) has been linked to hypertension, cardiovascular disease, type 2 diabetes, and early mortality, and risks vary by cortisol level.

“To adequately decide whether treatment should be surgery or medical management of possible complications, it is essential to know the risk associated with the actual level of ACS,” write Albin Kjellbom, MD, of Skåne University Hospital, Lund, Sweden, and colleagues, in their article published May 25 in Annals of Internal Medicine.

Asked to comment, Salila Kurra, MD, of the Columbia adrenal center, Columbia University, New York, told this news organization that “this idea that mild cortisol excess that doesn’t meet the threshold for overt Cushing’s can, in and of itself, cause increased morbidity and mortality is something people have been thinking about for many years now.”

“But there isn’t very clear guidance on exactly what to do in that situation, whether the incidentaloma should be removed, medically managed, or the patient should just be watched ... It may be clinically significant, but the way to sort that out is to do other testing.”   
 

Most deaths were from cardiovascular disease or cancer

Adrenal lesions are found incidentally in approximately 2% to 7% of the adult population who undergo abdominal imaging, and up to a third of those have ACS in the absence of clinical signs of Cushing syndrome.

European guidelines state that a plasma cortisol level of 138 nmol/L (5 µg/dL) or greater following DST defines ACS, and a level less than 50 nmol/L (1.8 µg/dL) rules it out, while values 50-137 (1.8-5 µg/dL) are deemed “possible” ACS.

For their study, the authors retrospectively analyzed 1,048 consecutive patients with adrenal incidentalomas seen at two Swedish hospitals between 2005 and September 2015 who were followed for up to 14 years.

The patients were a median age of 64.9 years, and 58.5% were women.

At baseline, 45.1% had a cortisol level of 50 nmol/L (1.8 µg/dL) or higher following DST, 52.9% had hypertension, 18.7% had diabetes, and 20.6% had a medical history of one or more cardiovascular events. A total of 54 patients underwent adrenalectomy, eight of them more than 2 years after the DST.

Researchers found a linear increase in mortality risk with increasing cortisol values up to 200 nmol/L (7.25 µg/dL) following DST.

Over 14 years, 16.2% (170 patients) died. Compared with cortisol less than 50 nmol/L (1.8 µg/dL) following DST, adjusted hazard ratios for mortality were 2.30 and 3.04 for cortisol levels 83 to 137 nmol/L (3-5 µg/dL) and 138 nmol/L (5 µg/dL) or greater, respectively, and both were significant.

Among the patients who died, causes of death were cardiovascular disease in 38%, cancer in 30%, infection in 4%, and other diseases in 28%.

Patients with post-DST cortisol levels of 83 nmol/L (3 µg/dL) or higher had increased cardiovascular mortality, while those with levels of 50-82 nmol/L (1.8-3.0 µg/dL) did not. In contrast, mortality rates from cancer, infection, and other diseases didn’t vary across groups.
 

Implications: Further testing, prospective studies needed

“The increase in mortality associated with cortisol DST values of 83 nmol/L or higher has implications,” the authors say.

“We suggest [medical] treatment of known cardiovascular risk factors in these patients and incorporation of our results in the decision about which patients to recommend for adrenalectomy.”

In contrast, ACS with lower cortisol (<83 nmol/L or 3 µg/dL) following DST “is not associated with clinically relevant increased mortality within 5 to 10 years,” they observe.

Dr. Kurra said she would perform further testing for any patient with an adrenal incidentaloma and a cortisol level 50-137 nmol/L (1.8-5 µg/dL) following DST: Specifically, a dehydroepiandrosterone sulfate (DHEAS) test.

“If DHEAS is low and the patient has metabolic complications, then I will work them up more, with adrenocorticotropin (ACTH) and 24-hour urine and go down that path of looking for the extent of overproduction of cortisol.”

She recommended an algorithm published in 2017 of an age- and sex-adjusted DHEAS ratio that provides a sensitive and specific screening test for subclinical hypercortisolism in patients with adrenal incidentalomas.

In further analyses by Dr. Kjellbom and colleagues into incidentaloma size, bilateralism, basal ACTH less than 2.0 pmol/L, or DHEAS less than 1.04 mmol/L, only DHEAS significantly predicted mortality.

“This should be studied further, specific to sex, age, and [post-DST]-cortisol strata,” Dr. Kjellbom and colleagues say.

In conclusion, Dr. Kurra said the new data “confirm something that people have postulated. But because it’s a retrospective review, we need prospective studies. It is an interesting finding that needs further study before we can change clinical practice.”

The study was funded by unrestricted grants from the Lisa and Johan Grönberg Foundation and the Gyllenstiernska Krapperup Foundation. Dr. Kjellbom and Dr. Kurra have reported no relevant financial relationships.

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

Mortality is two to three times higher in patients with adrenal incidentalomas who have autonomous cortisol secretion levels of 83 nmol/L (3 µg/dL) or more after a 1 mg dexamethasone suppression test (DST), compared with those with levels below this, new research finds.

Autonomous cortisol secretion (ACS) has been linked to hypertension, cardiovascular disease, type 2 diabetes, and early mortality, and risks vary by cortisol level.

“To adequately decide whether treatment should be surgery or medical management of possible complications, it is essential to know the risk associated with the actual level of ACS,” write Albin Kjellbom, MD, of Skåne University Hospital, Lund, Sweden, and colleagues, in their article published May 25 in Annals of Internal Medicine.

Asked to comment, Salila Kurra, MD, of the Columbia adrenal center, Columbia University, New York, told this news organization that “this idea that mild cortisol excess that doesn’t meet the threshold for overt Cushing’s can, in and of itself, cause increased morbidity and mortality is something people have been thinking about for many years now.”

“But there isn’t very clear guidance on exactly what to do in that situation, whether the incidentaloma should be removed, medically managed, or the patient should just be watched ... It may be clinically significant, but the way to sort that out is to do other testing.”   
 

Most deaths were from cardiovascular disease or cancer

Adrenal lesions are found incidentally in approximately 2% to 7% of the adult population who undergo abdominal imaging, and up to a third of those have ACS in the absence of clinical signs of Cushing syndrome.

European guidelines state that a plasma cortisol level of 138 nmol/L (5 µg/dL) or greater following DST defines ACS, and a level less than 50 nmol/L (1.8 µg/dL) rules it out, while values 50-137 (1.8-5 µg/dL) are deemed “possible” ACS.

For their study, the authors retrospectively analyzed 1,048 consecutive patients with adrenal incidentalomas seen at two Swedish hospitals between 2005 and September 2015 who were followed for up to 14 years.

The patients were a median age of 64.9 years, and 58.5% were women.

At baseline, 45.1% had a cortisol level of 50 nmol/L (1.8 µg/dL) or higher following DST, 52.9% had hypertension, 18.7% had diabetes, and 20.6% had a medical history of one or more cardiovascular events. A total of 54 patients underwent adrenalectomy, eight of them more than 2 years after the DST.

Researchers found a linear increase in mortality risk with increasing cortisol values up to 200 nmol/L (7.25 µg/dL) following DST.

Over 14 years, 16.2% (170 patients) died. Compared with cortisol less than 50 nmol/L (1.8 µg/dL) following DST, adjusted hazard ratios for mortality were 2.30 and 3.04 for cortisol levels 83 to 137 nmol/L (3-5 µg/dL) and 138 nmol/L (5 µg/dL) or greater, respectively, and both were significant.

Among the patients who died, causes of death were cardiovascular disease in 38%, cancer in 30%, infection in 4%, and other diseases in 28%.

Patients with post-DST cortisol levels of 83 nmol/L (3 µg/dL) or higher had increased cardiovascular mortality, while those with levels of 50-82 nmol/L (1.8-3.0 µg/dL) did not. In contrast, mortality rates from cancer, infection, and other diseases didn’t vary across groups.
 

Implications: Further testing, prospective studies needed

“The increase in mortality associated with cortisol DST values of 83 nmol/L or higher has implications,” the authors say.

“We suggest [medical] treatment of known cardiovascular risk factors in these patients and incorporation of our results in the decision about which patients to recommend for adrenalectomy.”

In contrast, ACS with lower cortisol (<83 nmol/L or 3 µg/dL) following DST “is not associated with clinically relevant increased mortality within 5 to 10 years,” they observe.

Dr. Kurra said she would perform further testing for any patient with an adrenal incidentaloma and a cortisol level 50-137 nmol/L (1.8-5 µg/dL) following DST: Specifically, a dehydroepiandrosterone sulfate (DHEAS) test.

“If DHEAS is low and the patient has metabolic complications, then I will work them up more, with adrenocorticotropin (ACTH) and 24-hour urine and go down that path of looking for the extent of overproduction of cortisol.”

She recommended an algorithm published in 2017 of an age- and sex-adjusted DHEAS ratio that provides a sensitive and specific screening test for subclinical hypercortisolism in patients with adrenal incidentalomas.

In further analyses by Dr. Kjellbom and colleagues into incidentaloma size, bilateralism, basal ACTH less than 2.0 pmol/L, or DHEAS less than 1.04 mmol/L, only DHEAS significantly predicted mortality.

“This should be studied further, specific to sex, age, and [post-DST]-cortisol strata,” Dr. Kjellbom and colleagues say.

In conclusion, Dr. Kurra said the new data “confirm something that people have postulated. But because it’s a retrospective review, we need prospective studies. It is an interesting finding that needs further study before we can change clinical practice.”

The study was funded by unrestricted grants from the Lisa and Johan Grönberg Foundation and the Gyllenstiernska Krapperup Foundation. Dr. Kjellbom and Dr. Kurra have reported no relevant financial relationships.

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

Mortality is two to three times higher in patients with adrenal incidentalomas who have autonomous cortisol secretion levels of 83 nmol/L (3 µg/dL) or more after a 1 mg dexamethasone suppression test (DST), compared with those with levels below this, new research finds.

Autonomous cortisol secretion (ACS) has been linked to hypertension, cardiovascular disease, type 2 diabetes, and early mortality, and risks vary by cortisol level.

“To adequately decide whether treatment should be surgery or medical management of possible complications, it is essential to know the risk associated with the actual level of ACS,” write Albin Kjellbom, MD, of Skåne University Hospital, Lund, Sweden, and colleagues, in their article published May 25 in Annals of Internal Medicine.

Asked to comment, Salila Kurra, MD, of the Columbia adrenal center, Columbia University, New York, told this news organization that “this idea that mild cortisol excess that doesn’t meet the threshold for overt Cushing’s can, in and of itself, cause increased morbidity and mortality is something people have been thinking about for many years now.”

“But there isn’t very clear guidance on exactly what to do in that situation, whether the incidentaloma should be removed, medically managed, or the patient should just be watched ... It may be clinically significant, but the way to sort that out is to do other testing.”   
 

Most deaths were from cardiovascular disease or cancer

Adrenal lesions are found incidentally in approximately 2% to 7% of the adult population who undergo abdominal imaging, and up to a third of those have ACS in the absence of clinical signs of Cushing syndrome.

European guidelines state that a plasma cortisol level of 138 nmol/L (5 µg/dL) or greater following DST defines ACS, and a level less than 50 nmol/L (1.8 µg/dL) rules it out, while values 50-137 (1.8-5 µg/dL) are deemed “possible” ACS.

For their study, the authors retrospectively analyzed 1,048 consecutive patients with adrenal incidentalomas seen at two Swedish hospitals between 2005 and September 2015 who were followed for up to 14 years.

The patients were a median age of 64.9 years, and 58.5% were women.

At baseline, 45.1% had a cortisol level of 50 nmol/L (1.8 µg/dL) or higher following DST, 52.9% had hypertension, 18.7% had diabetes, and 20.6% had a medical history of one or more cardiovascular events. A total of 54 patients underwent adrenalectomy, eight of them more than 2 years after the DST.

Researchers found a linear increase in mortality risk with increasing cortisol values up to 200 nmol/L (7.25 µg/dL) following DST.

Over 14 years, 16.2% (170 patients) died. Compared with cortisol less than 50 nmol/L (1.8 µg/dL) following DST, adjusted hazard ratios for mortality were 2.30 and 3.04 for cortisol levels 83 to 137 nmol/L (3-5 µg/dL) and 138 nmol/L (5 µg/dL) or greater, respectively, and both were significant.

Among the patients who died, causes of death were cardiovascular disease in 38%, cancer in 30%, infection in 4%, and other diseases in 28%.

Patients with post-DST cortisol levels of 83 nmol/L (3 µg/dL) or higher had increased cardiovascular mortality, while those with levels of 50-82 nmol/L (1.8-3.0 µg/dL) did not. In contrast, mortality rates from cancer, infection, and other diseases didn’t vary across groups.
 

Implications: Further testing, prospective studies needed

“The increase in mortality associated with cortisol DST values of 83 nmol/L or higher has implications,” the authors say.

“We suggest [medical] treatment of known cardiovascular risk factors in these patients and incorporation of our results in the decision about which patients to recommend for adrenalectomy.”

In contrast, ACS with lower cortisol (<83 nmol/L or 3 µg/dL) following DST “is not associated with clinically relevant increased mortality within 5 to 10 years,” they observe.

Dr. Kurra said she would perform further testing for any patient with an adrenal incidentaloma and a cortisol level 50-137 nmol/L (1.8-5 µg/dL) following DST: Specifically, a dehydroepiandrosterone sulfate (DHEAS) test.

“If DHEAS is low and the patient has metabolic complications, then I will work them up more, with adrenocorticotropin (ACTH) and 24-hour urine and go down that path of looking for the extent of overproduction of cortisol.”

She recommended an algorithm published in 2017 of an age- and sex-adjusted DHEAS ratio that provides a sensitive and specific screening test for subclinical hypercortisolism in patients with adrenal incidentalomas.

In further analyses by Dr. Kjellbom and colleagues into incidentaloma size, bilateralism, basal ACTH less than 2.0 pmol/L, or DHEAS less than 1.04 mmol/L, only DHEAS significantly predicted mortality.

“This should be studied further, specific to sex, age, and [post-DST]-cortisol strata,” Dr. Kjellbom and colleagues say.

In conclusion, Dr. Kurra said the new data “confirm something that people have postulated. But because it’s a retrospective review, we need prospective studies. It is an interesting finding that needs further study before we can change clinical practice.”

The study was funded by unrestricted grants from the Lisa and Johan Grönberg Foundation and the Gyllenstiernska Krapperup Foundation. Dr. Kjellbom and Dr. Kurra have reported no relevant financial relationships.

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

Internal medicine primarily affords us the skill to cope with disorders of chronicity that rarely disappear. For every pneumococcal pneumonia we eradicate, we have multiple patients with HIV who will be treated indefinitely. Diabetes, once a lethal disease, is now a chronic condition for most patients, and even with treatment the trajectory is usually one of progression.

One gratifying exception in my professional lifetime has been the introduction of gastric surgeries that reduce morbidity and seem to extend the life span of those who successfully undergo these procedures. The Roux-en-Y gastric bypass and sleeve gastrectomy have kept thousands of patients in better health for many years, giving them a second chance. For a subset, however, this second chance comes with a stumbling block of substance use – most notably alcohol – that exceeds their preoperative use.
 

Increased alcohol use after surgery

A group affiliated with the Department of Veterans Affairs (VA) recently reviewed the large central database to identify changes in alcohol consumption among patients who had undergone successful bariatric surgery. The VA regularly administers the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), a survey validated as a reliable estimate of individual alcohol consumption. It is inserted into the VA electronic health record where it can be readily retrieved. By matching these survey results with individuals who underwent bariatric surgery at the VA and survived at least 8 years post op, the authors were able to follow trends in alcohol consumption, beginning 2 years before surgery through 8 years after.

Using the same database, the authors identified a larger number of nonoperative control patients with slightly less obesity but otherwise matched for several elements of comorbidity, such as hypertension, certain psychiatric disorders, and personal habits, including alcohol consumption.

Alcohol use was categorized as none, minor social use, and “unhealthy” use. Among those with no or minor social use preoperatively, 4% converted to unhealthy use at 3 years and about 5% at 8 years, significantly more than in the nonoperative control group. Those who had gastric bypass had somewhat more conversion than did those who had sleeve gastrectomy, though not significantly so.

Patients with an alcohol concern preoperatively took an interesting course. Consumption declined from 2 years pre op to the year of surgery, suggesting that curtailing its use may have been a surgical precondition. Postoperatively, they returned to unhealthy drinking levels. Those who underwent the sleeve gastrectomy consumed about the same amount of alcohol as did their matched nonoperative controls, but those who underwent bypass increased their baseline unhealthy use beyond that of the controls.

Because total abstinence is often the recommendation for treating alcoholism, the research group assessed how adherent the excessive drinkers were to abstinence. In anticipation of surgery, the rates of abstinence increased until the year of surgery, but by 3 years post op, consumption was often up to unhealthy levels, though no more than that of control participants with preexisting drinking problems.
 

Smoking and illicit drug use

Although increased alcohol consumption has generated the most studies, some attention has been given to smoking and illicit drug use, which may also increase over time.

One small study looked at composite tobacco, alcohol, and drug use pre- and postoperatively over 2 years, using population data. The authors found a parallel pattern of users voluntarily reducing their substance use in anticipation of surgery but relapsing as the procedure made them more functional and perhaps more independent. Of the substances people resumed, alcohol by far involved the largest increase in use from the preoperative baseline.

These studies, as important as they are, reveal what happened more effectively than they disclose why it happened. The latter requires some clinical experience. Curtailing cigarettes and alcohol use preoperatively may have been done to stay in the good graces of the surgeon. Many patients may have seen this as their path to a second chance that they intended to maintain.

The incentive to proceed to surgical weight loss, which incurs a measure of risk and forces changes in long ingrained eating habits, involves avoiding future morbidity and promoting longevity. Thus, the postoperative behaviors that threaten the long-term goal need to become a component of ongoing follow-up.

The acquisition of adverse behaviors not present preoperatively seems more difficult to sort out, and obligates those of us following these patients to ask about changes in alcohol use and provide resources for them should they need intervention.

Dr. Plotzker is a retired endocrinologist with 40 years of experience treating patients in both private practice and hospital settings.

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

Internal medicine primarily affords us the skill to cope with disorders of chronicity that rarely disappear. For every pneumococcal pneumonia we eradicate, we have multiple patients with HIV who will be treated indefinitely. Diabetes, once a lethal disease, is now a chronic condition for most patients, and even with treatment the trajectory is usually one of progression.

One gratifying exception in my professional lifetime has been the introduction of gastric surgeries that reduce morbidity and seem to extend the life span of those who successfully undergo these procedures. The Roux-en-Y gastric bypass and sleeve gastrectomy have kept thousands of patients in better health for many years, giving them a second chance. For a subset, however, this second chance comes with a stumbling block of substance use – most notably alcohol – that exceeds their preoperative use.
 

Increased alcohol use after surgery

A group affiliated with the Department of Veterans Affairs (VA) recently reviewed the large central database to identify changes in alcohol consumption among patients who had undergone successful bariatric surgery. The VA regularly administers the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), a survey validated as a reliable estimate of individual alcohol consumption. It is inserted into the VA electronic health record where it can be readily retrieved. By matching these survey results with individuals who underwent bariatric surgery at the VA and survived at least 8 years post op, the authors were able to follow trends in alcohol consumption, beginning 2 years before surgery through 8 years after.

Using the same database, the authors identified a larger number of nonoperative control patients with slightly less obesity but otherwise matched for several elements of comorbidity, such as hypertension, certain psychiatric disorders, and personal habits, including alcohol consumption.

Alcohol use was categorized as none, minor social use, and “unhealthy” use. Among those with no or minor social use preoperatively, 4% converted to unhealthy use at 3 years and about 5% at 8 years, significantly more than in the nonoperative control group. Those who had gastric bypass had somewhat more conversion than did those who had sleeve gastrectomy, though not significantly so.

Patients with an alcohol concern preoperatively took an interesting course. Consumption declined from 2 years pre op to the year of surgery, suggesting that curtailing its use may have been a surgical precondition. Postoperatively, they returned to unhealthy drinking levels. Those who underwent the sleeve gastrectomy consumed about the same amount of alcohol as did their matched nonoperative controls, but those who underwent bypass increased their baseline unhealthy use beyond that of the controls.

Because total abstinence is often the recommendation for treating alcoholism, the research group assessed how adherent the excessive drinkers were to abstinence. In anticipation of surgery, the rates of abstinence increased until the year of surgery, but by 3 years post op, consumption was often up to unhealthy levels, though no more than that of control participants with preexisting drinking problems.
 

Smoking and illicit drug use

Although increased alcohol consumption has generated the most studies, some attention has been given to smoking and illicit drug use, which may also increase over time.

One small study looked at composite tobacco, alcohol, and drug use pre- and postoperatively over 2 years, using population data. The authors found a parallel pattern of users voluntarily reducing their substance use in anticipation of surgery but relapsing as the procedure made them more functional and perhaps more independent. Of the substances people resumed, alcohol by far involved the largest increase in use from the preoperative baseline.

These studies, as important as they are, reveal what happened more effectively than they disclose why it happened. The latter requires some clinical experience. Curtailing cigarettes and alcohol use preoperatively may have been done to stay in the good graces of the surgeon. Many patients may have seen this as their path to a second chance that they intended to maintain.

The incentive to proceed to surgical weight loss, which incurs a measure of risk and forces changes in long ingrained eating habits, involves avoiding future morbidity and promoting longevity. Thus, the postoperative behaviors that threaten the long-term goal need to become a component of ongoing follow-up.

The acquisition of adverse behaviors not present preoperatively seems more difficult to sort out, and obligates those of us following these patients to ask about changes in alcohol use and provide resources for them should they need intervention.

Dr. Plotzker is a retired endocrinologist with 40 years of experience treating patients in both private practice and hospital settings.

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

Internal medicine primarily affords us the skill to cope with disorders of chronicity that rarely disappear. For every pneumococcal pneumonia we eradicate, we have multiple patients with HIV who will be treated indefinitely. Diabetes, once a lethal disease, is now a chronic condition for most patients, and even with treatment the trajectory is usually one of progression.

One gratifying exception in my professional lifetime has been the introduction of gastric surgeries that reduce morbidity and seem to extend the life span of those who successfully undergo these procedures. The Roux-en-Y gastric bypass and sleeve gastrectomy have kept thousands of patients in better health for many years, giving them a second chance. For a subset, however, this second chance comes with a stumbling block of substance use – most notably alcohol – that exceeds their preoperative use.
 

Increased alcohol use after surgery

A group affiliated with the Department of Veterans Affairs (VA) recently reviewed the large central database to identify changes in alcohol consumption among patients who had undergone successful bariatric surgery. The VA regularly administers the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), a survey validated as a reliable estimate of individual alcohol consumption. It is inserted into the VA electronic health record where it can be readily retrieved. By matching these survey results with individuals who underwent bariatric surgery at the VA and survived at least 8 years post op, the authors were able to follow trends in alcohol consumption, beginning 2 years before surgery through 8 years after.

Using the same database, the authors identified a larger number of nonoperative control patients with slightly less obesity but otherwise matched for several elements of comorbidity, such as hypertension, certain psychiatric disorders, and personal habits, including alcohol consumption.

Alcohol use was categorized as none, minor social use, and “unhealthy” use. Among those with no or minor social use preoperatively, 4% converted to unhealthy use at 3 years and about 5% at 8 years, significantly more than in the nonoperative control group. Those who had gastric bypass had somewhat more conversion than did those who had sleeve gastrectomy, though not significantly so.

Patients with an alcohol concern preoperatively took an interesting course. Consumption declined from 2 years pre op to the year of surgery, suggesting that curtailing its use may have been a surgical precondition. Postoperatively, they returned to unhealthy drinking levels. Those who underwent the sleeve gastrectomy consumed about the same amount of alcohol as did their matched nonoperative controls, but those who underwent bypass increased their baseline unhealthy use beyond that of the controls.

Because total abstinence is often the recommendation for treating alcoholism, the research group assessed how adherent the excessive drinkers were to abstinence. In anticipation of surgery, the rates of abstinence increased until the year of surgery, but by 3 years post op, consumption was often up to unhealthy levels, though no more than that of control participants with preexisting drinking problems.
 

Smoking and illicit drug use

Although increased alcohol consumption has generated the most studies, some attention has been given to smoking and illicit drug use, which may also increase over time.

One small study looked at composite tobacco, alcohol, and drug use pre- and postoperatively over 2 years, using population data. The authors found a parallel pattern of users voluntarily reducing their substance use in anticipation of surgery but relapsing as the procedure made them more functional and perhaps more independent. Of the substances people resumed, alcohol by far involved the largest increase in use from the preoperative baseline.

These studies, as important as they are, reveal what happened more effectively than they disclose why it happened. The latter requires some clinical experience. Curtailing cigarettes and alcohol use preoperatively may have been done to stay in the good graces of the surgeon. Many patients may have seen this as their path to a second chance that they intended to maintain.

The incentive to proceed to surgical weight loss, which incurs a measure of risk and forces changes in long ingrained eating habits, involves avoiding future morbidity and promoting longevity. Thus, the postoperative behaviors that threaten the long-term goal need to become a component of ongoing follow-up.

The acquisition of adverse behaviors not present preoperatively seems more difficult to sort out, and obligates those of us following these patients to ask about changes in alcohol use and provide resources for them should they need intervention.

Dr. Plotzker is a retired endocrinologist with 40 years of experience treating patients in both private practice and hospital settings.

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

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

[email protected]

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

[email protected]

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

[email protected]

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

[email protected]

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

[email protected]

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

[email protected]

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

Primary care physicians are more likely to write a prescription for statins for their patients at risk for cardiovascular adverse events in the morning than in the afternoon, new research suggests.

RogerAshford/Thinkstock

In an observational cohort study, researchers from the nudge unit, University of Pennsylvania, Philadelphia, found that patients who had the first appointments of the day were most likely to have statins prescribed for them, and that this likelihood decreased as the day went on.

The study was published online May 11, 2021, in JAMA Network Open.

“Physicians are faced with decision fatigue, where they are seeing 20 patients in a day and may not have the mental bandwidth or cognitive bandwidth to fully think through every decision for every patient and to make all the appropriate decisions all of the time,” lead author Allison J. Hare, medical student and clinical informatics fellow in the nudge unit, said in an interview.

The Penn Medicine nudge unit attempts to better align clinician decision-making with current standards in best practices for the provision of various therapies, Ms. Hare explained.

“As we see more and more best-practice guidelines come out, we also see that there is a gap in the intention to treat and actual provision of these therapies,” she said. “There are also increasing expectations for clinicians to provide all of these different evidence-backed therapies. It can be hard to keep up with all these guidelines, especially when you are expected to take care of more and more patients, more and more efficiently.”

Guideline-directed statin therapy has been demonstrated to reduce the risk for major adverse cardiovascular events, yet 50% of statin-eligible patients have not been prescribed one.

“In our prior work at the nudge unit, we observed that rates of preventive care, including flu vaccination and cancer screening, declined as the clinic day progressed. We wanted to see if this occurred with statin scripts,” Ms. Hare said.

The researchers obtained data from 28 Penn Medicine primary care practices that included 10,757 patients at risk for heart disease for the period from March 2019 to February 2020.

Their mean age was 66.0 years (standard deviation, 10.5 years), 5,072 (47.2%) were female, and 7,071 (65.7%) were White. Patient characteristics were similar between morning and afternoon appointments.

All patients had clinical atherosclerotic cardiovascular disease, familial hypercholesterolemia, or LDL cholesterol of at least 190 mg/dL, conditions which qualified them for statins based on the U.S. Preventive Services Task Force guidelines.

The appointment times for each patient were broken down into hour blocks, ranging from the 8:00 a.m. hour to the 4:00 p.m. hour, which bookend open times in most practices.

Overall, statins were prescribed in 36% (n = 3,864) of visits.

The data showed a clear decline in statin prescribing as the day went on. For example, compared with patients who came in at 8:00 a.m. (the reference group), patients who came in at 9:00 a.m. were 12% less likely to get a prescription.

Patients coming in for noon appointments were 37% less likely to get a statin prescription, which made them the least likely to get a script. After the noon visits, there was a slight increase, but the likelihood of a statin prescription remained 27% less likely or worse for the rest of the day.

“In the context of the myriad tasks that clinicians are faced with doing for a single patient, and then also within the context of seeing 20 patients in 15-minute increments, it is easy to see how certain things fall through the cracks,” Ms. Hare said. “It’s impossible for any clinician to remember every single little thing for their patient every single time, so if we can augment the clinician’s ability to make those appropriate decisions with electronic tools, we can narrow that gap a little bit.”
 

Why the variability?

“The nudge unit uses prompts to ask the physician about prescribing statins. The question is, what is causing the variability in statin prescriptions?” Nieca Goldberg, MD, medical director of the New York University women’s heart program, said in an interview.

“Is it fatigue, lack of familiarity of guidelines, or is this due to the volume of patients and lack of time to discuss the therapy and make a shared decision with their patient? The answer to these questions was not part of the study,” said Dr. Goldberg, who is also an American Heart Association volunteer expert. “It would be interesting to know the thoughts of the physicians who were studied after they were informed of the results. Also, having a nudge to write the prescription will increase the prescriptions of statins, but will patients take the medication?”

The study was funded in part by a grant from the National Institute on Aging. Ms. Hare and Dr. Goldberg reported no relevant financial relationships.

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

Primary care physicians are more likely to write a prescription for statins for their patients at risk for cardiovascular adverse events in the morning than in the afternoon, new research suggests.

RogerAshford/Thinkstock

In an observational cohort study, researchers from the nudge unit, University of Pennsylvania, Philadelphia, found that patients who had the first appointments of the day were most likely to have statins prescribed for them, and that this likelihood decreased as the day went on.

The study was published online May 11, 2021, in JAMA Network Open.

“Physicians are faced with decision fatigue, where they are seeing 20 patients in a day and may not have the mental bandwidth or cognitive bandwidth to fully think through every decision for every patient and to make all the appropriate decisions all of the time,” lead author Allison J. Hare, medical student and clinical informatics fellow in the nudge unit, said in an interview.

The Penn Medicine nudge unit attempts to better align clinician decision-making with current standards in best practices for the provision of various therapies, Ms. Hare explained.

“As we see more and more best-practice guidelines come out, we also see that there is a gap in the intention to treat and actual provision of these therapies,” she said. “There are also increasing expectations for clinicians to provide all of these different evidence-backed therapies. It can be hard to keep up with all these guidelines, especially when you are expected to take care of more and more patients, more and more efficiently.”

Guideline-directed statin therapy has been demonstrated to reduce the risk for major adverse cardiovascular events, yet 50% of statin-eligible patients have not been prescribed one.

“In our prior work at the nudge unit, we observed that rates of preventive care, including flu vaccination and cancer screening, declined as the clinic day progressed. We wanted to see if this occurred with statin scripts,” Ms. Hare said.

The researchers obtained data from 28 Penn Medicine primary care practices that included 10,757 patients at risk for heart disease for the period from March 2019 to February 2020.

Their mean age was 66.0 years (standard deviation, 10.5 years), 5,072 (47.2%) were female, and 7,071 (65.7%) were White. Patient characteristics were similar between morning and afternoon appointments.

All patients had clinical atherosclerotic cardiovascular disease, familial hypercholesterolemia, or LDL cholesterol of at least 190 mg/dL, conditions which qualified them for statins based on the U.S. Preventive Services Task Force guidelines.

The appointment times for each patient were broken down into hour blocks, ranging from the 8:00 a.m. hour to the 4:00 p.m. hour, which bookend open times in most practices.

Overall, statins were prescribed in 36% (n = 3,864) of visits.

The data showed a clear decline in statin prescribing as the day went on. For example, compared with patients who came in at 8:00 a.m. (the reference group), patients who came in at 9:00 a.m. were 12% less likely to get a prescription.

Patients coming in for noon appointments were 37% less likely to get a statin prescription, which made them the least likely to get a script. After the noon visits, there was a slight increase, but the likelihood of a statin prescription remained 27% less likely or worse for the rest of the day.

“In the context of the myriad tasks that clinicians are faced with doing for a single patient, and then also within the context of seeing 20 patients in 15-minute increments, it is easy to see how certain things fall through the cracks,” Ms. Hare said. “It’s impossible for any clinician to remember every single little thing for their patient every single time, so if we can augment the clinician’s ability to make those appropriate decisions with electronic tools, we can narrow that gap a little bit.”
 

Why the variability?

“The nudge unit uses prompts to ask the physician about prescribing statins. The question is, what is causing the variability in statin prescriptions?” Nieca Goldberg, MD, medical director of the New York University women’s heart program, said in an interview.

“Is it fatigue, lack of familiarity of guidelines, or is this due to the volume of patients and lack of time to discuss the therapy and make a shared decision with their patient? The answer to these questions was not part of the study,” said Dr. Goldberg, who is also an American Heart Association volunteer expert. “It would be interesting to know the thoughts of the physicians who were studied after they were informed of the results. Also, having a nudge to write the prescription will increase the prescriptions of statins, but will patients take the medication?”

The study was funded in part by a grant from the National Institute on Aging. Ms. Hare and Dr. Goldberg reported no relevant financial relationships.

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

Primary care physicians are more likely to write a prescription for statins for their patients at risk for cardiovascular adverse events in the morning than in the afternoon, new research suggests.

RogerAshford/Thinkstock

In an observational cohort study, researchers from the nudge unit, University of Pennsylvania, Philadelphia, found that patients who had the first appointments of the day were most likely to have statins prescribed for them, and that this likelihood decreased as the day went on.

The study was published online May 11, 2021, in JAMA Network Open.

“Physicians are faced with decision fatigue, where they are seeing 20 patients in a day and may not have the mental bandwidth or cognitive bandwidth to fully think through every decision for every patient and to make all the appropriate decisions all of the time,” lead author Allison J. Hare, medical student and clinical informatics fellow in the nudge unit, said in an interview.

The Penn Medicine nudge unit attempts to better align clinician decision-making with current standards in best practices for the provision of various therapies, Ms. Hare explained.

“As we see more and more best-practice guidelines come out, we also see that there is a gap in the intention to treat and actual provision of these therapies,” she said. “There are also increasing expectations for clinicians to provide all of these different evidence-backed therapies. It can be hard to keep up with all these guidelines, especially when you are expected to take care of more and more patients, more and more efficiently.”

Guideline-directed statin therapy has been demonstrated to reduce the risk for major adverse cardiovascular events, yet 50% of statin-eligible patients have not been prescribed one.

“In our prior work at the nudge unit, we observed that rates of preventive care, including flu vaccination and cancer screening, declined as the clinic day progressed. We wanted to see if this occurred with statin scripts,” Ms. Hare said.

The researchers obtained data from 28 Penn Medicine primary care practices that included 10,757 patients at risk for heart disease for the period from March 2019 to February 2020.

Their mean age was 66.0 years (standard deviation, 10.5 years), 5,072 (47.2%) were female, and 7,071 (65.7%) were White. Patient characteristics were similar between morning and afternoon appointments.

All patients had clinical atherosclerotic cardiovascular disease, familial hypercholesterolemia, or LDL cholesterol of at least 190 mg/dL, conditions which qualified them for statins based on the U.S. Preventive Services Task Force guidelines.

The appointment times for each patient were broken down into hour blocks, ranging from the 8:00 a.m. hour to the 4:00 p.m. hour, which bookend open times in most practices.

Overall, statins were prescribed in 36% (n = 3,864) of visits.

The data showed a clear decline in statin prescribing as the day went on. For example, compared with patients who came in at 8:00 a.m. (the reference group), patients who came in at 9:00 a.m. were 12% less likely to get a prescription.

Patients coming in for noon appointments were 37% less likely to get a statin prescription, which made them the least likely to get a script. After the noon visits, there was a slight increase, but the likelihood of a statin prescription remained 27% less likely or worse for the rest of the day.

“In the context of the myriad tasks that clinicians are faced with doing for a single patient, and then also within the context of seeing 20 patients in 15-minute increments, it is easy to see how certain things fall through the cracks,” Ms. Hare said. “It’s impossible for any clinician to remember every single little thing for their patient every single time, so if we can augment the clinician’s ability to make those appropriate decisions with electronic tools, we can narrow that gap a little bit.”
 

Why the variability?

“The nudge unit uses prompts to ask the physician about prescribing statins. The question is, what is causing the variability in statin prescriptions?” Nieca Goldberg, MD, medical director of the New York University women’s heart program, said in an interview.

“Is it fatigue, lack of familiarity of guidelines, or is this due to the volume of patients and lack of time to discuss the therapy and make a shared decision with their patient? The answer to these questions was not part of the study,” said Dr. Goldberg, who is also an American Heart Association volunteer expert. “It would be interesting to know the thoughts of the physicians who were studied after they were informed of the results. Also, having a nudge to write the prescription will increase the prescriptions of statins, but will patients take the medication?”

The study was funded in part by a grant from the National Institute on Aging. Ms. Hare and Dr. Goldberg reported no relevant financial relationships.

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

No matter where an initial fracture occurs in a postmenopausal woman, there is a subsequent increased risk of another fracture, with the risk surprisingly highest in the youngest postmenopausal group and among certain minorities, new data indicate.

“To our knowledge, no previous prospective study has reported detailed patterns of subsequent fracture locations after initial fracture according to age strata among women in the U.S.,” the authors noted in their article, published online May 5, 2021, in EClinicalMedicine.

The results show that a first fracture of the lower arm or wrist; upper arm; or shoulder, upper leg, knee, lower leg, or ankle – as well as those of the hip or pelvis – were associated with an approximately three- to sixfold increased risk for subsequent fractures. The findings have important implications for clinicians, said lead author Carolyn J. Crandall, MD, professor of medicine at the University of California, Los Angeles.

“By not paying attention to which types of fractures increase the risk of future fractures, we are missing the opportunity to identify people at increased risk of future fracture and counsel them regarding risk reduction,” she said in a press statement.

Commenting on the research, Michael R. McClung, MD, stressed this message to clinicians needs to be underscored.

“This paper is one of a series of papers highlighting the fact that having a previous fracture is a risk factor for subsequent fractures,” he said in an interview.

“This has been known for a very long time, but it is a point still not appreciated by patients and primary care doctors, so having another study pointing this out is important,” emphasized Dr. McClung, of the Oregon Osteoporosis Center in Portland.
 

30% of women’s health initiative participants had a fracture

For the study, Dr. Crandall and colleagues evaluated data on 157,282 women between the ages of 50 and 79 who were enrolled in the Women’s Health Initiative between 1993 and 2018.

The women were a mean age of 63.1 years and 47,126 (30%) experienced an incident fracture during the study period.

With a mean follow-up of 15.4 years, each type of fracture was associated with an increased risk of a subsequent fracture after adjusting for age, race/ethnicity, body mass index, hormone therapy use, and other factors.

A wide range of initial risk fractures – including an initial lower arm or wrist fracture (adjusted hazard ratio, 4.80), upper arm or shoulder fracture (aHR, 5.06), upper leg fracture (aHR, 5.11), knee fracture (aHR, 5.03), lower leg/ankle fracture (aHR, 4.10), and spinal fracture (aHR, 6.69) – increased the risk of sustaining a subsequent hip fracture. 

For initial fractures of the lower arm or wrist, there was an increased risk of a subsequent fracture of the upper arm/shoulder, upper leg, knee, lower leg/ankle, hip/pelvis, and spine (aHRs ranged from 2.63 to 5.68). 

“The finding that knee fracture has the same prognostic value for subsequent fracture as hip or wrist fracture is a novel key finding, as knee fracture is generally not considered ‘osteoporotic’,” the authors noted.

The risk of fracture after sustaining an initial hip or pelvis fracture was exceptionally high – with as much as a 27-fold higher risk of a subsequent upper leg (nonhip) fracture (aHR, 27.18).

“Thirty-four percent of women who experienced initial hip or pelvis fracture experienced a subsequent nonhip fracture,” the authors noted.

However, the risks associated with an initial hip fracture are already well established, and the study’s more notable findings are the risks of other bone breaks, Dr. Crandall told this news organization.

“The (increased risk with hip fracture) is a rather substantial result,” she said. “However, the more major point of this study is that no matter where the initial fracture happened, the risk of the future fracture was elevated.”
 

Don’t disregard risks in younger women, racial/ethnic groups

The findings regarding age are also important. The highest risk was observed in the youngest postmenopausal age group of 50-59 years (aHR, 6.45), which decreased slightly in the 60- to 69-year age group (aHR, 6.04) and further decreased in the 70- to 79-year age group (aHR, 4.99).

“This was a surprise, and it highlights that clinicians should not disregard initial fractures among young postmenopausal women,” Dr. Crandall told this news organization.

Even greater increased risks for a subsequent fracture following an initial lower extremity fracture were observed in non-Hispanic Black women, Hispanic or Latina women, and women of Asian Pacific Islander ethnicity, ranging from ninefold to 14-fold, versus a sevenfold risk among non-Hispanic White women.

“This has public health implications because it means that we may have been missing the opportunity to prevent fractures among younger postmenopausal women and underrepresented racial/ethnic groups,” Dr. Crandall noted.

Is risk greatest 1-2 years after the initial fracture?

The findings suggest that current treatment guidelines may need to be revisited in light of inconsistencies regarding when, and for which fracture types, to initiate treatment.

“It will be important to determine whether existing risk calculators can be adapted (or new calculators developed) to help refine decision-making to determine which of the women with fractures other than hip or vertebral fractures should be treated,” the authors wrote.

Dr. McClung said a randomized, controlled trial of osteoporosis treatment in people who present with all types of fractures would help determine whether having a knee or a wrist fracture does indeed warrant such therapy.

He further commented that future studies should evaluate the shorter- versus longer-term risks.

“The most recent research suggests that the risk of having a second fracture is much higher in the first year or 2 after the first or incident fracture,” he observed. “So, the next stage in research with this dataset would be to ask not what happens over a 10-year time frame but what happens over the first year or 2 after the fracture.”

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Crandall reported no relevant financial relationships. Dr. McClung reported being a consultant and on the speakers bureau for Amgen and being a speaker for Alexion.

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

No matter where an initial fracture occurs in a postmenopausal woman, there is a subsequent increased risk of another fracture, with the risk surprisingly highest in the youngest postmenopausal group and among certain minorities, new data indicate.

“To our knowledge, no previous prospective study has reported detailed patterns of subsequent fracture locations after initial fracture according to age strata among women in the U.S.,” the authors noted in their article, published online May 5, 2021, in EClinicalMedicine.

The results show that a first fracture of the lower arm or wrist; upper arm; or shoulder, upper leg, knee, lower leg, or ankle – as well as those of the hip or pelvis – were associated with an approximately three- to sixfold increased risk for subsequent fractures. The findings have important implications for clinicians, said lead author Carolyn J. Crandall, MD, professor of medicine at the University of California, Los Angeles.

“By not paying attention to which types of fractures increase the risk of future fractures, we are missing the opportunity to identify people at increased risk of future fracture and counsel them regarding risk reduction,” she said in a press statement.

Commenting on the research, Michael R. McClung, MD, stressed this message to clinicians needs to be underscored.

“This paper is one of a series of papers highlighting the fact that having a previous fracture is a risk factor for subsequent fractures,” he said in an interview.

“This has been known for a very long time, but it is a point still not appreciated by patients and primary care doctors, so having another study pointing this out is important,” emphasized Dr. McClung, of the Oregon Osteoporosis Center in Portland.
 

30% of women’s health initiative participants had a fracture

For the study, Dr. Crandall and colleagues evaluated data on 157,282 women between the ages of 50 and 79 who were enrolled in the Women’s Health Initiative between 1993 and 2018.

The women were a mean age of 63.1 years and 47,126 (30%) experienced an incident fracture during the study period.

With a mean follow-up of 15.4 years, each type of fracture was associated with an increased risk of a subsequent fracture after adjusting for age, race/ethnicity, body mass index, hormone therapy use, and other factors.

A wide range of initial risk fractures – including an initial lower arm or wrist fracture (adjusted hazard ratio, 4.80), upper arm or shoulder fracture (aHR, 5.06), upper leg fracture (aHR, 5.11), knee fracture (aHR, 5.03), lower leg/ankle fracture (aHR, 4.10), and spinal fracture (aHR, 6.69) – increased the risk of sustaining a subsequent hip fracture. 

For initial fractures of the lower arm or wrist, there was an increased risk of a subsequent fracture of the upper arm/shoulder, upper leg, knee, lower leg/ankle, hip/pelvis, and spine (aHRs ranged from 2.63 to 5.68). 

“The finding that knee fracture has the same prognostic value for subsequent fracture as hip or wrist fracture is a novel key finding, as knee fracture is generally not considered ‘osteoporotic’,” the authors noted.

The risk of fracture after sustaining an initial hip or pelvis fracture was exceptionally high – with as much as a 27-fold higher risk of a subsequent upper leg (nonhip) fracture (aHR, 27.18).

“Thirty-four percent of women who experienced initial hip or pelvis fracture experienced a subsequent nonhip fracture,” the authors noted.

However, the risks associated with an initial hip fracture are already well established, and the study’s more notable findings are the risks of other bone breaks, Dr. Crandall told this news organization.

“The (increased risk with hip fracture) is a rather substantial result,” she said. “However, the more major point of this study is that no matter where the initial fracture happened, the risk of the future fracture was elevated.”
 

Don’t disregard risks in younger women, racial/ethnic groups

The findings regarding age are also important. The highest risk was observed in the youngest postmenopausal age group of 50-59 years (aHR, 6.45), which decreased slightly in the 60- to 69-year age group (aHR, 6.04) and further decreased in the 70- to 79-year age group (aHR, 4.99).

“This was a surprise, and it highlights that clinicians should not disregard initial fractures among young postmenopausal women,” Dr. Crandall told this news organization.

Even greater increased risks for a subsequent fracture following an initial lower extremity fracture were observed in non-Hispanic Black women, Hispanic or Latina women, and women of Asian Pacific Islander ethnicity, ranging from ninefold to 14-fold, versus a sevenfold risk among non-Hispanic White women.

“This has public health implications because it means that we may have been missing the opportunity to prevent fractures among younger postmenopausal women and underrepresented racial/ethnic groups,” Dr. Crandall noted.

Is risk greatest 1-2 years after the initial fracture?

The findings suggest that current treatment guidelines may need to be revisited in light of inconsistencies regarding when, and for which fracture types, to initiate treatment.

“It will be important to determine whether existing risk calculators can be adapted (or new calculators developed) to help refine decision-making to determine which of the women with fractures other than hip or vertebral fractures should be treated,” the authors wrote.

Dr. McClung said a randomized, controlled trial of osteoporosis treatment in people who present with all types of fractures would help determine whether having a knee or a wrist fracture does indeed warrant such therapy.

He further commented that future studies should evaluate the shorter- versus longer-term risks.

“The most recent research suggests that the risk of having a second fracture is much higher in the first year or 2 after the first or incident fracture,” he observed. “So, the next stage in research with this dataset would be to ask not what happens over a 10-year time frame but what happens over the first year or 2 after the fracture.”

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Crandall reported no relevant financial relationships. Dr. McClung reported being a consultant and on the speakers bureau for Amgen and being a speaker for Alexion.

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

No matter where an initial fracture occurs in a postmenopausal woman, there is a subsequent increased risk of another fracture, with the risk surprisingly highest in the youngest postmenopausal group and among certain minorities, new data indicate.

“To our knowledge, no previous prospective study has reported detailed patterns of subsequent fracture locations after initial fracture according to age strata among women in the U.S.,” the authors noted in their article, published online May 5, 2021, in EClinicalMedicine.

The results show that a first fracture of the lower arm or wrist; upper arm; or shoulder, upper leg, knee, lower leg, or ankle – as well as those of the hip or pelvis – were associated with an approximately three- to sixfold increased risk for subsequent fractures. The findings have important implications for clinicians, said lead author Carolyn J. Crandall, MD, professor of medicine at the University of California, Los Angeles.

“By not paying attention to which types of fractures increase the risk of future fractures, we are missing the opportunity to identify people at increased risk of future fracture and counsel them regarding risk reduction,” she said in a press statement.

Commenting on the research, Michael R. McClung, MD, stressed this message to clinicians needs to be underscored.

“This paper is one of a series of papers highlighting the fact that having a previous fracture is a risk factor for subsequent fractures,” he said in an interview.

“This has been known for a very long time, but it is a point still not appreciated by patients and primary care doctors, so having another study pointing this out is important,” emphasized Dr. McClung, of the Oregon Osteoporosis Center in Portland.
 

30% of women’s health initiative participants had a fracture

For the study, Dr. Crandall and colleagues evaluated data on 157,282 women between the ages of 50 and 79 who were enrolled in the Women’s Health Initiative between 1993 and 2018.

The women were a mean age of 63.1 years and 47,126 (30%) experienced an incident fracture during the study period.

With a mean follow-up of 15.4 years, each type of fracture was associated with an increased risk of a subsequent fracture after adjusting for age, race/ethnicity, body mass index, hormone therapy use, and other factors.

A wide range of initial risk fractures – including an initial lower arm or wrist fracture (adjusted hazard ratio, 4.80), upper arm or shoulder fracture (aHR, 5.06), upper leg fracture (aHR, 5.11), knee fracture (aHR, 5.03), lower leg/ankle fracture (aHR, 4.10), and spinal fracture (aHR, 6.69) – increased the risk of sustaining a subsequent hip fracture. 

For initial fractures of the lower arm or wrist, there was an increased risk of a subsequent fracture of the upper arm/shoulder, upper leg, knee, lower leg/ankle, hip/pelvis, and spine (aHRs ranged from 2.63 to 5.68). 

“The finding that knee fracture has the same prognostic value for subsequent fracture as hip or wrist fracture is a novel key finding, as knee fracture is generally not considered ‘osteoporotic’,” the authors noted.

The risk of fracture after sustaining an initial hip or pelvis fracture was exceptionally high – with as much as a 27-fold higher risk of a subsequent upper leg (nonhip) fracture (aHR, 27.18).

“Thirty-four percent of women who experienced initial hip or pelvis fracture experienced a subsequent nonhip fracture,” the authors noted.

However, the risks associated with an initial hip fracture are already well established, and the study’s more notable findings are the risks of other bone breaks, Dr. Crandall told this news organization.

“The (increased risk with hip fracture) is a rather substantial result,” she said. “However, the more major point of this study is that no matter where the initial fracture happened, the risk of the future fracture was elevated.”
 

Don’t disregard risks in younger women, racial/ethnic groups

The findings regarding age are also important. The highest risk was observed in the youngest postmenopausal age group of 50-59 years (aHR, 6.45), which decreased slightly in the 60- to 69-year age group (aHR, 6.04) and further decreased in the 70- to 79-year age group (aHR, 4.99).

“This was a surprise, and it highlights that clinicians should not disregard initial fractures among young postmenopausal women,” Dr. Crandall told this news organization.

Even greater increased risks for a subsequent fracture following an initial lower extremity fracture were observed in non-Hispanic Black women, Hispanic or Latina women, and women of Asian Pacific Islander ethnicity, ranging from ninefold to 14-fold, versus a sevenfold risk among non-Hispanic White women.

“This has public health implications because it means that we may have been missing the opportunity to prevent fractures among younger postmenopausal women and underrepresented racial/ethnic groups,” Dr. Crandall noted.

Is risk greatest 1-2 years after the initial fracture?

The findings suggest that current treatment guidelines may need to be revisited in light of inconsistencies regarding when, and for which fracture types, to initiate treatment.

“It will be important to determine whether existing risk calculators can be adapted (or new calculators developed) to help refine decision-making to determine which of the women with fractures other than hip or vertebral fractures should be treated,” the authors wrote.

Dr. McClung said a randomized, controlled trial of osteoporosis treatment in people who present with all types of fractures would help determine whether having a knee or a wrist fracture does indeed warrant such therapy.

He further commented that future studies should evaluate the shorter- versus longer-term risks.

“The most recent research suggests that the risk of having a second fracture is much higher in the first year or 2 after the first or incident fracture,” he observed. “So, the next stage in research with this dataset would be to ask not what happens over a 10-year time frame but what happens over the first year or 2 after the fracture.”

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Crandall reported no relevant financial relationships. Dr. McClung reported being a consultant and on the speakers bureau for Amgen and being a speaker for Alexion.

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