Type 2 Diabetes ICYMI

The more fast food restaurants a person lives near in the United States, the more likely they are to develop type 2 diabetes, new research indicates.  

The national study of more than 4 million U.S. veterans also found the opposite association with supermarkets in suburban and rural communities but not others.

“Neighborhood food environment was associated with type 2 diabetes risk among U.S. veterans in multiple community types, suggesting potential avenues for action to address the burden of type 2 diabetes,” say Rania Kanchi, MPH, of the department of population health, New York University Langone Health, and colleagues.

Restriction of fast food establishments could benefit all types of communities, while interventions to increase supermarket availability could help minimize diabetes risk in suburban and rural communities, they stress.

“These actions, combined with increasing awareness of the risk of type 2 diabetes and the importance of healthy diet intake, might be associated with a decrease in the burden of type 2 diabetes among adults in the U.S.,” the researchers add.

The data were published online Oct. 29 in JAMA Network Open.

“The more we learn about the relationship between the food environment and chronic diseases like type 2 diabetes, the more policymakers can act by improving the mix of healthy food options sold in restaurants and food outlets, or by creating better zoning laws that promote optimal food options for residents,” commented Lorna Thorpe, PhD, MPH, professor in the department of population health at NYU Langone and senior author of the study in a press release.

In an accompanying editorial, Elham Hatef, MD, MPH, of the Center for Population Health IT at Johns Hopkins Bloomberg School of Public Health, Baltimore, calls the study “a great example of the capabilities of [health information technology] to provide a comprehensive assessment of a person’s health, which goes beyond just documenting clinical diseases and medical interventions.”
 

Research has large geographic breadth

The study is notable for its large geographic breadth, say the researchers.

“Most studies that examine the built food environment and its relationship to chronic diseases have been much smaller or conducted in localized areas,” Ms. Kanchi said in the press statement.

“Our study design is national in scope and allowed us to identify the types of communities that people are living in, characterize their food environment, and observe what happens to them over time. The size of our cohort allows for geographic generalizability in a way that other studies do not,” Ms. Kanchi continued.

The research included data for 4,100,650 individuals from the Veterans Affairs electronic health records (EHRs) who didn’t have type 2 diabetes at baseline, between 2008 and 2016. After a median follow-up of 5.5 person-years, 13.2% developed type 2 diabetes. Cumulative incidence was greater among those who were older, those who were non-Hispanic Black compared with other races, and those with disabilities and lower incomes.

The proportion of adults with type 2 diabetes was highest among those living in high-density urban communities (14.3%), followed by low-density urban (13.1%), rural (13.2%), and suburban (12.6%) communities.

Overall, a 10% increase in the number of fast food restaurants compared with other food establishments in a given neighborhood was associated with a 1% increased risk for incident type 2 diabetes in high-density urban, low-density urban, and rural communities and a 2% increased risk in suburban communities.

In contrast, a 10% increase in supermarket density compared with other food stores was associated with a lower risk for type 2 diabetes in suburban and rural communities, but the association wasn’t significant elsewhere.

“Taken together, our findings suggest that policies specific to fast food restaurants, such as [those] ... restricting the siting of fast food restaurants and healthy beverage default laws, may be effective in reducing type 2 diabetes risk in all community types,” say the authors.

“In urban areas where population and retail density are growing, it will be even more important to focus on these policies,” they emphasize.
 

Great example of capabilities of health information technology

In the editorial, Dr. Hatef notes that methodological advances, such as natural language processing and machine learning, have enabled health systems to use real-world data such as the free-text notes in the EHR to identify patient-level risk factors for diseases or disease complications.

Such methods could be further used to “evaluate the associations between social needs and place-based [social determinants of health] and type 2 diabetes incidence and management,” Dr. Hatef adds.

And linkage of data from the EHR to such community-level data “would help to comprehensively assess and identify patients likely to experience type 2 diabetes and its complications as a result of their risk factors or characteristics of the neighborhoods where they reside.”

“This approach could foster collaborations between the health systems and at-risk communities they serve and help to reallocate health system resources to those in most need in the community to reduce the burden of type 2 diabetes and other chronic conditions among racial minority groups and socioeconomically disadvantaged patients and to advance population health.”

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Aging, the Commonwealth Universal Research Enhancement program funded by the Pennsylvania Department of Health, the Urban Health Collaborative at Drexel University, and the Built Environment and Health Research Group at Columbia University. Ms. Kanchi and Dr. Hatef have reported no relevant financial relationships.

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

The more fast food restaurants a person lives near in the United States, the more likely they are to develop type 2 diabetes, new research indicates.  

The national study of more than 4 million U.S. veterans also found the opposite association with supermarkets in suburban and rural communities but not others.

“Neighborhood food environment was associated with type 2 diabetes risk among U.S. veterans in multiple community types, suggesting potential avenues for action to address the burden of type 2 diabetes,” say Rania Kanchi, MPH, of the department of population health, New York University Langone Health, and colleagues.

Restriction of fast food establishments could benefit all types of communities, while interventions to increase supermarket availability could help minimize diabetes risk in suburban and rural communities, they stress.

“These actions, combined with increasing awareness of the risk of type 2 diabetes and the importance of healthy diet intake, might be associated with a decrease in the burden of type 2 diabetes among adults in the U.S.,” the researchers add.

The data were published online Oct. 29 in JAMA Network Open.

“The more we learn about the relationship between the food environment and chronic diseases like type 2 diabetes, the more policymakers can act by improving the mix of healthy food options sold in restaurants and food outlets, or by creating better zoning laws that promote optimal food options for residents,” commented Lorna Thorpe, PhD, MPH, professor in the department of population health at NYU Langone and senior author of the study in a press release.

In an accompanying editorial, Elham Hatef, MD, MPH, of the Center for Population Health IT at Johns Hopkins Bloomberg School of Public Health, Baltimore, calls the study “a great example of the capabilities of [health information technology] to provide a comprehensive assessment of a person’s health, which goes beyond just documenting clinical diseases and medical interventions.”
 

Research has large geographic breadth

The study is notable for its large geographic breadth, say the researchers.

“Most studies that examine the built food environment and its relationship to chronic diseases have been much smaller or conducted in localized areas,” Ms. Kanchi said in the press statement.

“Our study design is national in scope and allowed us to identify the types of communities that people are living in, characterize their food environment, and observe what happens to them over time. The size of our cohort allows for geographic generalizability in a way that other studies do not,” Ms. Kanchi continued.

The research included data for 4,100,650 individuals from the Veterans Affairs electronic health records (EHRs) who didn’t have type 2 diabetes at baseline, between 2008 and 2016. After a median follow-up of 5.5 person-years, 13.2% developed type 2 diabetes. Cumulative incidence was greater among those who were older, those who were non-Hispanic Black compared with other races, and those with disabilities and lower incomes.

The proportion of adults with type 2 diabetes was highest among those living in high-density urban communities (14.3%), followed by low-density urban (13.1%), rural (13.2%), and suburban (12.6%) communities.

Overall, a 10% increase in the number of fast food restaurants compared with other food establishments in a given neighborhood was associated with a 1% increased risk for incident type 2 diabetes in high-density urban, low-density urban, and rural communities and a 2% increased risk in suburban communities.

In contrast, a 10% increase in supermarket density compared with other food stores was associated with a lower risk for type 2 diabetes in suburban and rural communities, but the association wasn’t significant elsewhere.

“Taken together, our findings suggest that policies specific to fast food restaurants, such as [those] ... restricting the siting of fast food restaurants and healthy beverage default laws, may be effective in reducing type 2 diabetes risk in all community types,” say the authors.

“In urban areas where population and retail density are growing, it will be even more important to focus on these policies,” they emphasize.
 

Great example of capabilities of health information technology

In the editorial, Dr. Hatef notes that methodological advances, such as natural language processing and machine learning, have enabled health systems to use real-world data such as the free-text notes in the EHR to identify patient-level risk factors for diseases or disease complications.

Such methods could be further used to “evaluate the associations between social needs and place-based [social determinants of health] and type 2 diabetes incidence and management,” Dr. Hatef adds.

And linkage of data from the EHR to such community-level data “would help to comprehensively assess and identify patients likely to experience type 2 diabetes and its complications as a result of their risk factors or characteristics of the neighborhoods where they reside.”

“This approach could foster collaborations between the health systems and at-risk communities they serve and help to reallocate health system resources to those in most need in the community to reduce the burden of type 2 diabetes and other chronic conditions among racial minority groups and socioeconomically disadvantaged patients and to advance population health.”

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Aging, the Commonwealth Universal Research Enhancement program funded by the Pennsylvania Department of Health, the Urban Health Collaborative at Drexel University, and the Built Environment and Health Research Group at Columbia University. Ms. Kanchi and Dr. Hatef have reported no relevant financial relationships.

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

The more fast food restaurants a person lives near in the United States, the more likely they are to develop type 2 diabetes, new research indicates.  

The national study of more than 4 million U.S. veterans also found the opposite association with supermarkets in suburban and rural communities but not others.

“Neighborhood food environment was associated with type 2 diabetes risk among U.S. veterans in multiple community types, suggesting potential avenues for action to address the burden of type 2 diabetes,” say Rania Kanchi, MPH, of the department of population health, New York University Langone Health, and colleagues.

Restriction of fast food establishments could benefit all types of communities, while interventions to increase supermarket availability could help minimize diabetes risk in suburban and rural communities, they stress.

“These actions, combined with increasing awareness of the risk of type 2 diabetes and the importance of healthy diet intake, might be associated with a decrease in the burden of type 2 diabetes among adults in the U.S.,” the researchers add.

The data were published online Oct. 29 in JAMA Network Open.

“The more we learn about the relationship between the food environment and chronic diseases like type 2 diabetes, the more policymakers can act by improving the mix of healthy food options sold in restaurants and food outlets, or by creating better zoning laws that promote optimal food options for residents,” commented Lorna Thorpe, PhD, MPH, professor in the department of population health at NYU Langone and senior author of the study in a press release.

In an accompanying editorial, Elham Hatef, MD, MPH, of the Center for Population Health IT at Johns Hopkins Bloomberg School of Public Health, Baltimore, calls the study “a great example of the capabilities of [health information technology] to provide a comprehensive assessment of a person’s health, which goes beyond just documenting clinical diseases and medical interventions.”
 

Research has large geographic breadth

The study is notable for its large geographic breadth, say the researchers.

“Most studies that examine the built food environment and its relationship to chronic diseases have been much smaller or conducted in localized areas,” Ms. Kanchi said in the press statement.

“Our study design is national in scope and allowed us to identify the types of communities that people are living in, characterize their food environment, and observe what happens to them over time. The size of our cohort allows for geographic generalizability in a way that other studies do not,” Ms. Kanchi continued.

The research included data for 4,100,650 individuals from the Veterans Affairs electronic health records (EHRs) who didn’t have type 2 diabetes at baseline, between 2008 and 2016. After a median follow-up of 5.5 person-years, 13.2% developed type 2 diabetes. Cumulative incidence was greater among those who were older, those who were non-Hispanic Black compared with other races, and those with disabilities and lower incomes.

The proportion of adults with type 2 diabetes was highest among those living in high-density urban communities (14.3%), followed by low-density urban (13.1%), rural (13.2%), and suburban (12.6%) communities.

Overall, a 10% increase in the number of fast food restaurants compared with other food establishments in a given neighborhood was associated with a 1% increased risk for incident type 2 diabetes in high-density urban, low-density urban, and rural communities and a 2% increased risk in suburban communities.

In contrast, a 10% increase in supermarket density compared with other food stores was associated with a lower risk for type 2 diabetes in suburban and rural communities, but the association wasn’t significant elsewhere.

“Taken together, our findings suggest that policies specific to fast food restaurants, such as [those] ... restricting the siting of fast food restaurants and healthy beverage default laws, may be effective in reducing type 2 diabetes risk in all community types,” say the authors.

“In urban areas where population and retail density are growing, it will be even more important to focus on these policies,” they emphasize.
 

Great example of capabilities of health information technology

In the editorial, Dr. Hatef notes that methodological advances, such as natural language processing and machine learning, have enabled health systems to use real-world data such as the free-text notes in the EHR to identify patient-level risk factors for diseases or disease complications.

Such methods could be further used to “evaluate the associations between social needs and place-based [social determinants of health] and type 2 diabetes incidence and management,” Dr. Hatef adds.

And linkage of data from the EHR to such community-level data “would help to comprehensively assess and identify patients likely to experience type 2 diabetes and its complications as a result of their risk factors or characteristics of the neighborhoods where they reside.”

“This approach could foster collaborations between the health systems and at-risk communities they serve and help to reallocate health system resources to those in most need in the community to reduce the burden of type 2 diabetes and other chronic conditions among racial minority groups and socioeconomically disadvantaged patients and to advance population health.”

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Aging, the Commonwealth Universal Research Enhancement program funded by the Pennsylvania Department of Health, the Urban Health Collaborative at Drexel University, and the Built Environment and Health Research Group at Columbia University. Ms. Kanchi and Dr. Hatef have reported no relevant financial relationships.

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

A novel investigational allogeneic stem cell–derived treatment resulted in near reversal of type 1 diabetes in a patient who had lived with the condition for about 40 years.

CIPhotos/Getty Images

The patient was the first in Vertex Pharmaceuticals’ phase 1/2 multicenter, single-arm, open-label clinical trial of the insulin-producing islet cell therapy VX-880 for patients with type 1 diabetes who have impaired hypoglycemic awareness and severe hypoglycemia.

The cells are delivered by infusion into the hepatic portal vein. As of now, chronic immunosuppression is required to prevent rejection, but several approaches are being studied to overcome the limitation.

“There’s hope that this is a real advance. It’s been long awaited, and it looks really encouraging,” James Markmann, MD, PhD, the surgeon who performed the procedure, told this news organization.

The use of insulin-producing pancreatic beta cells derived from human pluripotent stem cells, first reported in 2014 by a team at the Harvard Stem Cell Institute, Boston, is seen as a major advance over use of cadaveric donor islet cells because stem cell–derived islets are available in unlimited and uncontaminated supplies.

Cadaveric donor islets are being used in products such as donislecel (CellTrans), which was endorsed by a Food and Drug Administration advisory committee in the summer for the treatment of type 1 diabetes that can’t be managed with current therapies.

The patient in the Vertex trial isn’t the first reported stem cell–derived islet recipient with type 1 diabetes, but these cells are the first to be transplanted into the liver.

“This Vertex patient stood out because the reduction in insulin requirement ... was so striking,” noted Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston, who has been transplanting islet cells from cadaveric donors into humans via the hepatic portal vein for over 20 years.

“Nobody knew what to expect, as it hadn’t been done before, but certainly the results in this patient are better than what I would have expected from a deceased donor islet transplant,” he added.

Asked to comment, A.M. James Shapiro, MD, agreed. “I think the most important finding is that a stem cell–derived islet is now transplanted into the liver of a patient safely, so far,” he said in an interview.

Dr. Shapiro is clinical director of the living donor and islet cell transplantation programs at the University of Alberta, Edmonton. He pioneered cadaveric donor islet cell transplantation more than 20 years ago with the watershed Edmonton Protocol.

‘Impressive finding ... bodes well for ongoing efforts’

Vertex announced the result by press release. The company plans to transplant another 16 patients, staggering them over time at multiple centers.

The first patient was treated with a single infusion of VX-880 at half the target dose (per protocol for the first two study subjects), along with standard immunosuppressive therapy. At 90 days, the patient’s C-peptide, a measure of endogenous insulin secretion, rose from undetectable to 280 pmol/L fasting and 560 pmol/L post mixed-meal tolerance testing.

Over the same period, the patient’s hemoglobin A1c dropped from 8.6% at baseline to 7.2%. And within 7 days, the individual’s daily exogenous insulin requirement dropped from an average of 34 units to just 2.9 units, a 91% decrease.

The patient had experienced five severe hypoglycemic episodes in the year prior to transplant. They experienced some mild hypoglycemia soon after the procedure while insulin doses were being adjusted, but none thereafter. 

Dr. Shapiro said in an interview: “I was absolutely thrilled to see the first patient results with high C-peptide and a 91% reduction in insulin. That’s a pretty impressive finding for half dosing in the very first patient in a trial. I think it bodes really well for ongoing efforts in this area by Vertex and by others that have similar kinds of cells. It’s very exciting.”

However, he cautioned, “we do need some longer-term data to be sure there’s no off-target growth or other concerns. But based on the purity of this product, that risk is likely to be low.”

And he noted, “I think we still have to address the challenges of setting this process up. A huge amount of work has gone into manufacturing the cell product for a single patient. I think it remains to be seen whether the same technology can be delivered at a larger scale ... i.e., being able to treat hundreds or thousands of patients.”

A blog post on the website of diabetes charity JDRF called the result “outstanding.” “It’s a big deal,” they added. However, they also cautioned: “There are a few things to keep in mind while assessing the data. One is that these are only results from a single person. Data are needed from many more to fully evaluate the potential of this therapy. The second is that this person only received half the target dose of cells.”

Dr. Shapiro is working with another company, ViaCyte, which has also developed stem cell–derived islets. In contrast to the Vertex product, which is fully differentiated and delivered to the liver, ViaCyte’s PEC-Direct product is comprised of stem cell-derived pancreatic islet progenitor cells that are implanted subcutaneously in a pouch, allowing for vascularization.

In a late-breaking poster at the annual scientific sessions of the American Diabetes Association in June 2021, ViaCyte reported on a patient given PEC-Direct. In that patient, stimulated C-peptide increased from 0.1 ng/mL at baseline to 0.8 ng/mL at week 39, and there was a drop in A1c from 7.4% to 6.6%, with no adverse events.

Immunosuppression: Which approach will come closer to cure?

Thus far, the requirement for lifelong immunosuppression has meant that any islet cell replacement approach, including with stem cell–derived islets, has been limited to use in people with type 1 diabetes who have hypoglycemic unawareness or severely unpredictable blood glucose levels.

Two broad approaches are simultaneously being explored to overcome the rejection problem: Encapsulation of the cells to protect them from the immune system, and genetic modification of the cells so that they don’t provoke the immune system in the first place.

In 2022, Vertex plans to file an investigational new drug application for an encapsulated islet cell program with the FDA.

Dr. Markmann believes the genetic modification approach is more promising. “I’m not a believer in encapsulation. I think the foreign body response is hard to overcome. I think the answer will ultimately be genetically modifying the [cell] lines. ... The cell could express something that would potentially turn off the lymphocytes or interfere with the lymphocytes trying to attack them.”

Moreover, he said, “you don’t have to get rid of immunosuppression completely. It’s all [a] risk-benefit [equation]. Even if you could get it down to a single less-toxic [immunosuppressive] agent that would be a huge step.”

Dr. Shapiro commented: “All efforts and eyes are laser-focused on developing cells or approaches that will allow transplantation of this kind of stem cell without any immunosuppression or with low-dose immunosuppression that could be regarded as being exceedingly low risk.”

“Then, and only then, I think we could offer this kind of treatment to children who are just diagnosed with diabetes or to [a bigger proportion of] patients with type 1 or type 2 diabetes. ... The science has to be done in a step-wise fashion,” he added.

Microencapsulation, Dr. Shapiro noted, “is a big challenge because the process of capturing the cells and putting them into a device is really injurious to their survival. ... That may or may not work.”

Dr. Shapiro and his Edmonton team are now embarking on a new trial with ViaCyte and CRISPR Therapeutics using gene-edited cells that contain two knock-in genes and two knock-out genes shown to be less immunogenic and anti-inflammatory in rodent models.

“They look to be promising. We’re going to start a first-in-human trial in the next few months with those cells to see if they really are able to withstand a transplant without the need for immunosuppression. That will be a very exciting trial in itself,” Dr. Shapiro said, noting that they expect to enroll the first patients in the next few months.

However, he cautioned, “first we have to make sure that the gene-edited product continues to function in patients in the way that the original product did, that the cells survive, and that the gene modifications are actually effective. ... Maybe other iterations will be needed.”

“I think, as we move forward, we will ultimately have a gene-edited stem cell–derived product that is immune evasive and will survive. So, I’m ... optimistic that this is not as long term as you might think, and it’s ... happening much more rapidly – at least in first-in-human trials to test safety and preliminary efficacy.”

Dr. Shapiro is a consultant for ViaCyte.

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

A novel investigational allogeneic stem cell–derived treatment resulted in near reversal of type 1 diabetes in a patient who had lived with the condition for about 40 years.

CIPhotos/Getty Images

The patient was the first in Vertex Pharmaceuticals’ phase 1/2 multicenter, single-arm, open-label clinical trial of the insulin-producing islet cell therapy VX-880 for patients with type 1 diabetes who have impaired hypoglycemic awareness and severe hypoglycemia.

The cells are delivered by infusion into the hepatic portal vein. As of now, chronic immunosuppression is required to prevent rejection, but several approaches are being studied to overcome the limitation.

“There’s hope that this is a real advance. It’s been long awaited, and it looks really encouraging,” James Markmann, MD, PhD, the surgeon who performed the procedure, told this news organization.

The use of insulin-producing pancreatic beta cells derived from human pluripotent stem cells, first reported in 2014 by a team at the Harvard Stem Cell Institute, Boston, is seen as a major advance over use of cadaveric donor islet cells because stem cell–derived islets are available in unlimited and uncontaminated supplies.

Cadaveric donor islets are being used in products such as donislecel (CellTrans), which was endorsed by a Food and Drug Administration advisory committee in the summer for the treatment of type 1 diabetes that can’t be managed with current therapies.

The patient in the Vertex trial isn’t the first reported stem cell–derived islet recipient with type 1 diabetes, but these cells are the first to be transplanted into the liver.

“This Vertex patient stood out because the reduction in insulin requirement ... was so striking,” noted Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston, who has been transplanting islet cells from cadaveric donors into humans via the hepatic portal vein for over 20 years.

“Nobody knew what to expect, as it hadn’t been done before, but certainly the results in this patient are better than what I would have expected from a deceased donor islet transplant,” he added.

Asked to comment, A.M. James Shapiro, MD, agreed. “I think the most important finding is that a stem cell–derived islet is now transplanted into the liver of a patient safely, so far,” he said in an interview.

Dr. Shapiro is clinical director of the living donor and islet cell transplantation programs at the University of Alberta, Edmonton. He pioneered cadaveric donor islet cell transplantation more than 20 years ago with the watershed Edmonton Protocol.

‘Impressive finding ... bodes well for ongoing efforts’

Vertex announced the result by press release. The company plans to transplant another 16 patients, staggering them over time at multiple centers.

The first patient was treated with a single infusion of VX-880 at half the target dose (per protocol for the first two study subjects), along with standard immunosuppressive therapy. At 90 days, the patient’s C-peptide, a measure of endogenous insulin secretion, rose from undetectable to 280 pmol/L fasting and 560 pmol/L post mixed-meal tolerance testing.

Over the same period, the patient’s hemoglobin A1c dropped from 8.6% at baseline to 7.2%. And within 7 days, the individual’s daily exogenous insulin requirement dropped from an average of 34 units to just 2.9 units, a 91% decrease.

The patient had experienced five severe hypoglycemic episodes in the year prior to transplant. They experienced some mild hypoglycemia soon after the procedure while insulin doses were being adjusted, but none thereafter. 

Dr. Shapiro said in an interview: “I was absolutely thrilled to see the first patient results with high C-peptide and a 91% reduction in insulin. That’s a pretty impressive finding for half dosing in the very first patient in a trial. I think it bodes really well for ongoing efforts in this area by Vertex and by others that have similar kinds of cells. It’s very exciting.”

However, he cautioned, “we do need some longer-term data to be sure there’s no off-target growth or other concerns. But based on the purity of this product, that risk is likely to be low.”

And he noted, “I think we still have to address the challenges of setting this process up. A huge amount of work has gone into manufacturing the cell product for a single patient. I think it remains to be seen whether the same technology can be delivered at a larger scale ... i.e., being able to treat hundreds or thousands of patients.”

A blog post on the website of diabetes charity JDRF called the result “outstanding.” “It’s a big deal,” they added. However, they also cautioned: “There are a few things to keep in mind while assessing the data. One is that these are only results from a single person. Data are needed from many more to fully evaluate the potential of this therapy. The second is that this person only received half the target dose of cells.”

Dr. Shapiro is working with another company, ViaCyte, which has also developed stem cell–derived islets. In contrast to the Vertex product, which is fully differentiated and delivered to the liver, ViaCyte’s PEC-Direct product is comprised of stem cell-derived pancreatic islet progenitor cells that are implanted subcutaneously in a pouch, allowing for vascularization.

In a late-breaking poster at the annual scientific sessions of the American Diabetes Association in June 2021, ViaCyte reported on a patient given PEC-Direct. In that patient, stimulated C-peptide increased from 0.1 ng/mL at baseline to 0.8 ng/mL at week 39, and there was a drop in A1c from 7.4% to 6.6%, with no adverse events.

Immunosuppression: Which approach will come closer to cure?

Thus far, the requirement for lifelong immunosuppression has meant that any islet cell replacement approach, including with stem cell–derived islets, has been limited to use in people with type 1 diabetes who have hypoglycemic unawareness or severely unpredictable blood glucose levels.

Two broad approaches are simultaneously being explored to overcome the rejection problem: Encapsulation of the cells to protect them from the immune system, and genetic modification of the cells so that they don’t provoke the immune system in the first place.

In 2022, Vertex plans to file an investigational new drug application for an encapsulated islet cell program with the FDA.

Dr. Markmann believes the genetic modification approach is more promising. “I’m not a believer in encapsulation. I think the foreign body response is hard to overcome. I think the answer will ultimately be genetically modifying the [cell] lines. ... The cell could express something that would potentially turn off the lymphocytes or interfere with the lymphocytes trying to attack them.”

Moreover, he said, “you don’t have to get rid of immunosuppression completely. It’s all [a] risk-benefit [equation]. Even if you could get it down to a single less-toxic [immunosuppressive] agent that would be a huge step.”

Dr. Shapiro commented: “All efforts and eyes are laser-focused on developing cells or approaches that will allow transplantation of this kind of stem cell without any immunosuppression or with low-dose immunosuppression that could be regarded as being exceedingly low risk.”

“Then, and only then, I think we could offer this kind of treatment to children who are just diagnosed with diabetes or to [a bigger proportion of] patients with type 1 or type 2 diabetes. ... The science has to be done in a step-wise fashion,” he added.

Microencapsulation, Dr. Shapiro noted, “is a big challenge because the process of capturing the cells and putting them into a device is really injurious to their survival. ... That may or may not work.”

Dr. Shapiro and his Edmonton team are now embarking on a new trial with ViaCyte and CRISPR Therapeutics using gene-edited cells that contain two knock-in genes and two knock-out genes shown to be less immunogenic and anti-inflammatory in rodent models.

“They look to be promising. We’re going to start a first-in-human trial in the next few months with those cells to see if they really are able to withstand a transplant without the need for immunosuppression. That will be a very exciting trial in itself,” Dr. Shapiro said, noting that they expect to enroll the first patients in the next few months.

However, he cautioned, “first we have to make sure that the gene-edited product continues to function in patients in the way that the original product did, that the cells survive, and that the gene modifications are actually effective. ... Maybe other iterations will be needed.”

“I think, as we move forward, we will ultimately have a gene-edited stem cell–derived product that is immune evasive and will survive. So, I’m ... optimistic that this is not as long term as you might think, and it’s ... happening much more rapidly – at least in first-in-human trials to test safety and preliminary efficacy.”

Dr. Shapiro is a consultant for ViaCyte.

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

A novel investigational allogeneic stem cell–derived treatment resulted in near reversal of type 1 diabetes in a patient who had lived with the condition for about 40 years.

CIPhotos/Getty Images

The patient was the first in Vertex Pharmaceuticals’ phase 1/2 multicenter, single-arm, open-label clinical trial of the insulin-producing islet cell therapy VX-880 for patients with type 1 diabetes who have impaired hypoglycemic awareness and severe hypoglycemia.

The cells are delivered by infusion into the hepatic portal vein. As of now, chronic immunosuppression is required to prevent rejection, but several approaches are being studied to overcome the limitation.

“There’s hope that this is a real advance. It’s been long awaited, and it looks really encouraging,” James Markmann, MD, PhD, the surgeon who performed the procedure, told this news organization.

The use of insulin-producing pancreatic beta cells derived from human pluripotent stem cells, first reported in 2014 by a team at the Harvard Stem Cell Institute, Boston, is seen as a major advance over use of cadaveric donor islet cells because stem cell–derived islets are available in unlimited and uncontaminated supplies.

Cadaveric donor islets are being used in products such as donislecel (CellTrans), which was endorsed by a Food and Drug Administration advisory committee in the summer for the treatment of type 1 diabetes that can’t be managed with current therapies.

The patient in the Vertex trial isn’t the first reported stem cell–derived islet recipient with type 1 diabetes, but these cells are the first to be transplanted into the liver.

“This Vertex patient stood out because the reduction in insulin requirement ... was so striking,” noted Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston, who has been transplanting islet cells from cadaveric donors into humans via the hepatic portal vein for over 20 years.

“Nobody knew what to expect, as it hadn’t been done before, but certainly the results in this patient are better than what I would have expected from a deceased donor islet transplant,” he added.

Asked to comment, A.M. James Shapiro, MD, agreed. “I think the most important finding is that a stem cell–derived islet is now transplanted into the liver of a patient safely, so far,” he said in an interview.

Dr. Shapiro is clinical director of the living donor and islet cell transplantation programs at the University of Alberta, Edmonton. He pioneered cadaveric donor islet cell transplantation more than 20 years ago with the watershed Edmonton Protocol.

‘Impressive finding ... bodes well for ongoing efforts’

Vertex announced the result by press release. The company plans to transplant another 16 patients, staggering them over time at multiple centers.

The first patient was treated with a single infusion of VX-880 at half the target dose (per protocol for the first two study subjects), along with standard immunosuppressive therapy. At 90 days, the patient’s C-peptide, a measure of endogenous insulin secretion, rose from undetectable to 280 pmol/L fasting and 560 pmol/L post mixed-meal tolerance testing.

Over the same period, the patient’s hemoglobin A1c dropped from 8.6% at baseline to 7.2%. And within 7 days, the individual’s daily exogenous insulin requirement dropped from an average of 34 units to just 2.9 units, a 91% decrease.

The patient had experienced five severe hypoglycemic episodes in the year prior to transplant. They experienced some mild hypoglycemia soon after the procedure while insulin doses were being adjusted, but none thereafter. 

Dr. Shapiro said in an interview: “I was absolutely thrilled to see the first patient results with high C-peptide and a 91% reduction in insulin. That’s a pretty impressive finding for half dosing in the very first patient in a trial. I think it bodes really well for ongoing efforts in this area by Vertex and by others that have similar kinds of cells. It’s very exciting.”

However, he cautioned, “we do need some longer-term data to be sure there’s no off-target growth or other concerns. But based on the purity of this product, that risk is likely to be low.”

And he noted, “I think we still have to address the challenges of setting this process up. A huge amount of work has gone into manufacturing the cell product for a single patient. I think it remains to be seen whether the same technology can be delivered at a larger scale ... i.e., being able to treat hundreds or thousands of patients.”

A blog post on the website of diabetes charity JDRF called the result “outstanding.” “It’s a big deal,” they added. However, they also cautioned: “There are a few things to keep in mind while assessing the data. One is that these are only results from a single person. Data are needed from many more to fully evaluate the potential of this therapy. The second is that this person only received half the target dose of cells.”

Dr. Shapiro is working with another company, ViaCyte, which has also developed stem cell–derived islets. In contrast to the Vertex product, which is fully differentiated and delivered to the liver, ViaCyte’s PEC-Direct product is comprised of stem cell-derived pancreatic islet progenitor cells that are implanted subcutaneously in a pouch, allowing for vascularization.

In a late-breaking poster at the annual scientific sessions of the American Diabetes Association in June 2021, ViaCyte reported on a patient given PEC-Direct. In that patient, stimulated C-peptide increased from 0.1 ng/mL at baseline to 0.8 ng/mL at week 39, and there was a drop in A1c from 7.4% to 6.6%, with no adverse events.

Immunosuppression: Which approach will come closer to cure?

Thus far, the requirement for lifelong immunosuppression has meant that any islet cell replacement approach, including with stem cell–derived islets, has been limited to use in people with type 1 diabetes who have hypoglycemic unawareness or severely unpredictable blood glucose levels.

Two broad approaches are simultaneously being explored to overcome the rejection problem: Encapsulation of the cells to protect them from the immune system, and genetic modification of the cells so that they don’t provoke the immune system in the first place.

In 2022, Vertex plans to file an investigational new drug application for an encapsulated islet cell program with the FDA.

Dr. Markmann believes the genetic modification approach is more promising. “I’m not a believer in encapsulation. I think the foreign body response is hard to overcome. I think the answer will ultimately be genetically modifying the [cell] lines. ... The cell could express something that would potentially turn off the lymphocytes or interfere with the lymphocytes trying to attack them.”

Moreover, he said, “you don’t have to get rid of immunosuppression completely. It’s all [a] risk-benefit [equation]. Even if you could get it down to a single less-toxic [immunosuppressive] agent that would be a huge step.”

Dr. Shapiro commented: “All efforts and eyes are laser-focused on developing cells or approaches that will allow transplantation of this kind of stem cell without any immunosuppression or with low-dose immunosuppression that could be regarded as being exceedingly low risk.”

“Then, and only then, I think we could offer this kind of treatment to children who are just diagnosed with diabetes or to [a bigger proportion of] patients with type 1 or type 2 diabetes. ... The science has to be done in a step-wise fashion,” he added.

Microencapsulation, Dr. Shapiro noted, “is a big challenge because the process of capturing the cells and putting them into a device is really injurious to their survival. ... That may or may not work.”

Dr. Shapiro and his Edmonton team are now embarking on a new trial with ViaCyte and CRISPR Therapeutics using gene-edited cells that contain two knock-in genes and two knock-out genes shown to be less immunogenic and anti-inflammatory in rodent models.

“They look to be promising. We’re going to start a first-in-human trial in the next few months with those cells to see if they really are able to withstand a transplant without the need for immunosuppression. That will be a very exciting trial in itself,” Dr. Shapiro said, noting that they expect to enroll the first patients in the next few months.

However, he cautioned, “first we have to make sure that the gene-edited product continues to function in patients in the way that the original product did, that the cells survive, and that the gene modifications are actually effective. ... Maybe other iterations will be needed.”

“I think, as we move forward, we will ultimately have a gene-edited stem cell–derived product that is immune evasive and will survive. So, I’m ... optimistic that this is not as long term as you might think, and it’s ... happening much more rapidly – at least in first-in-human trials to test safety and preliminary efficacy.”

Dr. Shapiro is a consultant for ViaCyte.

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

A “green” adaptation to the traditional Mediterranean diet could help improve insulin sensitivity and reduce visceral fat by increasing levels of ghrelin, the “hunger hormone,” new research suggests.

The current study is a new analysis of data from the randomized DIRECT-PLUS trial, which showed that the addition of green tea and substitution of red meat for a plant-based (Mankai) protein shake at dinner – dubbed the “green Mediterranean diet” – resulted in further improved cardiometabolic benefits compared with the traditional Mediterranean diet among people with baseline abdominal obesity and/or dyslipidemia, according to the researchers.

They specifically looked at ghrelin, nicknamed the “hunger hormone,” a neuropeptide mainly secreted by the gastric epithelium. It acts on the pituitary gland to release growth hormone. Ghrelin concentrations increase during fasting and decrease after eating. Lower levels are associated with insulin resistance and obesity.

Fasting ghrelin levels were elevated with weight loss, but those increases were associated with improved insulin sensitivity and regression of visceral adipose tissue even beyond weight loss.

Although the caloric restriction and weight loss were comparable with the two Mediterranean diets, the green Mediterranean diet group had double the increase in fasting ghrelin as the traditional Mediterranean diet group, the researchers point out in their report .
 

‘Hypothesis-generating’ study pushes many hot topic buttons

“This specific study is the first to show that ghrelin levels play an important role in metabolic adaptation to a dietary or lifestyle intervention and that ghrelin is an important player in the axis of adiposity, insulin resistance, and metabolic health,” lead researcher Gal Tsaban, MD, told this news organization.

The data partially explain some of the prior beneficial effects seen with the Green Mediterranean diet, even after adjustment for weight loss, he explained, noting that the revised version of the diet “could be considered as an alternative lifestyle intervention with possible metabolic benefits even beyond the Mediterranean diet, which is what we currently recommend for patients.”

Asked for comment, Christopher Gardner, PhD, was not as enthusiastic.

He took issue with the fact that ghrelin wasn’t a primary or even a prespecified secondary outcome of the DIRECT-PLUS trial and because the specific plant-based ingredients of the green Mediterranean diet used in the study may not be widely available or desirable and therefore limit the study’s generalizability.

Dr. Gardner, who is director of nutrition studies at the Stanford Prevention Research Center, California, also said: “They’re tying lots of interesting things together. The Mediterranean diet is a cool thing, ghrelin is a cool thing, and insulin resistance is hugely important in this day and age, even though we don’t all agree on how to measure it.”

“But it gets tough as you try to link them all together for an exploratory outcome. ... To me it’s an interesting hypothesis-generating study that pushes a lot of interesting buttons that are hot topics in the field.”
 

Green Mediterranean diet led to higher ghrelin, metabolic benefits

In DIRECT-PLUS, a total of 294 adults (88% men) older than 30 years of age with abdominal obesity (waist circumference >102 cm for men or >88 cm for women), or dyslipidemia (triglycerides >150 mg/dL and HDL-cholesterol ≤40 mg/dL for men or ≤50 mg/dL for women) were included. Half had prediabetes or type 2 diabetes.

They were randomized to one of three diets: a diet based on standard healthy dietary guidelines; a traditional Mediterranean diet low in simple carbohydrates, rich in vegetables, with poultry and fish replacing beef and lamb and 28 g/day of walnuts; or the Green-Mediterranean diet, including 3-4 cups/day of green tea and 100 g/day of a green shake made from the Mankai strain of Wolffia globosa (also known as duckweed) replacing dinner, and 28 g/day of walnuts.

The Green Mediterranean diet included 800 mg more polyphenols than the traditional Mediterranean diet. Both were equally calorie-restricted, at about 1,500-1,800 kcal/day for men and 1,200-1,400 kcal/day for women. All three groups were instructed to engage in regular physical activity and were given free gym memberships.

The retention rate was 98.3% after 6 months and 89.8% after 18 months.

Weight loss was similar between the two Mediterranean diet groups (2.9% and 3.9% for the traditional and green versions, respectively) compared with the standard healthy diet (0.6%) (P < .05 for both Mediterranean diet groups vs. control).

After 6 months, fasting ghrelin increased in the traditional (8.0%; P = .015) and green (10.5%; P = 0.031) Mediterranean groups versus baseline, with no significant change in the control group.

By 18 months, fasting ghrelin was significantly greater compared with baseline only in the green Mediterranean group (P = .012).

Because the differences in fasting ghrelin trajectories were only significant in men – likely due to the small sample size of women – a subsequent 18-month analysis was limited to the men. In a multivariate model adjusted for age, intervention group, baseline biomarker values, and 18-month weight changes, the 18-month change in fasting ghrelin remained a significant predictor for changes in A1c and homeostatic model of insulin resistance (HOMA-IR; P = .022).

Because weight loss remained the most significant predictor of improved insulin resistance, a further analysis examined the association between changes in fasting ghrelin levels with changes in the fraction of insulin resistance marker that were not attributed to weight loss, per se. With the other adjustments, fasting ghrelin was associated with residual reductions in A1c (P = .003), HOMA-IR (P = .021), increased HDL-cholesterol (P = .024), and relative visceral adipose tissue loss (P = .003).  
 

No specific product needed to push Mediterranean diet towards vegan

Dr. Tsaban, a nutritional researcher and cardiologist at Ben-Gurion University and Soroka University Medical Center, Be’er-Sheva, Israel, said the Mankai shake is commonly consumed in Israel but is also available worldwide. The study participants, all employees at an isolated nuclear research facility in the Negev, were particularly motivated. “They didn’t have a satiety problem with the drink. It made them very full,” he said. The manufacturer supplied the shakes but didn’t fund the study, he added.

However, Dr. Tsaban said that the “green Mediterranean diet” doesn’t depend on specific products.

Rather, “the concept is to push the Mediterranean diet a bit further and to replace the animal-based protein with vegetable-based protein, to shift your dietary habits towards a more vegan lifestyle. It’s not completely vegan, but it’s trending there. ... Our main goal was to increase the polyphenol intake, the antioxidant intake from vegetables. ... I think it can be replicated.”

Dr. Gardner said, “At the end of the day, it’s an exploratory study. ... It raises some interesting points that give the rest of us room to follow-up on.”

The study was funded by grants from the German Research Foundation, the Israel Ministry of Health, the Israel Ministry of Science and Technology, and the California Walnut Commission. Dr. Tsaban has reported no further relevant financial relationships. Dr. Gardner has reported receiving study funding from Beyond Meat.

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

A “green” adaptation to the traditional Mediterranean diet could help improve insulin sensitivity and reduce visceral fat by increasing levels of ghrelin, the “hunger hormone,” new research suggests.

The current study is a new analysis of data from the randomized DIRECT-PLUS trial, which showed that the addition of green tea and substitution of red meat for a plant-based (Mankai) protein shake at dinner – dubbed the “green Mediterranean diet” – resulted in further improved cardiometabolic benefits compared with the traditional Mediterranean diet among people with baseline abdominal obesity and/or dyslipidemia, according to the researchers.

They specifically looked at ghrelin, nicknamed the “hunger hormone,” a neuropeptide mainly secreted by the gastric epithelium. It acts on the pituitary gland to release growth hormone. Ghrelin concentrations increase during fasting and decrease after eating. Lower levels are associated with insulin resistance and obesity.

Fasting ghrelin levels were elevated with weight loss, but those increases were associated with improved insulin sensitivity and regression of visceral adipose tissue even beyond weight loss.

Although the caloric restriction and weight loss were comparable with the two Mediterranean diets, the green Mediterranean diet group had double the increase in fasting ghrelin as the traditional Mediterranean diet group, the researchers point out in their report .
 

‘Hypothesis-generating’ study pushes many hot topic buttons

“This specific study is the first to show that ghrelin levels play an important role in metabolic adaptation to a dietary or lifestyle intervention and that ghrelin is an important player in the axis of adiposity, insulin resistance, and metabolic health,” lead researcher Gal Tsaban, MD, told this news organization.

The data partially explain some of the prior beneficial effects seen with the Green Mediterranean diet, even after adjustment for weight loss, he explained, noting that the revised version of the diet “could be considered as an alternative lifestyle intervention with possible metabolic benefits even beyond the Mediterranean diet, which is what we currently recommend for patients.”

Asked for comment, Christopher Gardner, PhD, was not as enthusiastic.

He took issue with the fact that ghrelin wasn’t a primary or even a prespecified secondary outcome of the DIRECT-PLUS trial and because the specific plant-based ingredients of the green Mediterranean diet used in the study may not be widely available or desirable and therefore limit the study’s generalizability.

Dr. Gardner, who is director of nutrition studies at the Stanford Prevention Research Center, California, also said: “They’re tying lots of interesting things together. The Mediterranean diet is a cool thing, ghrelin is a cool thing, and insulin resistance is hugely important in this day and age, even though we don’t all agree on how to measure it.”

“But it gets tough as you try to link them all together for an exploratory outcome. ... To me it’s an interesting hypothesis-generating study that pushes a lot of interesting buttons that are hot topics in the field.”
 

Green Mediterranean diet led to higher ghrelin, metabolic benefits

In DIRECT-PLUS, a total of 294 adults (88% men) older than 30 years of age with abdominal obesity (waist circumference >102 cm for men or >88 cm for women), or dyslipidemia (triglycerides >150 mg/dL and HDL-cholesterol ≤40 mg/dL for men or ≤50 mg/dL for women) were included. Half had prediabetes or type 2 diabetes.

They were randomized to one of three diets: a diet based on standard healthy dietary guidelines; a traditional Mediterranean diet low in simple carbohydrates, rich in vegetables, with poultry and fish replacing beef and lamb and 28 g/day of walnuts; or the Green-Mediterranean diet, including 3-4 cups/day of green tea and 100 g/day of a green shake made from the Mankai strain of Wolffia globosa (also known as duckweed) replacing dinner, and 28 g/day of walnuts.

The Green Mediterranean diet included 800 mg more polyphenols than the traditional Mediterranean diet. Both were equally calorie-restricted, at about 1,500-1,800 kcal/day for men and 1,200-1,400 kcal/day for women. All three groups were instructed to engage in regular physical activity and were given free gym memberships.

The retention rate was 98.3% after 6 months and 89.8% after 18 months.

Weight loss was similar between the two Mediterranean diet groups (2.9% and 3.9% for the traditional and green versions, respectively) compared with the standard healthy diet (0.6%) (P < .05 for both Mediterranean diet groups vs. control).

After 6 months, fasting ghrelin increased in the traditional (8.0%; P = .015) and green (10.5%; P = 0.031) Mediterranean groups versus baseline, with no significant change in the control group.

By 18 months, fasting ghrelin was significantly greater compared with baseline only in the green Mediterranean group (P = .012).

Because the differences in fasting ghrelin trajectories were only significant in men – likely due to the small sample size of women – a subsequent 18-month analysis was limited to the men. In a multivariate model adjusted for age, intervention group, baseline biomarker values, and 18-month weight changes, the 18-month change in fasting ghrelin remained a significant predictor for changes in A1c and homeostatic model of insulin resistance (HOMA-IR; P = .022).

Because weight loss remained the most significant predictor of improved insulin resistance, a further analysis examined the association between changes in fasting ghrelin levels with changes in the fraction of insulin resistance marker that were not attributed to weight loss, per se. With the other adjustments, fasting ghrelin was associated with residual reductions in A1c (P = .003), HOMA-IR (P = .021), increased HDL-cholesterol (P = .024), and relative visceral adipose tissue loss (P = .003).  
 

No specific product needed to push Mediterranean diet towards vegan

Dr. Tsaban, a nutritional researcher and cardiologist at Ben-Gurion University and Soroka University Medical Center, Be’er-Sheva, Israel, said the Mankai shake is commonly consumed in Israel but is also available worldwide. The study participants, all employees at an isolated nuclear research facility in the Negev, were particularly motivated. “They didn’t have a satiety problem with the drink. It made them very full,” he said. The manufacturer supplied the shakes but didn’t fund the study, he added.

However, Dr. Tsaban said that the “green Mediterranean diet” doesn’t depend on specific products.

Rather, “the concept is to push the Mediterranean diet a bit further and to replace the animal-based protein with vegetable-based protein, to shift your dietary habits towards a more vegan lifestyle. It’s not completely vegan, but it’s trending there. ... Our main goal was to increase the polyphenol intake, the antioxidant intake from vegetables. ... I think it can be replicated.”

Dr. Gardner said, “At the end of the day, it’s an exploratory study. ... It raises some interesting points that give the rest of us room to follow-up on.”

The study was funded by grants from the German Research Foundation, the Israel Ministry of Health, the Israel Ministry of Science and Technology, and the California Walnut Commission. Dr. Tsaban has reported no further relevant financial relationships. Dr. Gardner has reported receiving study funding from Beyond Meat.

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

A “green” adaptation to the traditional Mediterranean diet could help improve insulin sensitivity and reduce visceral fat by increasing levels of ghrelin, the “hunger hormone,” new research suggests.

The current study is a new analysis of data from the randomized DIRECT-PLUS trial, which showed that the addition of green tea and substitution of red meat for a plant-based (Mankai) protein shake at dinner – dubbed the “green Mediterranean diet” – resulted in further improved cardiometabolic benefits compared with the traditional Mediterranean diet among people with baseline abdominal obesity and/or dyslipidemia, according to the researchers.

They specifically looked at ghrelin, nicknamed the “hunger hormone,” a neuropeptide mainly secreted by the gastric epithelium. It acts on the pituitary gland to release growth hormone. Ghrelin concentrations increase during fasting and decrease after eating. Lower levels are associated with insulin resistance and obesity.

Fasting ghrelin levels were elevated with weight loss, but those increases were associated with improved insulin sensitivity and regression of visceral adipose tissue even beyond weight loss.

Although the caloric restriction and weight loss were comparable with the two Mediterranean diets, the green Mediterranean diet group had double the increase in fasting ghrelin as the traditional Mediterranean diet group, the researchers point out in their report .
 

‘Hypothesis-generating’ study pushes many hot topic buttons

“This specific study is the first to show that ghrelin levels play an important role in metabolic adaptation to a dietary or lifestyle intervention and that ghrelin is an important player in the axis of adiposity, insulin resistance, and metabolic health,” lead researcher Gal Tsaban, MD, told this news organization.

The data partially explain some of the prior beneficial effects seen with the Green Mediterranean diet, even after adjustment for weight loss, he explained, noting that the revised version of the diet “could be considered as an alternative lifestyle intervention with possible metabolic benefits even beyond the Mediterranean diet, which is what we currently recommend for patients.”

Asked for comment, Christopher Gardner, PhD, was not as enthusiastic.

He took issue with the fact that ghrelin wasn’t a primary or even a prespecified secondary outcome of the DIRECT-PLUS trial and because the specific plant-based ingredients of the green Mediterranean diet used in the study may not be widely available or desirable and therefore limit the study’s generalizability.

Dr. Gardner, who is director of nutrition studies at the Stanford Prevention Research Center, California, also said: “They’re tying lots of interesting things together. The Mediterranean diet is a cool thing, ghrelin is a cool thing, and insulin resistance is hugely important in this day and age, even though we don’t all agree on how to measure it.”

“But it gets tough as you try to link them all together for an exploratory outcome. ... To me it’s an interesting hypothesis-generating study that pushes a lot of interesting buttons that are hot topics in the field.”
 

Green Mediterranean diet led to higher ghrelin, metabolic benefits

In DIRECT-PLUS, a total of 294 adults (88% men) older than 30 years of age with abdominal obesity (waist circumference >102 cm for men or >88 cm for women), or dyslipidemia (triglycerides >150 mg/dL and HDL-cholesterol ≤40 mg/dL for men or ≤50 mg/dL for women) were included. Half had prediabetes or type 2 diabetes.

They were randomized to one of three diets: a diet based on standard healthy dietary guidelines; a traditional Mediterranean diet low in simple carbohydrates, rich in vegetables, with poultry and fish replacing beef and lamb and 28 g/day of walnuts; or the Green-Mediterranean diet, including 3-4 cups/day of green tea and 100 g/day of a green shake made from the Mankai strain of Wolffia globosa (also known as duckweed) replacing dinner, and 28 g/day of walnuts.

The Green Mediterranean diet included 800 mg more polyphenols than the traditional Mediterranean diet. Both were equally calorie-restricted, at about 1,500-1,800 kcal/day for men and 1,200-1,400 kcal/day for women. All three groups were instructed to engage in regular physical activity and were given free gym memberships.

The retention rate was 98.3% after 6 months and 89.8% after 18 months.

Weight loss was similar between the two Mediterranean diet groups (2.9% and 3.9% for the traditional and green versions, respectively) compared with the standard healthy diet (0.6%) (P < .05 for both Mediterranean diet groups vs. control).

After 6 months, fasting ghrelin increased in the traditional (8.0%; P = .015) and green (10.5%; P = 0.031) Mediterranean groups versus baseline, with no significant change in the control group.

By 18 months, fasting ghrelin was significantly greater compared with baseline only in the green Mediterranean group (P = .012).

Because the differences in fasting ghrelin trajectories were only significant in men – likely due to the small sample size of women – a subsequent 18-month analysis was limited to the men. In a multivariate model adjusted for age, intervention group, baseline biomarker values, and 18-month weight changes, the 18-month change in fasting ghrelin remained a significant predictor for changes in A1c and homeostatic model of insulin resistance (HOMA-IR; P = .022).

Because weight loss remained the most significant predictor of improved insulin resistance, a further analysis examined the association between changes in fasting ghrelin levels with changes in the fraction of insulin resistance marker that were not attributed to weight loss, per se. With the other adjustments, fasting ghrelin was associated with residual reductions in A1c (P = .003), HOMA-IR (P = .021), increased HDL-cholesterol (P = .024), and relative visceral adipose tissue loss (P = .003).  
 

No specific product needed to push Mediterranean diet towards vegan

Dr. Tsaban, a nutritional researcher and cardiologist at Ben-Gurion University and Soroka University Medical Center, Be’er-Sheva, Israel, said the Mankai shake is commonly consumed in Israel but is also available worldwide. The study participants, all employees at an isolated nuclear research facility in the Negev, were particularly motivated. “They didn’t have a satiety problem with the drink. It made them very full,” he said. The manufacturer supplied the shakes but didn’t fund the study, he added.

However, Dr. Tsaban said that the “green Mediterranean diet” doesn’t depend on specific products.

Rather, “the concept is to push the Mediterranean diet a bit further and to replace the animal-based protein with vegetable-based protein, to shift your dietary habits towards a more vegan lifestyle. It’s not completely vegan, but it’s trending there. ... Our main goal was to increase the polyphenol intake, the antioxidant intake from vegetables. ... I think it can be replicated.”

Dr. Gardner said, “At the end of the day, it’s an exploratory study. ... It raises some interesting points that give the rest of us room to follow-up on.”

The study was funded by grants from the German Research Foundation, the Israel Ministry of Health, the Israel Ministry of Science and Technology, and the California Walnut Commission. Dr. Tsaban has reported no further relevant financial relationships. Dr. Gardner has reported receiving study funding from Beyond Meat.

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

Trick-or-treaters may not be so easily tricked into loving sugar-free treats, thanks to taste buds hard-wired to seek calorie-containing sweets, a new study suggests.

Taste isn’t all about choosing peanut butter cups over jelly beans. Since earliest humanity, our sense of taste has helped us detect salty, sweet, sour, savory, and bitter so that we can choose foods high in energy and low in poisons.

But these new findings suggest that our taste buds have another hidden talent: identifying foods that don’t give us any energy at all.

Scientists suspected this ability after research in mice showed that their taste buds could distinguish between sugar and calorie-free artificial sweeteners.

To test this possibility in humans, scientists asked people to drink a series of clear beverages and identify whether they were plain water or sweetened. The goal was to compare how people responded to glucose – a natural caloric sweetener in fruits, honey, and table sugar – and sucralose, a calorie-free artificial sweetener.

All participants wore nose plugs, ensuring that they would use only their taste buds and not their sense of smell for detection.

As expected, people could easily tell plain water from sweetened drinks, whether with glucose or sucralose, confirming that taste buds detect sweetness.

In a twist, researchers then mixed in flavorless chemicals that block taste buds from picking up sweetness. With these drinks, people could no longer distinguish sucralose-sweetened beverages from plain water. But they could still tell when they had a beverage sweetened with glucose.

This finding indicates that two separate pathways underlie the mouth’s response to sugar, researchers report in PLOS One. The first pathway identifies sweet flavors, and the second one detects foods that contain energy that can be used for fuel.

Scientists might one day come up with calorie-free sweets that trick taste buds into detecting the presence of calories, enhancing their appeal. But in the lab studies, the participants had no visual cues or smell to guide their reactions, meaning how these other sensory inputs would affect treat perception isn’t known.

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

Trick-or-treaters may not be so easily tricked into loving sugar-free treats, thanks to taste buds hard-wired to seek calorie-containing sweets, a new study suggests.

Taste isn’t all about choosing peanut butter cups over jelly beans. Since earliest humanity, our sense of taste has helped us detect salty, sweet, sour, savory, and bitter so that we can choose foods high in energy and low in poisons.

But these new findings suggest that our taste buds have another hidden talent: identifying foods that don’t give us any energy at all.

Scientists suspected this ability after research in mice showed that their taste buds could distinguish between sugar and calorie-free artificial sweeteners.

To test this possibility in humans, scientists asked people to drink a series of clear beverages and identify whether they were plain water or sweetened. The goal was to compare how people responded to glucose – a natural caloric sweetener in fruits, honey, and table sugar – and sucralose, a calorie-free artificial sweetener.

All participants wore nose plugs, ensuring that they would use only their taste buds and not their sense of smell for detection.

As expected, people could easily tell plain water from sweetened drinks, whether with glucose or sucralose, confirming that taste buds detect sweetness.

In a twist, researchers then mixed in flavorless chemicals that block taste buds from picking up sweetness. With these drinks, people could no longer distinguish sucralose-sweetened beverages from plain water. But they could still tell when they had a beverage sweetened with glucose.

This finding indicates that two separate pathways underlie the mouth’s response to sugar, researchers report in PLOS One. The first pathway identifies sweet flavors, and the second one detects foods that contain energy that can be used for fuel.

Scientists might one day come up with calorie-free sweets that trick taste buds into detecting the presence of calories, enhancing their appeal. But in the lab studies, the participants had no visual cues or smell to guide their reactions, meaning how these other sensory inputs would affect treat perception isn’t known.

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

Trick-or-treaters may not be so easily tricked into loving sugar-free treats, thanks to taste buds hard-wired to seek calorie-containing sweets, a new study suggests.

Taste isn’t all about choosing peanut butter cups over jelly beans. Since earliest humanity, our sense of taste has helped us detect salty, sweet, sour, savory, and bitter so that we can choose foods high in energy and low in poisons.

But these new findings suggest that our taste buds have another hidden talent: identifying foods that don’t give us any energy at all.

Scientists suspected this ability after research in mice showed that their taste buds could distinguish between sugar and calorie-free artificial sweeteners.

To test this possibility in humans, scientists asked people to drink a series of clear beverages and identify whether they were plain water or sweetened. The goal was to compare how people responded to glucose – a natural caloric sweetener in fruits, honey, and table sugar – and sucralose, a calorie-free artificial sweetener.

All participants wore nose plugs, ensuring that they would use only their taste buds and not their sense of smell for detection.

As expected, people could easily tell plain water from sweetened drinks, whether with glucose or sucralose, confirming that taste buds detect sweetness.

In a twist, researchers then mixed in flavorless chemicals that block taste buds from picking up sweetness. With these drinks, people could no longer distinguish sucralose-sweetened beverages from plain water. But they could still tell when they had a beverage sweetened with glucose.

This finding indicates that two separate pathways underlie the mouth’s response to sugar, researchers report in PLOS One. The first pathway identifies sweet flavors, and the second one detects foods that contain energy that can be used for fuel.

Scientists might one day come up with calorie-free sweets that trick taste buds into detecting the presence of calories, enhancing their appeal. But in the lab studies, the participants had no visual cues or smell to guide their reactions, meaning how these other sensory inputs would affect treat perception isn’t known.

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

Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors does not appear to raise the risk for fractures in older adults, new research suggests.

The data come from a nationwide propensity score-matched study of U.S. Medicare recipients with type 2 diabetes who were new users of either an SGLT2 inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a glucagon-like peptide (GLP-1) receptor agonist.

“The use of SGLT2 inhibitors was not associated with an increased risk of nontraumatic fractures compared with DPP-4 inhibitors or GLP-1 agonists. Results were consistent across categories of sex, frailty, age, and insulin use,” say Min Zhuo, MD, of Harvard Medical School, Boston, and colleagues, who published their work online October 27 in JAMA Network Open.

“Our results add to the evidence base evaluating the safety profile of SGLT2 inhibitors in older adults outside of [randomized controlled trials] and further characterize the risk-benefit balance of SGLT2 inhibitors in clinical practice,” they write.

Asked to comment, Simeon I. Taylor, MD, PhD, told this news organization, “This is a high-quality study that is generally reassuring that relatively short, less than 1 year, treatment with an SGLT2 inhibitor does not appear to significantly increase the risk of bone fractures.”

However, Dr. Taylor, of the Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, also noted: “Notwithstanding these reassuring data, the paper also does a good job of pointing out important limitations.”

“Most importantly, these data do not address questions related to the risk of long-term chronic therapy. It is instructive to refer back to the published data demonstrating an approximately 2-year lag before a significant increase in the risk of fracture was observed in rosiglitazone-treated patients in the ADOPT study. The length of the lag is likely related to the baseline bone mineral density at the time drug therapy is initiated. These considerations may contribute to the observed variation in bone-related outcomes in different studies.”

Concern about SGLT2 inhibitors and fractures first arose in 2017 from the CANVAS study, in which the overall fracture risk with canagliflozin was a significant 26% higher than placebo. However, subsequent larger randomized trials of canagliflozin and other SGLT2 inhibitors did not find the same risk.

In addition, previous observational studies in younger adults have also not found use of SGLT2 inhibitors to be associated with increased fracture risk compared with DPP-4 inhibitors or GLP-1 agonists.
 

Understanding fracture risk with SGLT2 inhibitors is ‘critical’

Older adults with type 2 diabetes may benefit from reductions in atherosclerotic cardiovascular events, hospitalization for heart failure, end-stage kidney disease, and death associated with SGLT2 inhibitors, but the fact that aging may have negative effects on bone metabolism means “understanding the fracture risk associated with SGLT2 inhibitors in older adults with type 2 diabetes is critical,” say Dr. Zhuo and colleagues.

In the current study, they analyzed claims data for Medicare beneficiaries aged 66 years and older (1 year past Medicare eligibility) who were newly prescribed an SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1 agonist between April 1, 2013 and Dec. 31, 2017.

A total of 45,889 patients from each treatment group were propensity-matched using 58 baseline characteristics, for a total of 137,667 patients.

After matching, there were 501 events of the primary composite outcome (nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention) within 30 days. By treatment group, fracture rates per 1,000 person-years were 4.69, 5.26, and 4.71 for SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists respectively.

The differences between patients taking DPP-4 inhibitors or GLP-1 agonists compared with SGLT2 inhibitors were not significant, with hazard ratios of 0.90 and 1.00, respectively.     

Results remained consistent in various sensitivity and subgroup analyses, including limiting the data to just the canagliflozin group. Overall, the fracture rate was greater with female sex, frailty, older age, and insulin use, consistent across drug classes.

The risks for falls and hypoglycemia were lower in the SGLT2 inhibitor versus matched DPP-4 inhibitor groups (hazard ratio, 0.82), and there was no difference in syncope. None of those differences were significant for the SGLT2 inhibitor group compared with the GLP-1 agonist group.

Consistent with previous data, the risk for diabetic ketoacidosis was higher with SGLT2 inhibitors versus DPP-4 inhibitors and GLP-1 agonists (HR, 1.29 and 1.58), and the risk for heart failure hospitalization was lower (HR, 0.42 and 0.69).

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, Harvard Medical School. Dr. Zhuo was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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

Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors does not appear to raise the risk for fractures in older adults, new research suggests.

The data come from a nationwide propensity score-matched study of U.S. Medicare recipients with type 2 diabetes who were new users of either an SGLT2 inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a glucagon-like peptide (GLP-1) receptor agonist.

“The use of SGLT2 inhibitors was not associated with an increased risk of nontraumatic fractures compared with DPP-4 inhibitors or GLP-1 agonists. Results were consistent across categories of sex, frailty, age, and insulin use,” say Min Zhuo, MD, of Harvard Medical School, Boston, and colleagues, who published their work online October 27 in JAMA Network Open.

“Our results add to the evidence base evaluating the safety profile of SGLT2 inhibitors in older adults outside of [randomized controlled trials] and further characterize the risk-benefit balance of SGLT2 inhibitors in clinical practice,” they write.

Asked to comment, Simeon I. Taylor, MD, PhD, told this news organization, “This is a high-quality study that is generally reassuring that relatively short, less than 1 year, treatment with an SGLT2 inhibitor does not appear to significantly increase the risk of bone fractures.”

However, Dr. Taylor, of the Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, also noted: “Notwithstanding these reassuring data, the paper also does a good job of pointing out important limitations.”

“Most importantly, these data do not address questions related to the risk of long-term chronic therapy. It is instructive to refer back to the published data demonstrating an approximately 2-year lag before a significant increase in the risk of fracture was observed in rosiglitazone-treated patients in the ADOPT study. The length of the lag is likely related to the baseline bone mineral density at the time drug therapy is initiated. These considerations may contribute to the observed variation in bone-related outcomes in different studies.”

Concern about SGLT2 inhibitors and fractures first arose in 2017 from the CANVAS study, in which the overall fracture risk with canagliflozin was a significant 26% higher than placebo. However, subsequent larger randomized trials of canagliflozin and other SGLT2 inhibitors did not find the same risk.

In addition, previous observational studies in younger adults have also not found use of SGLT2 inhibitors to be associated with increased fracture risk compared with DPP-4 inhibitors or GLP-1 agonists.
 

Understanding fracture risk with SGLT2 inhibitors is ‘critical’

Older adults with type 2 diabetes may benefit from reductions in atherosclerotic cardiovascular events, hospitalization for heart failure, end-stage kidney disease, and death associated with SGLT2 inhibitors, but the fact that aging may have negative effects on bone metabolism means “understanding the fracture risk associated with SGLT2 inhibitors in older adults with type 2 diabetes is critical,” say Dr. Zhuo and colleagues.

In the current study, they analyzed claims data for Medicare beneficiaries aged 66 years and older (1 year past Medicare eligibility) who were newly prescribed an SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1 agonist between April 1, 2013 and Dec. 31, 2017.

A total of 45,889 patients from each treatment group were propensity-matched using 58 baseline characteristics, for a total of 137,667 patients.

After matching, there were 501 events of the primary composite outcome (nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention) within 30 days. By treatment group, fracture rates per 1,000 person-years were 4.69, 5.26, and 4.71 for SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists respectively.

The differences between patients taking DPP-4 inhibitors or GLP-1 agonists compared with SGLT2 inhibitors were not significant, with hazard ratios of 0.90 and 1.00, respectively.     

Results remained consistent in various sensitivity and subgroup analyses, including limiting the data to just the canagliflozin group. Overall, the fracture rate was greater with female sex, frailty, older age, and insulin use, consistent across drug classes.

The risks for falls and hypoglycemia were lower in the SGLT2 inhibitor versus matched DPP-4 inhibitor groups (hazard ratio, 0.82), and there was no difference in syncope. None of those differences were significant for the SGLT2 inhibitor group compared with the GLP-1 agonist group.

Consistent with previous data, the risk for diabetic ketoacidosis was higher with SGLT2 inhibitors versus DPP-4 inhibitors and GLP-1 agonists (HR, 1.29 and 1.58), and the risk for heart failure hospitalization was lower (HR, 0.42 and 0.69).

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, Harvard Medical School. Dr. Zhuo was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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

Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors does not appear to raise the risk for fractures in older adults, new research suggests.

The data come from a nationwide propensity score-matched study of U.S. Medicare recipients with type 2 diabetes who were new users of either an SGLT2 inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a glucagon-like peptide (GLP-1) receptor agonist.

“The use of SGLT2 inhibitors was not associated with an increased risk of nontraumatic fractures compared with DPP-4 inhibitors or GLP-1 agonists. Results were consistent across categories of sex, frailty, age, and insulin use,” say Min Zhuo, MD, of Harvard Medical School, Boston, and colleagues, who published their work online October 27 in JAMA Network Open.

“Our results add to the evidence base evaluating the safety profile of SGLT2 inhibitors in older adults outside of [randomized controlled trials] and further characterize the risk-benefit balance of SGLT2 inhibitors in clinical practice,” they write.

Asked to comment, Simeon I. Taylor, MD, PhD, told this news organization, “This is a high-quality study that is generally reassuring that relatively short, less than 1 year, treatment with an SGLT2 inhibitor does not appear to significantly increase the risk of bone fractures.”

However, Dr. Taylor, of the Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, also noted: “Notwithstanding these reassuring data, the paper also does a good job of pointing out important limitations.”

“Most importantly, these data do not address questions related to the risk of long-term chronic therapy. It is instructive to refer back to the published data demonstrating an approximately 2-year lag before a significant increase in the risk of fracture was observed in rosiglitazone-treated patients in the ADOPT study. The length of the lag is likely related to the baseline bone mineral density at the time drug therapy is initiated. These considerations may contribute to the observed variation in bone-related outcomes in different studies.”

Concern about SGLT2 inhibitors and fractures first arose in 2017 from the CANVAS study, in which the overall fracture risk with canagliflozin was a significant 26% higher than placebo. However, subsequent larger randomized trials of canagliflozin and other SGLT2 inhibitors did not find the same risk.

In addition, previous observational studies in younger adults have also not found use of SGLT2 inhibitors to be associated with increased fracture risk compared with DPP-4 inhibitors or GLP-1 agonists.
 

Understanding fracture risk with SGLT2 inhibitors is ‘critical’

Older adults with type 2 diabetes may benefit from reductions in atherosclerotic cardiovascular events, hospitalization for heart failure, end-stage kidney disease, and death associated with SGLT2 inhibitors, but the fact that aging may have negative effects on bone metabolism means “understanding the fracture risk associated with SGLT2 inhibitors in older adults with type 2 diabetes is critical,” say Dr. Zhuo and colleagues.

In the current study, they analyzed claims data for Medicare beneficiaries aged 66 years and older (1 year past Medicare eligibility) who were newly prescribed an SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1 agonist between April 1, 2013 and Dec. 31, 2017.

A total of 45,889 patients from each treatment group were propensity-matched using 58 baseline characteristics, for a total of 137,667 patients.

After matching, there were 501 events of the primary composite outcome (nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention) within 30 days. By treatment group, fracture rates per 1,000 person-years were 4.69, 5.26, and 4.71 for SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists respectively.

The differences between patients taking DPP-4 inhibitors or GLP-1 agonists compared with SGLT2 inhibitors were not significant, with hazard ratios of 0.90 and 1.00, respectively.     

Results remained consistent in various sensitivity and subgroup analyses, including limiting the data to just the canagliflozin group. Overall, the fracture rate was greater with female sex, frailty, older age, and insulin use, consistent across drug classes.

The risks for falls and hypoglycemia were lower in the SGLT2 inhibitor versus matched DPP-4 inhibitor groups (hazard ratio, 0.82), and there was no difference in syncope. None of those differences were significant for the SGLT2 inhibitor group compared with the GLP-1 agonist group.

Consistent with previous data, the risk for diabetic ketoacidosis was higher with SGLT2 inhibitors versus DPP-4 inhibitors and GLP-1 agonists (HR, 1.29 and 1.58), and the risk for heart failure hospitalization was lower (HR, 0.42 and 0.69).

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, Harvard Medical School. Dr. Zhuo was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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

“Short-term hospitalization [for reasons other than diabetes] may not be the time to intervene in long-term diabetes management,” researchers conclude.

They found that, in a national cohort of older almost entirely male veterans with non–insulin-treated type 2 diabetes who were hospitalized for non–diabetes-related common medical conditions, intensified diabetes treatment on hospital discharge was linked to an increased risk of severe hypoglycemia in the immediate postdischarge period.

However, diabetes treatment intensification – that is, receiving a prescription for a new or higher dose of diabetes medicine – was not associated with decreased risks of severe hyperglycemia or with improved glycemic (hemoglobin A1c) control at 30 days or 1 year, according to study results, published in JAMA Network Open.

“We didn’t see a reduction in diabetes emergencies in more intensively treated patients,” lead investigator Timothy S. Anderson, MD, said in an interview.

Also, importantly, there was a low rate of persistence with the new treatment. “Half of the patients were no longer taking these [intensified diabetes medicines] at 1 year, which tells me that context is key,” he pointed out. “If a patient is in the hospital for diabetes [unlike the patients in this study], I think it makes a lot of sense to modify and adjust their regimen to try to help them right then and there.”

The overall risk of severe hyperglycemia or severe hypoglycemia was pretty small in the overall cohort, Dr. Anderson noted, “but we do put people at risk of leaving the hospital and ending up back in the hospital with low blood sugar when we intensify medications, and there’s not necessarily a good signal to suggest that it’s all that urgent to change these medicines.”

Instead, the “safer path” may be to make recommendations to the patient’s outpatient physician and also inform the patient – for example, “We saw some concerns about your diabetes while you were in the hospital, and this is really something that should be looked at when you’re recovered and feeling better from the rest of your health standpoint” – rather than making a diabetes medication change while the person is acutely ill or recovering from illness, said Dr. Anderson, from Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.

The researchers also found an “unexpected” significant decrease in 30-day mortality in the patients with intensified diabetes treatment, which was probably because of confounding that was not accounted for, Dr. Anderson speculated, since clinical trials have consistently shown that benefits from diabetes medications take a longer time to show an effect.
 

‘Important study,’ but lacked newer meds

This is an “important” study for primary care and in-hospital physicians that shows that “hospitalization is really not the time and the place” to intensify diabetes medication, Rozalina G. McCoy, MD, coauthor of an invited commentary, told this news organization in an interview.

“While overcoming treatment inertia is important, [it should be] done appropriately, so that we don’t overtreat patients,” Dr. McCoy, of the Mayo Clinic in Rochester, Minn., stressed.

The very low rate of persistence of taking intensified medications is a major finding, she agreed. Hospitalized patients “are not in their usual state of health, so if we make long-term treatment decisions based on their acute abnormal situation, that may not be appropriate.”

However, patients with high A1c may benefit from a change at hospital discharge rather than when they see their primary care provider, with the caveat that they need close follow-up as an outpatient.

The study emphasizes the “need for longitudinal patient care rather than episodic patches,” according to Dr. McCoy.

For example, a patient who is hospitalized for a chronic obstructive pulmonary disease or asthma exacerbation may be receiving steroids that cause high blood glucose levels but as soon as they’re done with their steroid course, blood glucose will decrease, so the “need for close outpatient follow-up is very important.”

One limitation of the current work is that an earlier study in the same population by the research group showed that 49% of patients whose treatment regimens were intensified had limited life expectancy or were at or below their A1c goal, so they would not have benefited from the stepped-up treatment, she noted.

Another limitation is that the findings cannot be generalized to women or younger patients, or to patients treated with glucagonlike peptide 1 (GLP-1)–receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors.

The study patients were seen in the U.S. Veterans Health Administration health system when these newer agents were not used. Three-quarters of patients received intensified treatment with sulfonylurea or insulin, and only one patient received a new GLP-1–receptor agonist.

Ideally, Dr. McCoy said, patients should have been prescribed a GLP-1–receptor agonist if they had atherosclerotic cardiovascular disease or kidney disease, or an SGLT2 inhibitor if they had kidney disease or heart failure, which may have led to different results, and would need to be determined in further study.

Dr. Anderson agreed that “SGLT2 inhibitors and GLP1 agonists are broadly much safer than the older diabetes medicines, at least when it comes to risk of hypoglycemia, and may have more clear benefits in heart disease and mortality. So I would not want to extrapolate our findings to those new classes,” he said. “A similar set of studies would need to be done.”
 

Study rationale and findings

Hospitalized older adults with diabetes commonly have transiently elevated blood glucose levels that might lead clinicians to discharge them from hospital with a prescription for more intensive diabetes medications than they were on before they were hospitalized, but it is not clear if these diabetes medication changes would improve outcomes.

To investigate this, the researchers analyzed data from patients with diabetes who were 65 and older and hospitalized for common medical conditions in VHA hospitals during January 2011–September 2016, and then discharged to the community.

They excluded patients who were hospitalized for things that require immediate change in diabetes treatment and patients who were using insulin before their hospitalization (because instructions to modify insulin dosing frequently don’t have a new prescription).

The researchers identified 28,198 adults with diabetes who were not on insulin and were hospitalized in the VHA health system for heart failure (18%), coronary artery disease (13%), chronic obstructive pulmonary disease (10%), pneumonia (9.6%), and urinary tract infection (7.5%), and less often and not in decreasing order, for acute coronary syndrome, arrhythmia, asthma, chest pain, conduction disorders, heart valve disorders, sepsis, skin infection, stroke, and transient ischemic attack.

Of these patients, 2,768 patients (9.8%) received diabetes medication intensification, and the researchers matched 2,648 of these patients with an equal number of patients who did not receive this treatment intensification.

The patients in each group had a mean age of 73 and 98.5% were male; 78% were White.

They had a mean A1c of 7.9%. Most were receiving sulfonylurea (43%) or metformin (39%), and few were receiving thiazolidinediones (4.1%), alpha-glucosidase inhibitors (2.7%), dipeptidyl peptidase 4 inhibitors (2.0%), or other types of diabetes drugs (0.1%).

Of the 2,768 patients who received intensified diabetes medication, most received a prescription for insulin (51%) or sulfonylurea (23%).

In the propensity-matched cohort, patients with intensified diabetes medication had a higher rate of severe hypoglycemia at 30 days (1% vs. 0.5%), which translated into a significant twofold higher risk (hazard ratio, 2.17).

The rates of severe hypoglycemia at 1 year were similar in both groups (3.1% and 2.9%).

The incidence of severe hyperglycemia was the same in both groups at 30 days (0.3%) and 1 year (1.3%).

In secondary outcomes, at 1 year, 48% of new oral diabetes medications and 39% of new insulin prescriptions were no longer being filled.

Overall, patients who were discharged with intensified diabetes medication were significantly less likely to die within 30 days than the other patients (1.3% vs. 2.4%; HR, 0.55).

However, this mortality benefit was found only in the subgroup of 2,524 patients who had uncontrolled diabetes when they were admitted to hospital (A1c >7.5%; mean A1c, 9.1%), and not in the propensity-matched subgroup of 2,672 patients who had controlled diabetes then (A1c up to 7.5%; mean A1c, 6.8%).

There was no significant difference in 1-year mortality in patients with versus without intensified treatment (15.8% vs. 17.8%).

There were also no significant between-group difference in rates of hospital readmission at 30 days (roughly 17%) or 1 year (roughly 51%).

The decreases in mean A1c from hospital discharge to 1 year later were also the same in both groups (going from 7.9% to 7.7%).

The study was funded by grants from the National Institute on Aging and the American College of Cardiology. Dr. Anderson has no relevant financial disclosures. Dr. McCoy reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases, AARP, and the Patient-Centered Outcomes Research Institute outside the submitted work. The disclosures of the other authors and the editorial coauthor are available with the article and commentary.

“Short-term hospitalization [for reasons other than diabetes] may not be the time to intervene in long-term diabetes management,” researchers conclude.

They found that, in a national cohort of older almost entirely male veterans with non–insulin-treated type 2 diabetes who were hospitalized for non–diabetes-related common medical conditions, intensified diabetes treatment on hospital discharge was linked to an increased risk of severe hypoglycemia in the immediate postdischarge period.

However, diabetes treatment intensification – that is, receiving a prescription for a new or higher dose of diabetes medicine – was not associated with decreased risks of severe hyperglycemia or with improved glycemic (hemoglobin A1c) control at 30 days or 1 year, according to study results, published in JAMA Network Open.

“We didn’t see a reduction in diabetes emergencies in more intensively treated patients,” lead investigator Timothy S. Anderson, MD, said in an interview.

Also, importantly, there was a low rate of persistence with the new treatment. “Half of the patients were no longer taking these [intensified diabetes medicines] at 1 year, which tells me that context is key,” he pointed out. “If a patient is in the hospital for diabetes [unlike the patients in this study], I think it makes a lot of sense to modify and adjust their regimen to try to help them right then and there.”

The overall risk of severe hyperglycemia or severe hypoglycemia was pretty small in the overall cohort, Dr. Anderson noted, “but we do put people at risk of leaving the hospital and ending up back in the hospital with low blood sugar when we intensify medications, and there’s not necessarily a good signal to suggest that it’s all that urgent to change these medicines.”

Instead, the “safer path” may be to make recommendations to the patient’s outpatient physician and also inform the patient – for example, “We saw some concerns about your diabetes while you were in the hospital, and this is really something that should be looked at when you’re recovered and feeling better from the rest of your health standpoint” – rather than making a diabetes medication change while the person is acutely ill or recovering from illness, said Dr. Anderson, from Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.

The researchers also found an “unexpected” significant decrease in 30-day mortality in the patients with intensified diabetes treatment, which was probably because of confounding that was not accounted for, Dr. Anderson speculated, since clinical trials have consistently shown that benefits from diabetes medications take a longer time to show an effect.
 

‘Important study,’ but lacked newer meds

This is an “important” study for primary care and in-hospital physicians that shows that “hospitalization is really not the time and the place” to intensify diabetes medication, Rozalina G. McCoy, MD, coauthor of an invited commentary, told this news organization in an interview.

“While overcoming treatment inertia is important, [it should be] done appropriately, so that we don’t overtreat patients,” Dr. McCoy, of the Mayo Clinic in Rochester, Minn., stressed.

The very low rate of persistence of taking intensified medications is a major finding, she agreed. Hospitalized patients “are not in their usual state of health, so if we make long-term treatment decisions based on their acute abnormal situation, that may not be appropriate.”

However, patients with high A1c may benefit from a change at hospital discharge rather than when they see their primary care provider, with the caveat that they need close follow-up as an outpatient.

The study emphasizes the “need for longitudinal patient care rather than episodic patches,” according to Dr. McCoy.

For example, a patient who is hospitalized for a chronic obstructive pulmonary disease or asthma exacerbation may be receiving steroids that cause high blood glucose levels but as soon as they’re done with their steroid course, blood glucose will decrease, so the “need for close outpatient follow-up is very important.”

One limitation of the current work is that an earlier study in the same population by the research group showed that 49% of patients whose treatment regimens were intensified had limited life expectancy or were at or below their A1c goal, so they would not have benefited from the stepped-up treatment, she noted.

Another limitation is that the findings cannot be generalized to women or younger patients, or to patients treated with glucagonlike peptide 1 (GLP-1)–receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors.

The study patients were seen in the U.S. Veterans Health Administration health system when these newer agents were not used. Three-quarters of patients received intensified treatment with sulfonylurea or insulin, and only one patient received a new GLP-1–receptor agonist.

Ideally, Dr. McCoy said, patients should have been prescribed a GLP-1–receptor agonist if they had atherosclerotic cardiovascular disease or kidney disease, or an SGLT2 inhibitor if they had kidney disease or heart failure, which may have led to different results, and would need to be determined in further study.

Dr. Anderson agreed that “SGLT2 inhibitors and GLP1 agonists are broadly much safer than the older diabetes medicines, at least when it comes to risk of hypoglycemia, and may have more clear benefits in heart disease and mortality. So I would not want to extrapolate our findings to those new classes,” he said. “A similar set of studies would need to be done.”
 

Study rationale and findings

Hospitalized older adults with diabetes commonly have transiently elevated blood glucose levels that might lead clinicians to discharge them from hospital with a prescription for more intensive diabetes medications than they were on before they were hospitalized, but it is not clear if these diabetes medication changes would improve outcomes.

To investigate this, the researchers analyzed data from patients with diabetes who were 65 and older and hospitalized for common medical conditions in VHA hospitals during January 2011–September 2016, and then discharged to the community.

They excluded patients who were hospitalized for things that require immediate change in diabetes treatment and patients who were using insulin before their hospitalization (because instructions to modify insulin dosing frequently don’t have a new prescription).

The researchers identified 28,198 adults with diabetes who were not on insulin and were hospitalized in the VHA health system for heart failure (18%), coronary artery disease (13%), chronic obstructive pulmonary disease (10%), pneumonia (9.6%), and urinary tract infection (7.5%), and less often and not in decreasing order, for acute coronary syndrome, arrhythmia, asthma, chest pain, conduction disorders, heart valve disorders, sepsis, skin infection, stroke, and transient ischemic attack.

Of these patients, 2,768 patients (9.8%) received diabetes medication intensification, and the researchers matched 2,648 of these patients with an equal number of patients who did not receive this treatment intensification.

The patients in each group had a mean age of 73 and 98.5% were male; 78% were White.

They had a mean A1c of 7.9%. Most were receiving sulfonylurea (43%) or metformin (39%), and few were receiving thiazolidinediones (4.1%), alpha-glucosidase inhibitors (2.7%), dipeptidyl peptidase 4 inhibitors (2.0%), or other types of diabetes drugs (0.1%).

Of the 2,768 patients who received intensified diabetes medication, most received a prescription for insulin (51%) or sulfonylurea (23%).

In the propensity-matched cohort, patients with intensified diabetes medication had a higher rate of severe hypoglycemia at 30 days (1% vs. 0.5%), which translated into a significant twofold higher risk (hazard ratio, 2.17).

The rates of severe hypoglycemia at 1 year were similar in both groups (3.1% and 2.9%).

The incidence of severe hyperglycemia was the same in both groups at 30 days (0.3%) and 1 year (1.3%).

In secondary outcomes, at 1 year, 48% of new oral diabetes medications and 39% of new insulin prescriptions were no longer being filled.

Overall, patients who were discharged with intensified diabetes medication were significantly less likely to die within 30 days than the other patients (1.3% vs. 2.4%; HR, 0.55).

However, this mortality benefit was found only in the subgroup of 2,524 patients who had uncontrolled diabetes when they were admitted to hospital (A1c >7.5%; mean A1c, 9.1%), and not in the propensity-matched subgroup of 2,672 patients who had controlled diabetes then (A1c up to 7.5%; mean A1c, 6.8%).

There was no significant difference in 1-year mortality in patients with versus without intensified treatment (15.8% vs. 17.8%).

There were also no significant between-group difference in rates of hospital readmission at 30 days (roughly 17%) or 1 year (roughly 51%).

The decreases in mean A1c from hospital discharge to 1 year later were also the same in both groups (going from 7.9% to 7.7%).

The study was funded by grants from the National Institute on Aging and the American College of Cardiology. Dr. Anderson has no relevant financial disclosures. Dr. McCoy reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases, AARP, and the Patient-Centered Outcomes Research Institute outside the submitted work. The disclosures of the other authors and the editorial coauthor are available with the article and commentary.

“Short-term hospitalization [for reasons other than diabetes] may not be the time to intervene in long-term diabetes management,” researchers conclude.

They found that, in a national cohort of older almost entirely male veterans with non–insulin-treated type 2 diabetes who were hospitalized for non–diabetes-related common medical conditions, intensified diabetes treatment on hospital discharge was linked to an increased risk of severe hypoglycemia in the immediate postdischarge period.

However, diabetes treatment intensification – that is, receiving a prescription for a new or higher dose of diabetes medicine – was not associated with decreased risks of severe hyperglycemia or with improved glycemic (hemoglobin A1c) control at 30 days or 1 year, according to study results, published in JAMA Network Open.

“We didn’t see a reduction in diabetes emergencies in more intensively treated patients,” lead investigator Timothy S. Anderson, MD, said in an interview.

Also, importantly, there was a low rate of persistence with the new treatment. “Half of the patients were no longer taking these [intensified diabetes medicines] at 1 year, which tells me that context is key,” he pointed out. “If a patient is in the hospital for diabetes [unlike the patients in this study], I think it makes a lot of sense to modify and adjust their regimen to try to help them right then and there.”

The overall risk of severe hyperglycemia or severe hypoglycemia was pretty small in the overall cohort, Dr. Anderson noted, “but we do put people at risk of leaving the hospital and ending up back in the hospital with low blood sugar when we intensify medications, and there’s not necessarily a good signal to suggest that it’s all that urgent to change these medicines.”

Instead, the “safer path” may be to make recommendations to the patient’s outpatient physician and also inform the patient – for example, “We saw some concerns about your diabetes while you were in the hospital, and this is really something that should be looked at when you’re recovered and feeling better from the rest of your health standpoint” – rather than making a diabetes medication change while the person is acutely ill or recovering from illness, said Dr. Anderson, from Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.

The researchers also found an “unexpected” significant decrease in 30-day mortality in the patients with intensified diabetes treatment, which was probably because of confounding that was not accounted for, Dr. Anderson speculated, since clinical trials have consistently shown that benefits from diabetes medications take a longer time to show an effect.
 

‘Important study,’ but lacked newer meds

This is an “important” study for primary care and in-hospital physicians that shows that “hospitalization is really not the time and the place” to intensify diabetes medication, Rozalina G. McCoy, MD, coauthor of an invited commentary, told this news organization in an interview.

“While overcoming treatment inertia is important, [it should be] done appropriately, so that we don’t overtreat patients,” Dr. McCoy, of the Mayo Clinic in Rochester, Minn., stressed.

The very low rate of persistence of taking intensified medications is a major finding, she agreed. Hospitalized patients “are not in their usual state of health, so if we make long-term treatment decisions based on their acute abnormal situation, that may not be appropriate.”

However, patients with high A1c may benefit from a change at hospital discharge rather than when they see their primary care provider, with the caveat that they need close follow-up as an outpatient.

The study emphasizes the “need for longitudinal patient care rather than episodic patches,” according to Dr. McCoy.

For example, a patient who is hospitalized for a chronic obstructive pulmonary disease or asthma exacerbation may be receiving steroids that cause high blood glucose levels but as soon as they’re done with their steroid course, blood glucose will decrease, so the “need for close outpatient follow-up is very important.”

One limitation of the current work is that an earlier study in the same population by the research group showed that 49% of patients whose treatment regimens were intensified had limited life expectancy or were at or below their A1c goal, so they would not have benefited from the stepped-up treatment, she noted.

Another limitation is that the findings cannot be generalized to women or younger patients, or to patients treated with glucagonlike peptide 1 (GLP-1)–receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors.

The study patients were seen in the U.S. Veterans Health Administration health system when these newer agents were not used. Three-quarters of patients received intensified treatment with sulfonylurea or insulin, and only one patient received a new GLP-1–receptor agonist.

Ideally, Dr. McCoy said, patients should have been prescribed a GLP-1–receptor agonist if they had atherosclerotic cardiovascular disease or kidney disease, or an SGLT2 inhibitor if they had kidney disease or heart failure, which may have led to different results, and would need to be determined in further study.

Dr. Anderson agreed that “SGLT2 inhibitors and GLP1 agonists are broadly much safer than the older diabetes medicines, at least when it comes to risk of hypoglycemia, and may have more clear benefits in heart disease and mortality. So I would not want to extrapolate our findings to those new classes,” he said. “A similar set of studies would need to be done.”
 

Study rationale and findings

Hospitalized older adults with diabetes commonly have transiently elevated blood glucose levels that might lead clinicians to discharge them from hospital with a prescription for more intensive diabetes medications than they were on before they were hospitalized, but it is not clear if these diabetes medication changes would improve outcomes.

To investigate this, the researchers analyzed data from patients with diabetes who were 65 and older and hospitalized for common medical conditions in VHA hospitals during January 2011–September 2016, and then discharged to the community.

They excluded patients who were hospitalized for things that require immediate change in diabetes treatment and patients who were using insulin before their hospitalization (because instructions to modify insulin dosing frequently don’t have a new prescription).

The researchers identified 28,198 adults with diabetes who were not on insulin and were hospitalized in the VHA health system for heart failure (18%), coronary artery disease (13%), chronic obstructive pulmonary disease (10%), pneumonia (9.6%), and urinary tract infection (7.5%), and less often and not in decreasing order, for acute coronary syndrome, arrhythmia, asthma, chest pain, conduction disorders, heart valve disorders, sepsis, skin infection, stroke, and transient ischemic attack.

Of these patients, 2,768 patients (9.8%) received diabetes medication intensification, and the researchers matched 2,648 of these patients with an equal number of patients who did not receive this treatment intensification.

The patients in each group had a mean age of 73 and 98.5% were male; 78% were White.

They had a mean A1c of 7.9%. Most were receiving sulfonylurea (43%) or metformin (39%), and few were receiving thiazolidinediones (4.1%), alpha-glucosidase inhibitors (2.7%), dipeptidyl peptidase 4 inhibitors (2.0%), or other types of diabetes drugs (0.1%).

Of the 2,768 patients who received intensified diabetes medication, most received a prescription for insulin (51%) or sulfonylurea (23%).

In the propensity-matched cohort, patients with intensified diabetes medication had a higher rate of severe hypoglycemia at 30 days (1% vs. 0.5%), which translated into a significant twofold higher risk (hazard ratio, 2.17).

The rates of severe hypoglycemia at 1 year were similar in both groups (3.1% and 2.9%).

The incidence of severe hyperglycemia was the same in both groups at 30 days (0.3%) and 1 year (1.3%).

In secondary outcomes, at 1 year, 48% of new oral diabetes medications and 39% of new insulin prescriptions were no longer being filled.

Overall, patients who were discharged with intensified diabetes medication were significantly less likely to die within 30 days than the other patients (1.3% vs. 2.4%; HR, 0.55).

However, this mortality benefit was found only in the subgroup of 2,524 patients who had uncontrolled diabetes when they were admitted to hospital (A1c >7.5%; mean A1c, 9.1%), and not in the propensity-matched subgroup of 2,672 patients who had controlled diabetes then (A1c up to 7.5%; mean A1c, 6.8%).

There was no significant difference in 1-year mortality in patients with versus without intensified treatment (15.8% vs. 17.8%).

There were also no significant between-group difference in rates of hospital readmission at 30 days (roughly 17%) or 1 year (roughly 51%).

The decreases in mean A1c from hospital discharge to 1 year later were also the same in both groups (going from 7.9% to 7.7%).

The study was funded by grants from the National Institute on Aging and the American College of Cardiology. Dr. Anderson has no relevant financial disclosures. Dr. McCoy reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases, AARP, and the Patient-Centered Outcomes Research Institute outside the submitted work. The disclosures of the other authors and the editorial coauthor are available with the article and commentary.

The “twincretin” tirzepatide scored another pivotal-trial win in full, published results from the multicenter SURPASS-4 trial, which compared the investigational agent to insulin glargine for treatment of type 2 diabetes. The study comprised 1,995 randomized patients with inadequately controlled type 2 diabetes and high cardiovascular disease risk.

Positive results for tirzepatide from SURPASS-4, the fifth and final registration trial for the drug, as well as in the other four studies, tee up the agent for a planned approval submission to the Food and Drug Administration by the end of 2021.

SURPASS-4 differed from the four other pivotal trials not only in its comparator agent, but also by being the longest of the five and the only one that, by design, enrolled exclusively patients with either established cardiovascular disease or high risk for the disease.

The new results “provide initial support for glycemic control [by tirzepatide] being sustained for more than 1 year,” wrote Stefano Del Prato, MD, and associates in their published report in The Lancet.

Despite the trial’s primary endpoint of change in hemoglobin A1c after 52 weeks on treatment, the study continued for another year and had a median time on treatment of 85 weeks, with 7% of enrolled patients remaining on treatment for the maximum on-treatment follow-up of 104 weeks.

Potent glycemic control

The primary endpoint showed that treatment with tirzepatide produced an average incremental reduction in A1c of 0.99% among 328 patients treated with a 10 mg weekly subcutaneous dosage compared with the 1,000 patients who received insulin glargine (Basaglar, Lantus, Toujeo), and an average 1.14% incremental reduction in A1c among 338 patients on a 15-mg dosage once weekly, reported Dr. Del Prato, professor and chief of the section of diabetes at the University of Pisa (Italy).

This met the prespecified criteria for noninferiority of tirzepatide to insulin glargine for reduction of A1c, the study’s primary objective, and also met the study’s prespecified definition of superiority, both statistically significant results. The study also tested a weekly tirzepatide dosage of 5 mg that was significantly superior to insulin glargine for glycemic control.

“The magnitude of A1c reduction and the proportions of patients reaching glycemic targets appear to be larger than in similar studies in which GLP-1 [glucagon-like peptide–1] receptor agonists have been compared with glargine,” the investigators wrote in their report.

The A1c effect of tirzepatide seen across all five SURPASS trials “surpasses what we’ve seen with other [glycemia control] drugs, with the possible exception of insulin,” said Jan W. Eriksson, MD, PhD, professor of clinical diabetes and metabolism at Uppsala (Sweden) University.

MDedge News

Safety appears similar to GLP-1 receptor agonists

The safety profile of tirzepatide in SURPASS-4, as it was in all of the other four trials in the SURPASS series, was consistent with previously reported safety of agents in the GLP-1 receptor agonist class, said Dr. Del Prato. It was an expected finding as tirzepatide combines activity as a GLP-1 receptor agonist with activity as a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist in a single molecule.

The most common adverse effects were gastrointestinal, including diarrhea, nausea, decreased appetite, and vomiting. Most of these effects were mild or moderate, and they occurred most often during dose escalation of tirzepatide in the first 24 weeks on treatment.

The GIP receptor agonist effect of tirzepatide may diminish the nausea experienced by patients as a result of the drug’s GLP-1 receptor agonist action, Dr. Eriksson, designated discussant for the SURPASS trials, said during a session Sept. 30 at the virtual annual meeting of the European Association for the Study of Diabetes (EASD).

Clinically significant or severe hypoglycemia occurred in 8% of all patients on tirzepatide, with no apparent dose relationship, about half the rate of the patients treated with insulin glargine. Notably, the hypoglycemia episodes among patients treated with tirzepatide clustered almost entirely in the subgroup of patients who also took a sulfonylurea agent during the study. (SURPASS-4 allowed enrolled patients to be on their background antidiabetes regimen throughout the study, and at baseline 95% were taking metformin, 54% were on a sulfonylurea, and about a quarter were on a sodium-glucose cotransporter-2 inhibitor.)

“I would advise not using tirzepatide with insulin or with a sulfonylurea,” Dr. Eriksson said. Aside from this risk for hypoglycemia when tirzepatide is used concurrently with certain other antidiabetes drugs, the SURPASS trials have shown “no other important safety signals,” Dr. Eriksson added.

Cardiovascular safety

All enrolled patients had either known coronary, cerebrovascular, or peripheral arterial disease or were at high risk for having one or more of these conditions because they were at least 50 years old with a history of either chronic kidney disease with depressed glomerular filtration or heart failure.

During complete follow-up, the composite rate of cardiovascular death, MI, stroke, or hospitalization for unstable angina was numerically less in the patients who received tirzepatide, 5%, than in those on insulin glargine, 6%, a 26% relative risk reduction that did not achieve significance. The rate of total mortality was 3% in the tirzepatide group and 4% among those on glargine, a 30% relative risk reduction that was not significant.

The cardiovascular disease outcomes “suggest that tirzepatide is safe from a cardiovascular perspective,” Dr. Del Prato said when he presented the SURPASS-4 results during the virtual annual meeting of the EASD. However, a much larger cardiovascular outcomes trial of tirzepatide, SURPASS-CVOT, with more than 12,000 randomized patients and using a GLP-1 receptor agonist as the comparator, is now in progress, with a report on the findings expected in 2025.

Sara Freeman/MDedge News

Overall, results from all five SURPASS trials of tirzepatide have shown that the drug is “effective and safe in people with type 2 diabetes, providing stringent glycemic control and additional metabolic benefits including weight reduction and an improvement in other cardiometabolic markers,” said Melanie J. Davies, MD, professor of diabetes medicine at the University of Leicester, England.

Looking forward to when tirzepatide will be available for routine use, Dr. Eriksson positioned it near-term as part of a dual or triple regimen, especially for patients with type 2 diabetes who are obese or have uncontrolled hyperglycemia, renal impairment, high cardiovascular disease risk, or high risk for clinically significant or severe hypoglycemia. 
A role for tirzepatide as a first-line agent is currently “more speculative,” he added, with more data needed on cardiovascular outcomes, long-term safety, and cost effectiveness.

The existing evidence base for tirzepatide shows “very promising efficacy” for weight loss and glucose lowering with “reassuring safety and tolerability,” and is a “very important addition to current options,” although the long-term safety of chronic tirzepatide treatment remains unproven, he said.

Dr. Eriksson called the drug’s glycemic control “strong and durable” based on the entire SURPASS program, with a “major” weight loss effect. He also suggested that while the adverse effect profile of tirzepatide appears similar to the GLP-1 receptor agonists, the incidence of gastrointestinal adverse events may be lower with tirzepatide.

SURPASS-4 and the other SURPASS trials were funded by Lilly, the company developing tirzepatide. Dr. Del Prato has ties with Lilly, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Merck Sharpe and Dohme, Novartis, Novo Nordisk, and Sanofi. Dr. Davies has ties with Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, Novo Nordisk, Sanofi-Aventis, Servier, Gilead Sciences, Napp Pharmaceuticals, Mitsubishi Tanabe, and Takeda. Dr. Eriksson has ties with AstraZeneca, Ilya Pharma, Merck Sharp & Dohme, and Novo Nordisk.

[email protected]

The “twincretin” tirzepatide scored another pivotal-trial win in full, published results from the multicenter SURPASS-4 trial, which compared the investigational agent to insulin glargine for treatment of type 2 diabetes. The study comprised 1,995 randomized patients with inadequately controlled type 2 diabetes and high cardiovascular disease risk.

Positive results for tirzepatide from SURPASS-4, the fifth and final registration trial for the drug, as well as in the other four studies, tee up the agent for a planned approval submission to the Food and Drug Administration by the end of 2021.

SURPASS-4 differed from the four other pivotal trials not only in its comparator agent, but also by being the longest of the five and the only one that, by design, enrolled exclusively patients with either established cardiovascular disease or high risk for the disease.

The new results “provide initial support for glycemic control [by tirzepatide] being sustained for more than 1 year,” wrote Stefano Del Prato, MD, and associates in their published report in The Lancet.

Despite the trial’s primary endpoint of change in hemoglobin A1c after 52 weeks on treatment, the study continued for another year and had a median time on treatment of 85 weeks, with 7% of enrolled patients remaining on treatment for the maximum on-treatment follow-up of 104 weeks.

Potent glycemic control

The primary endpoint showed that treatment with tirzepatide produced an average incremental reduction in A1c of 0.99% among 328 patients treated with a 10 mg weekly subcutaneous dosage compared with the 1,000 patients who received insulin glargine (Basaglar, Lantus, Toujeo), and an average 1.14% incremental reduction in A1c among 338 patients on a 15-mg dosage once weekly, reported Dr. Del Prato, professor and chief of the section of diabetes at the University of Pisa (Italy).

This met the prespecified criteria for noninferiority of tirzepatide to insulin glargine for reduction of A1c, the study’s primary objective, and also met the study’s prespecified definition of superiority, both statistically significant results. The study also tested a weekly tirzepatide dosage of 5 mg that was significantly superior to insulin glargine for glycemic control.

“The magnitude of A1c reduction and the proportions of patients reaching glycemic targets appear to be larger than in similar studies in which GLP-1 [glucagon-like peptide–1] receptor agonists have been compared with glargine,” the investigators wrote in their report.

The A1c effect of tirzepatide seen across all five SURPASS trials “surpasses what we’ve seen with other [glycemia control] drugs, with the possible exception of insulin,” said Jan W. Eriksson, MD, PhD, professor of clinical diabetes and metabolism at Uppsala (Sweden) University.

MDedge News

Safety appears similar to GLP-1 receptor agonists

The safety profile of tirzepatide in SURPASS-4, as it was in all of the other four trials in the SURPASS series, was consistent with previously reported safety of agents in the GLP-1 receptor agonist class, said Dr. Del Prato. It was an expected finding as tirzepatide combines activity as a GLP-1 receptor agonist with activity as a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist in a single molecule.

The most common adverse effects were gastrointestinal, including diarrhea, nausea, decreased appetite, and vomiting. Most of these effects were mild or moderate, and they occurred most often during dose escalation of tirzepatide in the first 24 weeks on treatment.

The GIP receptor agonist effect of tirzepatide may diminish the nausea experienced by patients as a result of the drug’s GLP-1 receptor agonist action, Dr. Eriksson, designated discussant for the SURPASS trials, said during a session Sept. 30 at the virtual annual meeting of the European Association for the Study of Diabetes (EASD).

Clinically significant or severe hypoglycemia occurred in 8% of all patients on tirzepatide, with no apparent dose relationship, about half the rate of the patients treated with insulin glargine. Notably, the hypoglycemia episodes among patients treated with tirzepatide clustered almost entirely in the subgroup of patients who also took a sulfonylurea agent during the study. (SURPASS-4 allowed enrolled patients to be on their background antidiabetes regimen throughout the study, and at baseline 95% were taking metformin, 54% were on a sulfonylurea, and about a quarter were on a sodium-glucose cotransporter-2 inhibitor.)

“I would advise not using tirzepatide with insulin or with a sulfonylurea,” Dr. Eriksson said. Aside from this risk for hypoglycemia when tirzepatide is used concurrently with certain other antidiabetes drugs, the SURPASS trials have shown “no other important safety signals,” Dr. Eriksson added.

Cardiovascular safety

All enrolled patients had either known coronary, cerebrovascular, or peripheral arterial disease or were at high risk for having one or more of these conditions because they were at least 50 years old with a history of either chronic kidney disease with depressed glomerular filtration or heart failure.

During complete follow-up, the composite rate of cardiovascular death, MI, stroke, or hospitalization for unstable angina was numerically less in the patients who received tirzepatide, 5%, than in those on insulin glargine, 6%, a 26% relative risk reduction that did not achieve significance. The rate of total mortality was 3% in the tirzepatide group and 4% among those on glargine, a 30% relative risk reduction that was not significant.

The cardiovascular disease outcomes “suggest that tirzepatide is safe from a cardiovascular perspective,” Dr. Del Prato said when he presented the SURPASS-4 results during the virtual annual meeting of the EASD. However, a much larger cardiovascular outcomes trial of tirzepatide, SURPASS-CVOT, with more than 12,000 randomized patients and using a GLP-1 receptor agonist as the comparator, is now in progress, with a report on the findings expected in 2025.

Sara Freeman/MDedge News

Overall, results from all five SURPASS trials of tirzepatide have shown that the drug is “effective and safe in people with type 2 diabetes, providing stringent glycemic control and additional metabolic benefits including weight reduction and an improvement in other cardiometabolic markers,” said Melanie J. Davies, MD, professor of diabetes medicine at the University of Leicester, England.

Looking forward to when tirzepatide will be available for routine use, Dr. Eriksson positioned it near-term as part of a dual or triple regimen, especially for patients with type 2 diabetes who are obese or have uncontrolled hyperglycemia, renal impairment, high cardiovascular disease risk, or high risk for clinically significant or severe hypoglycemia. 
A role for tirzepatide as a first-line agent is currently “more speculative,” he added, with more data needed on cardiovascular outcomes, long-term safety, and cost effectiveness.

The existing evidence base for tirzepatide shows “very promising efficacy” for weight loss and glucose lowering with “reassuring safety and tolerability,” and is a “very important addition to current options,” although the long-term safety of chronic tirzepatide treatment remains unproven, he said.

Dr. Eriksson called the drug’s glycemic control “strong and durable” based on the entire SURPASS program, with a “major” weight loss effect. He also suggested that while the adverse effect profile of tirzepatide appears similar to the GLP-1 receptor agonists, the incidence of gastrointestinal adverse events may be lower with tirzepatide.

SURPASS-4 and the other SURPASS trials were funded by Lilly, the company developing tirzepatide. Dr. Del Prato has ties with Lilly, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Merck Sharpe and Dohme, Novartis, Novo Nordisk, and Sanofi. Dr. Davies has ties with Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, Novo Nordisk, Sanofi-Aventis, Servier, Gilead Sciences, Napp Pharmaceuticals, Mitsubishi Tanabe, and Takeda. Dr. Eriksson has ties with AstraZeneca, Ilya Pharma, Merck Sharp & Dohme, and Novo Nordisk.

[email protected]

The “twincretin” tirzepatide scored another pivotal-trial win in full, published results from the multicenter SURPASS-4 trial, which compared the investigational agent to insulin glargine for treatment of type 2 diabetes. The study comprised 1,995 randomized patients with inadequately controlled type 2 diabetes and high cardiovascular disease risk.

Positive results for tirzepatide from SURPASS-4, the fifth and final registration trial for the drug, as well as in the other four studies, tee up the agent for a planned approval submission to the Food and Drug Administration by the end of 2021.

SURPASS-4 differed from the four other pivotal trials not only in its comparator agent, but also by being the longest of the five and the only one that, by design, enrolled exclusively patients with either established cardiovascular disease or high risk for the disease.

The new results “provide initial support for glycemic control [by tirzepatide] being sustained for more than 1 year,” wrote Stefano Del Prato, MD, and associates in their published report in The Lancet.

Despite the trial’s primary endpoint of change in hemoglobin A1c after 52 weeks on treatment, the study continued for another year and had a median time on treatment of 85 weeks, with 7% of enrolled patients remaining on treatment for the maximum on-treatment follow-up of 104 weeks.

Potent glycemic control

The primary endpoint showed that treatment with tirzepatide produced an average incremental reduction in A1c of 0.99% among 328 patients treated with a 10 mg weekly subcutaneous dosage compared with the 1,000 patients who received insulin glargine (Basaglar, Lantus, Toujeo), and an average 1.14% incremental reduction in A1c among 338 patients on a 15-mg dosage once weekly, reported Dr. Del Prato, professor and chief of the section of diabetes at the University of Pisa (Italy).

This met the prespecified criteria for noninferiority of tirzepatide to insulin glargine for reduction of A1c, the study’s primary objective, and also met the study’s prespecified definition of superiority, both statistically significant results. The study also tested a weekly tirzepatide dosage of 5 mg that was significantly superior to insulin glargine for glycemic control.

“The magnitude of A1c reduction and the proportions of patients reaching glycemic targets appear to be larger than in similar studies in which GLP-1 [glucagon-like peptide–1] receptor agonists have been compared with glargine,” the investigators wrote in their report.

The A1c effect of tirzepatide seen across all five SURPASS trials “surpasses what we’ve seen with other [glycemia control] drugs, with the possible exception of insulin,” said Jan W. Eriksson, MD, PhD, professor of clinical diabetes and metabolism at Uppsala (Sweden) University.

MDedge News

Safety appears similar to GLP-1 receptor agonists

The safety profile of tirzepatide in SURPASS-4, as it was in all of the other four trials in the SURPASS series, was consistent with previously reported safety of agents in the GLP-1 receptor agonist class, said Dr. Del Prato. It was an expected finding as tirzepatide combines activity as a GLP-1 receptor agonist with activity as a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist in a single molecule.

The most common adverse effects were gastrointestinal, including diarrhea, nausea, decreased appetite, and vomiting. Most of these effects were mild or moderate, and they occurred most often during dose escalation of tirzepatide in the first 24 weeks on treatment.

The GIP receptor agonist effect of tirzepatide may diminish the nausea experienced by patients as a result of the drug’s GLP-1 receptor agonist action, Dr. Eriksson, designated discussant for the SURPASS trials, said during a session Sept. 30 at the virtual annual meeting of the European Association for the Study of Diabetes (EASD).

Clinically significant or severe hypoglycemia occurred in 8% of all patients on tirzepatide, with no apparent dose relationship, about half the rate of the patients treated with insulin glargine. Notably, the hypoglycemia episodes among patients treated with tirzepatide clustered almost entirely in the subgroup of patients who also took a sulfonylurea agent during the study. (SURPASS-4 allowed enrolled patients to be on their background antidiabetes regimen throughout the study, and at baseline 95% were taking metformin, 54% were on a sulfonylurea, and about a quarter were on a sodium-glucose cotransporter-2 inhibitor.)

“I would advise not using tirzepatide with insulin or with a sulfonylurea,” Dr. Eriksson said. Aside from this risk for hypoglycemia when tirzepatide is used concurrently with certain other antidiabetes drugs, the SURPASS trials have shown “no other important safety signals,” Dr. Eriksson added.

Cardiovascular safety

All enrolled patients had either known coronary, cerebrovascular, or peripheral arterial disease or were at high risk for having one or more of these conditions because they were at least 50 years old with a history of either chronic kidney disease with depressed glomerular filtration or heart failure.

During complete follow-up, the composite rate of cardiovascular death, MI, stroke, or hospitalization for unstable angina was numerically less in the patients who received tirzepatide, 5%, than in those on insulin glargine, 6%, a 26% relative risk reduction that did not achieve significance. The rate of total mortality was 3% in the tirzepatide group and 4% among those on glargine, a 30% relative risk reduction that was not significant.

The cardiovascular disease outcomes “suggest that tirzepatide is safe from a cardiovascular perspective,” Dr. Del Prato said when he presented the SURPASS-4 results during the virtual annual meeting of the EASD. However, a much larger cardiovascular outcomes trial of tirzepatide, SURPASS-CVOT, with more than 12,000 randomized patients and using a GLP-1 receptor agonist as the comparator, is now in progress, with a report on the findings expected in 2025.

Sara Freeman/MDedge News

Overall, results from all five SURPASS trials of tirzepatide have shown that the drug is “effective and safe in people with type 2 diabetes, providing stringent glycemic control and additional metabolic benefits including weight reduction and an improvement in other cardiometabolic markers,” said Melanie J. Davies, MD, professor of diabetes medicine at the University of Leicester, England.

Looking forward to when tirzepatide will be available for routine use, Dr. Eriksson positioned it near-term as part of a dual or triple regimen, especially for patients with type 2 diabetes who are obese or have uncontrolled hyperglycemia, renal impairment, high cardiovascular disease risk, or high risk for clinically significant or severe hypoglycemia. 
A role for tirzepatide as a first-line agent is currently “more speculative,” he added, with more data needed on cardiovascular outcomes, long-term safety, and cost effectiveness.

The existing evidence base for tirzepatide shows “very promising efficacy” for weight loss and glucose lowering with “reassuring safety and tolerability,” and is a “very important addition to current options,” although the long-term safety of chronic tirzepatide treatment remains unproven, he said.

Dr. Eriksson called the drug’s glycemic control “strong and durable” based on the entire SURPASS program, with a “major” weight loss effect. He also suggested that while the adverse effect profile of tirzepatide appears similar to the GLP-1 receptor agonists, the incidence of gastrointestinal adverse events may be lower with tirzepatide.

SURPASS-4 and the other SURPASS trials were funded by Lilly, the company developing tirzepatide. Dr. Del Prato has ties with Lilly, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Merck Sharpe and Dohme, Novartis, Novo Nordisk, and Sanofi. Dr. Davies has ties with Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, Novo Nordisk, Sanofi-Aventis, Servier, Gilead Sciences, Napp Pharmaceuticals, Mitsubishi Tanabe, and Takeda. Dr. Eriksson has ties with AstraZeneca, Ilya Pharma, Merck Sharp & Dohme, and Novo Nordisk.

[email protected]

Agents that form the sodium-glucose cotransporter 2 inhibitor class – including canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have show remarkably consistent cardiovascular efficacy and safety for treating patients with heart failure, chronic kidney disease, and higher-risk patients with type 2 diabetes.

But despite an essential role now established for drugs in the SGLT2 inhibitor class for patients with heart failure with reduced ejection fraction, progressive renal dysfunction, or – most recently – patients with heart failure with preserved ejection fraction, the scope may be less clear when using these agents in patients with type 2 diabetes because they fall across a broad spectrum of risk for cardiorenal disease.

“What makes patients with type 2 diabetes distinct from other patients in whom SGLT2 inhibitors have been studied, such as patients with heart failure, is that they have a much wider spectrum of risk. Low-risk patients with type 2 diabetes were not included in the SGLT2 inhibitor trials. Defining risk in patients with type 2 diabetes has the potential to inform prioritization” for treatment with an SGLT2 inhibitor, explained David D. Berg, MD, who has led one effort to develop risk scores that can risk-stratify patients with type 2 diabetes based on their vulnerability to incident heart failure and hospitalization for these episodes,

The hefty cost for these drugs, with retail prices that run over $6,000 annually for the most widely used and most potent agents in the class, has spurred researchers to try to find cost-effective ways to identify patients with type 2 diabetes who stand to benefit most from taking an SGLT2 inhibitor.
 

‘Cost must be considered’

“Cost must be considered, and at this point it’s probably more responsible on a societal level to advise using SGLT2 inhibitors mainly in patients [with type 2 diabetes] with compelling indications,” said Silvio Inzucchi, MD, professor and director of the Yale Medicine Diabetes Center in New Haven, Conn. Dr. Inzucchi added, however, that “I can easily foresee a day when these agents are considered foundational therapy for all patients with type 2 diabetes, after they go generic and cost is not a major issue. I’m starting to lean toward this very simplified approach, but the costs are prohibitive at this time.”

“If the SGLT2 inhibitors were available at a low cost, I’d argue that they should be used in all patients with type 2 diabetes who have no contraindications or tolerability issues; but we live in a world where they are not yet low cost,” agreed Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute in Kansas City, Mo.

“We can’t give SGLT2 inhibitors to everyone with type 2 diabetes right now because that would be too costly; these agents are so expensive. You start by targeting the patients with the highest risk” for incident heart failure, said Ambarish Pandey, MD, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.

The spotlight the SGLT2 inhibitor class has received, based on its unexpectedly potent efficacy in cutting rates of acute heart failure episodes in patients with type 2 diabetes, has also sharply raised the profile of this complication of type 2 diabetes, an outcome that until recently many clinicians had largely ignored, overshadowed by a focus on adverse outcomes from atherosclerotic cardiovascular disease such as MIs and strokes.

“Results from the SGLT2 inhibitor trials have reignited interest in the relationship between type 2 diabetes and heart failure and have started to shift the mindset of clinicians toward thinking about reducing both atherothrombotic risk and heart failure risk in patients with type 2 diabetes,” said Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston.

“Prior to the SGLT2 inhibitor trials, heart failure was on the radar of diabetes clinicians only as something to watch for as a potential side effect of certain glucose-lowering therapies. Now that there are therapies that can lower heart failure hospitalization, it’s made us think more about heart failure, how common it is in patients with type 2 diabetes, and what can we do to lower this risk,” commented Alice Y.Y. Cheng, MD, a diabetes specialist at the University of Toronto.
 

Banking on biomarkers

Risk scores for assessing the likelihood of people developing incident heart failure date back more than a decade. More recent efforts have focused on patients with type 2 diabetes, starting with scores that relied entirely on clinical markers of risk such as prior heart failure, established coronary artery disease, and chronic kidney disease. Reports of two of these validated scores appeared in 2019, one from a team led by Dr. Berg and associates in 2019, and a second score developed by Dr. Pandey and associates.

More recently, both research teams behind these two scores validated newer versions that further refined assessment of patients with diabetes by including biomarkers of incipient heart failure, such as N-terminal of the prohormone brain natriuretic peptide (NT-proBNP). The UT Southwestern group’s biomarker-based score relies on levels of NT-proBNP as well as on levels of high sensitivity troponin T (hsTnT) and C-reactive protein, plus ECG-based assessment of left ventricular hypertrophy to assess risk for incident heart failure. Developers reported in 2021 that this biomarker score could account for 74% (C-statistic) of the 5-year risk for heart failure among patients with diabetes.

The biomarker-based score devised by Dr. Berg and associates, relies on NT-proBNP, hsTnT, and a history of heart failure to predict the risk for a future hospitalization for heart failure. They reported in Diabetes Care that in validation testing this score accounted for 84% of the risk.

“I’m hopeful that both our original clinically-based risk score and our new biomarker-based score will be endorsed by professional society guidelines. The intent of the biomarker-based score is not to replace the clinical one,” Dr. Berg stressed in an interview. But he acknowledged that it uses biomarker values that currently are not routinely collected in U.S. practice. Biomarkers like NT-proBNP “are highly associated with future heart failure risk, but are not yet routinely assessed,” he said. Because of this, “widespread adoption of the [biomarker] risk tool will require some education.”

It may also require some sort of preliminary screening to determine the appropriateness of using it in a specific patient because of the relative expense of a test for NT-proBNP.

A Texas two-step process

“We can’t perform a [NT-proBNP] test on every patient with type 2 diabetes because cost is a huge barrier,” with a U.K. price of roughly £28 (about $40) per test, commented Naveed Sattar, MD, PhD, professor of metabolic medicine at the University of Glasgow. “NT-proBNP is the best biomarker by far to predict risk” for heart failure,” but “it’s too expensive. It’s not going to happen in everyone,” he said in an interview. He suggested taking a two-step approach to identify patients to test for NT-proBNP based on clinical measures like blood pressure, weight and height, lipid levels and renal function and the presence of suggestive symptoms like dyspnea, fatigue, and peripheral edema, an argument he recently spelled out in detail in an editorial he coauthored.

“More work is needed to define which patients would usefully have cardiac biomarkers measured,” Dr. Sattar wrote with his associate.

Two-step is the approach used in routine practice by clinicians at UT Southwestern Medical Center. “We screen all patients with type 2 diabetes and no diagnosed heart failure who are not already on an SGLT2 inhibitor” using their 2019 screening tool, called the WATCH-DM Risk score, said Dr. Pandey. Patients flagged at high risk by their clinical score receive an SGLT2 inhibitor (presuming no contraindications). The remaining patients with low or intermediate risk may then undergo biomarker-based assessment to find additional patients who warrant SGLT2 inhibitor treatment, he said in an interview.

Often, a record of the most important biomarker, NT-proBNP, is already in the patient’s record and less than a year old, in which case clinicians use that value. An NT-proBNP level of at least 125 pg/mL indicates increased risk in people with a body mass index of less than 30 kg/m², while for those with higher body mass indexes clinicians at Southwestern apply a threshold for higher risk of at least 100 pg/mL.

In addition to starting those patients on an SGLT2 inhibitor, the Southwestern protocol calls for intensified efforts at weight loss and improved fitness to further lower incident heart failure risk, and they are also considering targeting treatment with a glucagonlike peptide–1 receptor agonist to these patients as well. They have a research protocol in place, called WATCH-DM, that will prospectively assess the efficacy of this strategy.

Despite the cost, others also believe that the time is right for biomarker-based tests to boost access to the benefits that treatment with SGLT2 inhibitors can give patients with type 2 diabetes.

“In theory it’s reasonable” to use a risk score like the recent one reported by Dr. Berg and coauthors, said Vanita R. Aroda, MD, an endocrinologist and director of diabetes clinical research at Brigham and Women’s Hospital in Boston. “We need to pay attention to heart failure as an outcome and use risk stratification” to decide which patients with type 2 diabetes but without established cardiovascular disease warrant treatment with an SGLT2 inhibitor, she said in an interview. “Given the data, we need more concrete recommendations” from medical societies on how to reasonably use biomarkers and imaging to identify patients with type 2 diabetes who are at increased risk for heart failure and hence would benefit from treatment. “This should be of high interest to guidelines committees,” she added.

The earlier version of Dr. Berg’s score, based exclusively on clinical observations and conventional measures like estimated glomerular filtration rate and urinary creatinine to albumin ratio, had overlap with established criteria for starting treatment with an SGLT2 inhibitor, such as the presence of chronic kidney disease, she noted. “A biomarker-based score may provide the additional level of discrimination needed to characterize risk and potential benefit.”
 

Asymptomatic diabetic cardiomyopathy

Dr. Aroda and several coauthors recently published a review that describes a subset of patients with type 2 diabetes who might get picked up by intensified screening for heart failure risk: those with asymptomatic diabetic cardiomyopathy, a clinical state that they said represents patients with stage B heart failure based on the new Universal Definition and Classification of Heart Failure. Until recently, these patients with type 2 diabetes and asymptomatic cardiomyopathy have mostly gone unrecognized.

A recent report from Dr. Pandey and associates reviewed records from 2,900 U.S. patients with diabetes and no symptoms who had been included in any of three cohort studies and found echocardiographic evidence of early-stage cardiomyopathy in as many as two-thirds. In an editorial about this report, Dr. Aroda and coauthors called these patients a potential “window of opportunity for prevention and treatment of heart failure.”

“There is evidence of structural cardiac changes that progress through the stages of heart failure,” and starting treatment with an SGLT2 inhibitor during an earlier stage can potentially slow or prevent this progression and thereby limit future functional decline, Dr. Aroda said.

Dr. Sattar agreed. Type 2 diabetes appears to help cause “fluid derangements” and abnormal hemodynamics that produces cardiac stress, changes in heart structure, and adverse remodeling of the heart, a process that “some call cardiomyopathy,” which is exacerbated by other pathologic forces that are also often present in these patients such as obesity and hypertension. SGLT2 inhibitors can help these patients by producing “reverse remodeling of the heart.”

“This process was neglected because for many years our focus was on ischemic heart disease in patients with type 2 diabetes. It was there in plain sight, but we were missing it,” explained Dr. Sattar. Having agents from the SGLT2 inhibitor class “has allowed us to better understand this mechanism.”

The SGLT2 inhibitors are “absolutely the driving reason” why the diabetes–heart failure link has become so important, said Dr. Inzucchi. Having drugs that reduce heart failure risk provided clinicians with a tool that has “changed our mindset.”

“Heart failure prevention has been largely neglected in patients with type 2 diabetes. Reprioritizing heart failure prevention to first and foremost among patients with type 2 diabetes is long overdue,” commented Gregg C. Fonarow, MD, professor and chief of cardiology at the University of California, Los Angeles.
 

Clinicians don’t like risk scores

Will systematic screening for heart failure risk in selected patients with type 2 diabetes take hold, and with it expanded and better-targeted use of SGLT2 inhibitors?

“I hope so,” said Dr. Kosiborod, but one challenge is that “for the most part clinicians don’t like using risk scores.” Only a few have ever been widely incorporated into practice; mostly they become tools for research. Plus, SGLT2 inhibitor uptake has in general been slow to catch on, which Dr. Kosiborod blames primarily on clinical inertia, a pervasive issue that has also hampered optimal use of drugs as commonplace as statins, ACE inhibitors, and angiotensin-receptor blockers.

“Given the avalanche of positive data, uptake of SGLT2 inhibitors will continue to improve and accelerate; but unfortunately, unless something dramatic happens we’ll likely see their continued underuse for several more years,” he predicted. “Designing better systems of care that prioritize prevention are absolutely needed to improve implementation of effective therapies, including SGLT2 inhibitors.”

Despite their underuse the SGLT2 inhibitor class has, in just 6 years since results from the EMPA-REG OUTCOME trial came out and launched the current treatment era, transformed thinking about the risk that heart failure poses to patients with type 2 diabetes and the need to manage this risk.

“I thank the SGLT2 inhibitors for raising awareness of heart failure risk in patients with diabetes,” and for giving clinicians a new way to mitigate this risk, said Dr. Cheng.

Dr. Berg has been a consultant to AstraZeneca, and received research grant support to his institution from AstraZeneca and Pfizer. Dr. Cheng has received personal fees from multiple pharmaceutical companies. Dr. Kosiborod has been an adviser and consultant to multiple pharmaceutical companies; has received research grants from AstraZeneca and Boehringer Ingelheim; and has received other research support from AstraZeneca. Dr. Pandey has been an adviser to Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received research support from Gilead Sciences, Myovista, and Applied Therapeutics. Dr. Sattar has received consulting honoraria from multiple pharmaceutical companies, and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and Novartis. Dr. Aroda has been a consultant for several pharmaceutical companies; has a spouse employed with Janssen; and has received research support (institutional contracts) from multiple pharmaceutical companies. Dr. Fonarow has been a consultant to several pharmaceutical companies.

[email protected]

Agents that form the sodium-glucose cotransporter 2 inhibitor class – including canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have show remarkably consistent cardiovascular efficacy and safety for treating patients with heart failure, chronic kidney disease, and higher-risk patients with type 2 diabetes.

But despite an essential role now established for drugs in the SGLT2 inhibitor class for patients with heart failure with reduced ejection fraction, progressive renal dysfunction, or – most recently – patients with heart failure with preserved ejection fraction, the scope may be less clear when using these agents in patients with type 2 diabetes because they fall across a broad spectrum of risk for cardiorenal disease.

“What makes patients with type 2 diabetes distinct from other patients in whom SGLT2 inhibitors have been studied, such as patients with heart failure, is that they have a much wider spectrum of risk. Low-risk patients with type 2 diabetes were not included in the SGLT2 inhibitor trials. Defining risk in patients with type 2 diabetes has the potential to inform prioritization” for treatment with an SGLT2 inhibitor, explained David D. Berg, MD, who has led one effort to develop risk scores that can risk-stratify patients with type 2 diabetes based on their vulnerability to incident heart failure and hospitalization for these episodes,

The hefty cost for these drugs, with retail prices that run over $6,000 annually for the most widely used and most potent agents in the class, has spurred researchers to try to find cost-effective ways to identify patients with type 2 diabetes who stand to benefit most from taking an SGLT2 inhibitor.
 

‘Cost must be considered’

“Cost must be considered, and at this point it’s probably more responsible on a societal level to advise using SGLT2 inhibitors mainly in patients [with type 2 diabetes] with compelling indications,” said Silvio Inzucchi, MD, professor and director of the Yale Medicine Diabetes Center in New Haven, Conn. Dr. Inzucchi added, however, that “I can easily foresee a day when these agents are considered foundational therapy for all patients with type 2 diabetes, after they go generic and cost is not a major issue. I’m starting to lean toward this very simplified approach, but the costs are prohibitive at this time.”

“If the SGLT2 inhibitors were available at a low cost, I’d argue that they should be used in all patients with type 2 diabetes who have no contraindications or tolerability issues; but we live in a world where they are not yet low cost,” agreed Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute in Kansas City, Mo.

“We can’t give SGLT2 inhibitors to everyone with type 2 diabetes right now because that would be too costly; these agents are so expensive. You start by targeting the patients with the highest risk” for incident heart failure, said Ambarish Pandey, MD, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.

The spotlight the SGLT2 inhibitor class has received, based on its unexpectedly potent efficacy in cutting rates of acute heart failure episodes in patients with type 2 diabetes, has also sharply raised the profile of this complication of type 2 diabetes, an outcome that until recently many clinicians had largely ignored, overshadowed by a focus on adverse outcomes from atherosclerotic cardiovascular disease such as MIs and strokes.

“Results from the SGLT2 inhibitor trials have reignited interest in the relationship between type 2 diabetes and heart failure and have started to shift the mindset of clinicians toward thinking about reducing both atherothrombotic risk and heart failure risk in patients with type 2 diabetes,” said Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston.

“Prior to the SGLT2 inhibitor trials, heart failure was on the radar of diabetes clinicians only as something to watch for as a potential side effect of certain glucose-lowering therapies. Now that there are therapies that can lower heart failure hospitalization, it’s made us think more about heart failure, how common it is in patients with type 2 diabetes, and what can we do to lower this risk,” commented Alice Y.Y. Cheng, MD, a diabetes specialist at the University of Toronto.
 

Banking on biomarkers

Risk scores for assessing the likelihood of people developing incident heart failure date back more than a decade. More recent efforts have focused on patients with type 2 diabetes, starting with scores that relied entirely on clinical markers of risk such as prior heart failure, established coronary artery disease, and chronic kidney disease. Reports of two of these validated scores appeared in 2019, one from a team led by Dr. Berg and associates in 2019, and a second score developed by Dr. Pandey and associates.

More recently, both research teams behind these two scores validated newer versions that further refined assessment of patients with diabetes by including biomarkers of incipient heart failure, such as N-terminal of the prohormone brain natriuretic peptide (NT-proBNP). The UT Southwestern group’s biomarker-based score relies on levels of NT-proBNP as well as on levels of high sensitivity troponin T (hsTnT) and C-reactive protein, plus ECG-based assessment of left ventricular hypertrophy to assess risk for incident heart failure. Developers reported in 2021 that this biomarker score could account for 74% (C-statistic) of the 5-year risk for heart failure among patients with diabetes.

The biomarker-based score devised by Dr. Berg and associates, relies on NT-proBNP, hsTnT, and a history of heart failure to predict the risk for a future hospitalization for heart failure. They reported in Diabetes Care that in validation testing this score accounted for 84% of the risk.

“I’m hopeful that both our original clinically-based risk score and our new biomarker-based score will be endorsed by professional society guidelines. The intent of the biomarker-based score is not to replace the clinical one,” Dr. Berg stressed in an interview. But he acknowledged that it uses biomarker values that currently are not routinely collected in U.S. practice. Biomarkers like NT-proBNP “are highly associated with future heart failure risk, but are not yet routinely assessed,” he said. Because of this, “widespread adoption of the [biomarker] risk tool will require some education.”

It may also require some sort of preliminary screening to determine the appropriateness of using it in a specific patient because of the relative expense of a test for NT-proBNP.

A Texas two-step process

“We can’t perform a [NT-proBNP] test on every patient with type 2 diabetes because cost is a huge barrier,” with a U.K. price of roughly £28 (about $40) per test, commented Naveed Sattar, MD, PhD, professor of metabolic medicine at the University of Glasgow. “NT-proBNP is the best biomarker by far to predict risk” for heart failure,” but “it’s too expensive. It’s not going to happen in everyone,” he said in an interview. He suggested taking a two-step approach to identify patients to test for NT-proBNP based on clinical measures like blood pressure, weight and height, lipid levels and renal function and the presence of suggestive symptoms like dyspnea, fatigue, and peripheral edema, an argument he recently spelled out in detail in an editorial he coauthored.

“More work is needed to define which patients would usefully have cardiac biomarkers measured,” Dr. Sattar wrote with his associate.

Two-step is the approach used in routine practice by clinicians at UT Southwestern Medical Center. “We screen all patients with type 2 diabetes and no diagnosed heart failure who are not already on an SGLT2 inhibitor” using their 2019 screening tool, called the WATCH-DM Risk score, said Dr. Pandey. Patients flagged at high risk by their clinical score receive an SGLT2 inhibitor (presuming no contraindications). The remaining patients with low or intermediate risk may then undergo biomarker-based assessment to find additional patients who warrant SGLT2 inhibitor treatment, he said in an interview.

Often, a record of the most important biomarker, NT-proBNP, is already in the patient’s record and less than a year old, in which case clinicians use that value. An NT-proBNP level of at least 125 pg/mL indicates increased risk in people with a body mass index of less than 30 kg/m², while for those with higher body mass indexes clinicians at Southwestern apply a threshold for higher risk of at least 100 pg/mL.

In addition to starting those patients on an SGLT2 inhibitor, the Southwestern protocol calls for intensified efforts at weight loss and improved fitness to further lower incident heart failure risk, and they are also considering targeting treatment with a glucagonlike peptide–1 receptor agonist to these patients as well. They have a research protocol in place, called WATCH-DM, that will prospectively assess the efficacy of this strategy.

Despite the cost, others also believe that the time is right for biomarker-based tests to boost access to the benefits that treatment with SGLT2 inhibitors can give patients with type 2 diabetes.

“In theory it’s reasonable” to use a risk score like the recent one reported by Dr. Berg and coauthors, said Vanita R. Aroda, MD, an endocrinologist and director of diabetes clinical research at Brigham and Women’s Hospital in Boston. “We need to pay attention to heart failure as an outcome and use risk stratification” to decide which patients with type 2 diabetes but without established cardiovascular disease warrant treatment with an SGLT2 inhibitor, she said in an interview. “Given the data, we need more concrete recommendations” from medical societies on how to reasonably use biomarkers and imaging to identify patients with type 2 diabetes who are at increased risk for heart failure and hence would benefit from treatment. “This should be of high interest to guidelines committees,” she added.

The earlier version of Dr. Berg’s score, based exclusively on clinical observations and conventional measures like estimated glomerular filtration rate and urinary creatinine to albumin ratio, had overlap with established criteria for starting treatment with an SGLT2 inhibitor, such as the presence of chronic kidney disease, she noted. “A biomarker-based score may provide the additional level of discrimination needed to characterize risk and potential benefit.”
 

Asymptomatic diabetic cardiomyopathy

Dr. Aroda and several coauthors recently published a review that describes a subset of patients with type 2 diabetes who might get picked up by intensified screening for heart failure risk: those with asymptomatic diabetic cardiomyopathy, a clinical state that they said represents patients with stage B heart failure based on the new Universal Definition and Classification of Heart Failure. Until recently, these patients with type 2 diabetes and asymptomatic cardiomyopathy have mostly gone unrecognized.

A recent report from Dr. Pandey and associates reviewed records from 2,900 U.S. patients with diabetes and no symptoms who had been included in any of three cohort studies and found echocardiographic evidence of early-stage cardiomyopathy in as many as two-thirds. In an editorial about this report, Dr. Aroda and coauthors called these patients a potential “window of opportunity for prevention and treatment of heart failure.”

“There is evidence of structural cardiac changes that progress through the stages of heart failure,” and starting treatment with an SGLT2 inhibitor during an earlier stage can potentially slow or prevent this progression and thereby limit future functional decline, Dr. Aroda said.

Dr. Sattar agreed. Type 2 diabetes appears to help cause “fluid derangements” and abnormal hemodynamics that produces cardiac stress, changes in heart structure, and adverse remodeling of the heart, a process that “some call cardiomyopathy,” which is exacerbated by other pathologic forces that are also often present in these patients such as obesity and hypertension. SGLT2 inhibitors can help these patients by producing “reverse remodeling of the heart.”

“This process was neglected because for many years our focus was on ischemic heart disease in patients with type 2 diabetes. It was there in plain sight, but we were missing it,” explained Dr. Sattar. Having agents from the SGLT2 inhibitor class “has allowed us to better understand this mechanism.”

The SGLT2 inhibitors are “absolutely the driving reason” why the diabetes–heart failure link has become so important, said Dr. Inzucchi. Having drugs that reduce heart failure risk provided clinicians with a tool that has “changed our mindset.”

“Heart failure prevention has been largely neglected in patients with type 2 diabetes. Reprioritizing heart failure prevention to first and foremost among patients with type 2 diabetes is long overdue,” commented Gregg C. Fonarow, MD, professor and chief of cardiology at the University of California, Los Angeles.
 

Clinicians don’t like risk scores

Will systematic screening for heart failure risk in selected patients with type 2 diabetes take hold, and with it expanded and better-targeted use of SGLT2 inhibitors?

“I hope so,” said Dr. Kosiborod, but one challenge is that “for the most part clinicians don’t like using risk scores.” Only a few have ever been widely incorporated into practice; mostly they become tools for research. Plus, SGLT2 inhibitor uptake has in general been slow to catch on, which Dr. Kosiborod blames primarily on clinical inertia, a pervasive issue that has also hampered optimal use of drugs as commonplace as statins, ACE inhibitors, and angiotensin-receptor blockers.

“Given the avalanche of positive data, uptake of SGLT2 inhibitors will continue to improve and accelerate; but unfortunately, unless something dramatic happens we’ll likely see their continued underuse for several more years,” he predicted. “Designing better systems of care that prioritize prevention are absolutely needed to improve implementation of effective therapies, including SGLT2 inhibitors.”

Despite their underuse the SGLT2 inhibitor class has, in just 6 years since results from the EMPA-REG OUTCOME trial came out and launched the current treatment era, transformed thinking about the risk that heart failure poses to patients with type 2 diabetes and the need to manage this risk.

“I thank the SGLT2 inhibitors for raising awareness of heart failure risk in patients with diabetes,” and for giving clinicians a new way to mitigate this risk, said Dr. Cheng.

Dr. Berg has been a consultant to AstraZeneca, and received research grant support to his institution from AstraZeneca and Pfizer. Dr. Cheng has received personal fees from multiple pharmaceutical companies. Dr. Kosiborod has been an adviser and consultant to multiple pharmaceutical companies; has received research grants from AstraZeneca and Boehringer Ingelheim; and has received other research support from AstraZeneca. Dr. Pandey has been an adviser to Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received research support from Gilead Sciences, Myovista, and Applied Therapeutics. Dr. Sattar has received consulting honoraria from multiple pharmaceutical companies, and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and Novartis. Dr. Aroda has been a consultant for several pharmaceutical companies; has a spouse employed with Janssen; and has received research support (institutional contracts) from multiple pharmaceutical companies. Dr. Fonarow has been a consultant to several pharmaceutical companies.

[email protected]

Agents that form the sodium-glucose cotransporter 2 inhibitor class – including canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have show remarkably consistent cardiovascular efficacy and safety for treating patients with heart failure, chronic kidney disease, and higher-risk patients with type 2 diabetes.

But despite an essential role now established for drugs in the SGLT2 inhibitor class for patients with heart failure with reduced ejection fraction, progressive renal dysfunction, or – most recently – patients with heart failure with preserved ejection fraction, the scope may be less clear when using these agents in patients with type 2 diabetes because they fall across a broad spectrum of risk for cardiorenal disease.

“What makes patients with type 2 diabetes distinct from other patients in whom SGLT2 inhibitors have been studied, such as patients with heart failure, is that they have a much wider spectrum of risk. Low-risk patients with type 2 diabetes were not included in the SGLT2 inhibitor trials. Defining risk in patients with type 2 diabetes has the potential to inform prioritization” for treatment with an SGLT2 inhibitor, explained David D. Berg, MD, who has led one effort to develop risk scores that can risk-stratify patients with type 2 diabetes based on their vulnerability to incident heart failure and hospitalization for these episodes,

The hefty cost for these drugs, with retail prices that run over $6,000 annually for the most widely used and most potent agents in the class, has spurred researchers to try to find cost-effective ways to identify patients with type 2 diabetes who stand to benefit most from taking an SGLT2 inhibitor.
 

‘Cost must be considered’

“Cost must be considered, and at this point it’s probably more responsible on a societal level to advise using SGLT2 inhibitors mainly in patients [with type 2 diabetes] with compelling indications,” said Silvio Inzucchi, MD, professor and director of the Yale Medicine Diabetes Center in New Haven, Conn. Dr. Inzucchi added, however, that “I can easily foresee a day when these agents are considered foundational therapy for all patients with type 2 diabetes, after they go generic and cost is not a major issue. I’m starting to lean toward this very simplified approach, but the costs are prohibitive at this time.”

“If the SGLT2 inhibitors were available at a low cost, I’d argue that they should be used in all patients with type 2 diabetes who have no contraindications or tolerability issues; but we live in a world where they are not yet low cost,” agreed Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Cardiometabolic Center of Excellence at Saint Luke’s Mid-America Heart Institute in Kansas City, Mo.

“We can’t give SGLT2 inhibitors to everyone with type 2 diabetes right now because that would be too costly; these agents are so expensive. You start by targeting the patients with the highest risk” for incident heart failure, said Ambarish Pandey, MD, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.

The spotlight the SGLT2 inhibitor class has received, based on its unexpectedly potent efficacy in cutting rates of acute heart failure episodes in patients with type 2 diabetes, has also sharply raised the profile of this complication of type 2 diabetes, an outcome that until recently many clinicians had largely ignored, overshadowed by a focus on adverse outcomes from atherosclerotic cardiovascular disease such as MIs and strokes.

“Results from the SGLT2 inhibitor trials have reignited interest in the relationship between type 2 diabetes and heart failure and have started to shift the mindset of clinicians toward thinking about reducing both atherothrombotic risk and heart failure risk in patients with type 2 diabetes,” said Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston.

“Prior to the SGLT2 inhibitor trials, heart failure was on the radar of diabetes clinicians only as something to watch for as a potential side effect of certain glucose-lowering therapies. Now that there are therapies that can lower heart failure hospitalization, it’s made us think more about heart failure, how common it is in patients with type 2 diabetes, and what can we do to lower this risk,” commented Alice Y.Y. Cheng, MD, a diabetes specialist at the University of Toronto.
 

Banking on biomarkers

Risk scores for assessing the likelihood of people developing incident heart failure date back more than a decade. More recent efforts have focused on patients with type 2 diabetes, starting with scores that relied entirely on clinical markers of risk such as prior heart failure, established coronary artery disease, and chronic kidney disease. Reports of two of these validated scores appeared in 2019, one from a team led by Dr. Berg and associates in 2019, and a second score developed by Dr. Pandey and associates.

More recently, both research teams behind these two scores validated newer versions that further refined assessment of patients with diabetes by including biomarkers of incipient heart failure, such as N-terminal of the prohormone brain natriuretic peptide (NT-proBNP). The UT Southwestern group’s biomarker-based score relies on levels of NT-proBNP as well as on levels of high sensitivity troponin T (hsTnT) and C-reactive protein, plus ECG-based assessment of left ventricular hypertrophy to assess risk for incident heart failure. Developers reported in 2021 that this biomarker score could account for 74% (C-statistic) of the 5-year risk for heart failure among patients with diabetes.

The biomarker-based score devised by Dr. Berg and associates, relies on NT-proBNP, hsTnT, and a history of heart failure to predict the risk for a future hospitalization for heart failure. They reported in Diabetes Care that in validation testing this score accounted for 84% of the risk.

“I’m hopeful that both our original clinically-based risk score and our new biomarker-based score will be endorsed by professional society guidelines. The intent of the biomarker-based score is not to replace the clinical one,” Dr. Berg stressed in an interview. But he acknowledged that it uses biomarker values that currently are not routinely collected in U.S. practice. Biomarkers like NT-proBNP “are highly associated with future heart failure risk, but are not yet routinely assessed,” he said. Because of this, “widespread adoption of the [biomarker] risk tool will require some education.”

It may also require some sort of preliminary screening to determine the appropriateness of using it in a specific patient because of the relative expense of a test for NT-proBNP.

A Texas two-step process

“We can’t perform a [NT-proBNP] test on every patient with type 2 diabetes because cost is a huge barrier,” with a U.K. price of roughly £28 (about $40) per test, commented Naveed Sattar, MD, PhD, professor of metabolic medicine at the University of Glasgow. “NT-proBNP is the best biomarker by far to predict risk” for heart failure,” but “it’s too expensive. It’s not going to happen in everyone,” he said in an interview. He suggested taking a two-step approach to identify patients to test for NT-proBNP based on clinical measures like blood pressure, weight and height, lipid levels and renal function and the presence of suggestive symptoms like dyspnea, fatigue, and peripheral edema, an argument he recently spelled out in detail in an editorial he coauthored.

“More work is needed to define which patients would usefully have cardiac biomarkers measured,” Dr. Sattar wrote with his associate.

Two-step is the approach used in routine practice by clinicians at UT Southwestern Medical Center. “We screen all patients with type 2 diabetes and no diagnosed heart failure who are not already on an SGLT2 inhibitor” using their 2019 screening tool, called the WATCH-DM Risk score, said Dr. Pandey. Patients flagged at high risk by their clinical score receive an SGLT2 inhibitor (presuming no contraindications). The remaining patients with low or intermediate risk may then undergo biomarker-based assessment to find additional patients who warrant SGLT2 inhibitor treatment, he said in an interview.

Often, a record of the most important biomarker, NT-proBNP, is already in the patient’s record and less than a year old, in which case clinicians use that value. An NT-proBNP level of at least 125 pg/mL indicates increased risk in people with a body mass index of less than 30 kg/m², while for those with higher body mass indexes clinicians at Southwestern apply a threshold for higher risk of at least 100 pg/mL.

In addition to starting those patients on an SGLT2 inhibitor, the Southwestern protocol calls for intensified efforts at weight loss and improved fitness to further lower incident heart failure risk, and they are also considering targeting treatment with a glucagonlike peptide–1 receptor agonist to these patients as well. They have a research protocol in place, called WATCH-DM, that will prospectively assess the efficacy of this strategy.

Despite the cost, others also believe that the time is right for biomarker-based tests to boost access to the benefits that treatment with SGLT2 inhibitors can give patients with type 2 diabetes.

“In theory it’s reasonable” to use a risk score like the recent one reported by Dr. Berg and coauthors, said Vanita R. Aroda, MD, an endocrinologist and director of diabetes clinical research at Brigham and Women’s Hospital in Boston. “We need to pay attention to heart failure as an outcome and use risk stratification” to decide which patients with type 2 diabetes but without established cardiovascular disease warrant treatment with an SGLT2 inhibitor, she said in an interview. “Given the data, we need more concrete recommendations” from medical societies on how to reasonably use biomarkers and imaging to identify patients with type 2 diabetes who are at increased risk for heart failure and hence would benefit from treatment. “This should be of high interest to guidelines committees,” she added.

The earlier version of Dr. Berg’s score, based exclusively on clinical observations and conventional measures like estimated glomerular filtration rate and urinary creatinine to albumin ratio, had overlap with established criteria for starting treatment with an SGLT2 inhibitor, such as the presence of chronic kidney disease, she noted. “A biomarker-based score may provide the additional level of discrimination needed to characterize risk and potential benefit.”
 

Asymptomatic diabetic cardiomyopathy

Dr. Aroda and several coauthors recently published a review that describes a subset of patients with type 2 diabetes who might get picked up by intensified screening for heart failure risk: those with asymptomatic diabetic cardiomyopathy, a clinical state that they said represents patients with stage B heart failure based on the new Universal Definition and Classification of Heart Failure. Until recently, these patients with type 2 diabetes and asymptomatic cardiomyopathy have mostly gone unrecognized.

A recent report from Dr. Pandey and associates reviewed records from 2,900 U.S. patients with diabetes and no symptoms who had been included in any of three cohort studies and found echocardiographic evidence of early-stage cardiomyopathy in as many as two-thirds. In an editorial about this report, Dr. Aroda and coauthors called these patients a potential “window of opportunity for prevention and treatment of heart failure.”

“There is evidence of structural cardiac changes that progress through the stages of heart failure,” and starting treatment with an SGLT2 inhibitor during an earlier stage can potentially slow or prevent this progression and thereby limit future functional decline, Dr. Aroda said.

Dr. Sattar agreed. Type 2 diabetes appears to help cause “fluid derangements” and abnormal hemodynamics that produces cardiac stress, changes in heart structure, and adverse remodeling of the heart, a process that “some call cardiomyopathy,” which is exacerbated by other pathologic forces that are also often present in these patients such as obesity and hypertension. SGLT2 inhibitors can help these patients by producing “reverse remodeling of the heart.”

“This process was neglected because for many years our focus was on ischemic heart disease in patients with type 2 diabetes. It was there in plain sight, but we were missing it,” explained Dr. Sattar. Having agents from the SGLT2 inhibitor class “has allowed us to better understand this mechanism.”

The SGLT2 inhibitors are “absolutely the driving reason” why the diabetes–heart failure link has become so important, said Dr. Inzucchi. Having drugs that reduce heart failure risk provided clinicians with a tool that has “changed our mindset.”

“Heart failure prevention has been largely neglected in patients with type 2 diabetes. Reprioritizing heart failure prevention to first and foremost among patients with type 2 diabetes is long overdue,” commented Gregg C. Fonarow, MD, professor and chief of cardiology at the University of California, Los Angeles.
 

Clinicians don’t like risk scores

Will systematic screening for heart failure risk in selected patients with type 2 diabetes take hold, and with it expanded and better-targeted use of SGLT2 inhibitors?

“I hope so,” said Dr. Kosiborod, but one challenge is that “for the most part clinicians don’t like using risk scores.” Only a few have ever been widely incorporated into practice; mostly they become tools for research. Plus, SGLT2 inhibitor uptake has in general been slow to catch on, which Dr. Kosiborod blames primarily on clinical inertia, a pervasive issue that has also hampered optimal use of drugs as commonplace as statins, ACE inhibitors, and angiotensin-receptor blockers.

“Given the avalanche of positive data, uptake of SGLT2 inhibitors will continue to improve and accelerate; but unfortunately, unless something dramatic happens we’ll likely see their continued underuse for several more years,” he predicted. “Designing better systems of care that prioritize prevention are absolutely needed to improve implementation of effective therapies, including SGLT2 inhibitors.”

Despite their underuse the SGLT2 inhibitor class has, in just 6 years since results from the EMPA-REG OUTCOME trial came out and launched the current treatment era, transformed thinking about the risk that heart failure poses to patients with type 2 diabetes and the need to manage this risk.

“I thank the SGLT2 inhibitors for raising awareness of heart failure risk in patients with diabetes,” and for giving clinicians a new way to mitigate this risk, said Dr. Cheng.

Dr. Berg has been a consultant to AstraZeneca, and received research grant support to his institution from AstraZeneca and Pfizer. Dr. Cheng has received personal fees from multiple pharmaceutical companies. Dr. Kosiborod has been an adviser and consultant to multiple pharmaceutical companies; has received research grants from AstraZeneca and Boehringer Ingelheim; and has received other research support from AstraZeneca. Dr. Pandey has been an adviser to Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received research support from Gilead Sciences, Myovista, and Applied Therapeutics. Dr. Sattar has received consulting honoraria from multiple pharmaceutical companies, and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and Novartis. Dr. Aroda has been a consultant for several pharmaceutical companies; has a spouse employed with Janssen; and has received research support (institutional contracts) from multiple pharmaceutical companies. Dr. Fonarow has been a consultant to several pharmaceutical companies.

[email protected]

While type 2 diabetes is associated with a greater risk for cardiovascular events than type 1 diabetes, the latter is more associated with chronic kidney complications, according to data from a French observational study.

That’s not to say that type 1 diabetes isn’t also associated with poor heart health that is of concern, according to Denis Angoulvant, MD, of Tours (France) Regional University Hospital and Trousseau Hospital in Paris.

“The difference is that, in the middle or older ages, we suddenly see a surge of cardiovascular events in type 1 diabetic patients,” he said at the annual meeting of the European Association for the Study of Diabetes. “As a cardiologist, I must say that we are barely see these patients ahead of those complications, so we advocate that there’s a gap to be filled here to prevent these events in these patients.”

Few studies have looked at the comparative risks for cardiovascular and renal outcomes between patients with type 1 and type 2 diabetes, Dr. Angoulvant said, so the aim of the study he presented was to look at this in more detail.
 

Comparing cardiovascular and renal outcomes

Data from the French hospital discharge database (PMSI), which covers more than 98% of the country’s population, were used to find all adults with type 1 or type 2 diabetes who had at least 5 years of follow-up data starting from 2013.

Not surprisingly, there were eight times as many individuals with type 2 diabetes (425,207) than those with type 1 diabetes (50,623), and patients with type 2 diabetes tended to be older than those with type 1 diabetes (mean age, 68.6 vs. 61.4 years).

There were many significant differences between the two groups of patients in terms of clinical variables, such as patients with type 2 diabetes having more cardiovascular risk factors or preexisting heart problems, and those with type 1 diabetes more likely to have diabetic eye disease.

Indeed, Dr. Angoulvant pointed out that those with type 2 diabetes were significantly more likely (all P < .0001) than those with type 1 diabetes to have: hypertension (70.8% vs. 50.5%), heart failure (35.7% vs. 16.4%), valvular heart disease (7.2% vs. 3.5%), dilated cardiomyopathy (5.5% vs. 2.7%), coronary artery disease (27.6 vs. 18.6%), previous MI (3.0% vs. 2.4%), peripheral vascular disease (22.0% vs. 15.5%), and ischemic stroke (3.3 vs. 2.2%).

“Regarding more specific microvascular diabetic complications, we had a higher incidence of chronic kidney disease in type 2 diabetes patients [10.2% vs. 9.1%], but a higher incidence of diabetic retinopathy in type 1 diabetes patients [6.6% vs. 12.2%],” Dr. Angoulvant said.

Considering more than 2 million person-years of follow-up, the annual rates of MI, new-onset heart failure, ischemic stroke, and chronic kidney disease for the whole study population were respective 1.4%, 5.4%, 1.2%, and 3.4%. The annual rates for death from any cause was 9.7%, and for a cardiovascular reason was 2.4%.
 

Cardiovascular disease prevalence and event rates

The mean follow-up period was 4.3 years, and over this time the age- and sex-adjusted prevalence of cardiovascular disease was found to be highest in individuals with type 2 diabetes, especially after the age of 40 years.

Looking at the rates of different cardiovascular events showed that both younger (18-29 years) and older (60+ years) people with type 1 diabetes had a 1.2-fold higher risk for MI than similarly aged individuals with type 2 diabetes.

Furthermore, younger and older type 1 diabetes individuals had a 1.1- to 1.4-fold greater risk of new-onset heart failure than those with type 2 diabetes.

“Interestingly, regarding the incidence of ischemic stroke in our population, we found no significant difference between patients with type 1 diabetes, and patients with type 2 diabetes,” Dr. Angoulvant said.
 

Chronic kidney disease and risk for death

Chronic kidney disease was most common in individuals with type 1 diabetes who were aged between 18 and 69 years, with a greater prevalence also seen in those with type 2 diabetes only after age 80.

The risk of new chronic kidney disease was significantly increased in patients with type 1 diabetes, compared with patients with type 2 diabetes, with a 1.1- to 2.4-fold increase seen, first in individuals aged 18-49 years, and then again after the age of 60 years.

Dr. Angoulvant reported that the risk of dying from any cause was 1.1-fold higher in people with type 1 diabetes, compared with those with type 2 diabetes, but after the age of 60 years.

The risk of death from cardiovascular events was also increased in people with type 1 diabetes, but between the ages of 60 and 69 years.

Asked what his take-home message might be, Dr. Angoulvant stressed the importance of heart failure, in all patients with diabetes but particularly in those with type 1 diabetes.

“I think there is room for improvement in terms of assessing who is going to have heart failure, how to assess heart failure, and more importantly, how to prevent heart failure,” perhaps by “introducing those drugs that have shown tremendous benefit regarding hospitalization, such as [sodium-glucose transporter 2] inhibitors” in patients with type 1 diabetes ahead of the events, he said.

Dr. Angoulvant had no conflicts of interest to disclose.

While type 2 diabetes is associated with a greater risk for cardiovascular events than type 1 diabetes, the latter is more associated with chronic kidney complications, according to data from a French observational study.

That’s not to say that type 1 diabetes isn’t also associated with poor heart health that is of concern, according to Denis Angoulvant, MD, of Tours (France) Regional University Hospital and Trousseau Hospital in Paris.

“The difference is that, in the middle or older ages, we suddenly see a surge of cardiovascular events in type 1 diabetic patients,” he said at the annual meeting of the European Association for the Study of Diabetes. “As a cardiologist, I must say that we are barely see these patients ahead of those complications, so we advocate that there’s a gap to be filled here to prevent these events in these patients.”

Few studies have looked at the comparative risks for cardiovascular and renal outcomes between patients with type 1 and type 2 diabetes, Dr. Angoulvant said, so the aim of the study he presented was to look at this in more detail.
 

Comparing cardiovascular and renal outcomes

Data from the French hospital discharge database (PMSI), which covers more than 98% of the country’s population, were used to find all adults with type 1 or type 2 diabetes who had at least 5 years of follow-up data starting from 2013.

Not surprisingly, there were eight times as many individuals with type 2 diabetes (425,207) than those with type 1 diabetes (50,623), and patients with type 2 diabetes tended to be older than those with type 1 diabetes (mean age, 68.6 vs. 61.4 years).

There were many significant differences between the two groups of patients in terms of clinical variables, such as patients with type 2 diabetes having more cardiovascular risk factors or preexisting heart problems, and those with type 1 diabetes more likely to have diabetic eye disease.

Indeed, Dr. Angoulvant pointed out that those with type 2 diabetes were significantly more likely (all P < .0001) than those with type 1 diabetes to have: hypertension (70.8% vs. 50.5%), heart failure (35.7% vs. 16.4%), valvular heart disease (7.2% vs. 3.5%), dilated cardiomyopathy (5.5% vs. 2.7%), coronary artery disease (27.6 vs. 18.6%), previous MI (3.0% vs. 2.4%), peripheral vascular disease (22.0% vs. 15.5%), and ischemic stroke (3.3 vs. 2.2%).

“Regarding more specific microvascular diabetic complications, we had a higher incidence of chronic kidney disease in type 2 diabetes patients [10.2% vs. 9.1%], but a higher incidence of diabetic retinopathy in type 1 diabetes patients [6.6% vs. 12.2%],” Dr. Angoulvant said.

Considering more than 2 million person-years of follow-up, the annual rates of MI, new-onset heart failure, ischemic stroke, and chronic kidney disease for the whole study population were respective 1.4%, 5.4%, 1.2%, and 3.4%. The annual rates for death from any cause was 9.7%, and for a cardiovascular reason was 2.4%.
 

Cardiovascular disease prevalence and event rates

The mean follow-up period was 4.3 years, and over this time the age- and sex-adjusted prevalence of cardiovascular disease was found to be highest in individuals with type 2 diabetes, especially after the age of 40 years.

Looking at the rates of different cardiovascular events showed that both younger (18-29 years) and older (60+ years) people with type 1 diabetes had a 1.2-fold higher risk for MI than similarly aged individuals with type 2 diabetes.

Furthermore, younger and older type 1 diabetes individuals had a 1.1- to 1.4-fold greater risk of new-onset heart failure than those with type 2 diabetes.

“Interestingly, regarding the incidence of ischemic stroke in our population, we found no significant difference between patients with type 1 diabetes, and patients with type 2 diabetes,” Dr. Angoulvant said.
 

Chronic kidney disease and risk for death

Chronic kidney disease was most common in individuals with type 1 diabetes who were aged between 18 and 69 years, with a greater prevalence also seen in those with type 2 diabetes only after age 80.

The risk of new chronic kidney disease was significantly increased in patients with type 1 diabetes, compared with patients with type 2 diabetes, with a 1.1- to 2.4-fold increase seen, first in individuals aged 18-49 years, and then again after the age of 60 years.

Dr. Angoulvant reported that the risk of dying from any cause was 1.1-fold higher in people with type 1 diabetes, compared with those with type 2 diabetes, but after the age of 60 years.

The risk of death from cardiovascular events was also increased in people with type 1 diabetes, but between the ages of 60 and 69 years.

Asked what his take-home message might be, Dr. Angoulvant stressed the importance of heart failure, in all patients with diabetes but particularly in those with type 1 diabetes.

“I think there is room for improvement in terms of assessing who is going to have heart failure, how to assess heart failure, and more importantly, how to prevent heart failure,” perhaps by “introducing those drugs that have shown tremendous benefit regarding hospitalization, such as [sodium-glucose transporter 2] inhibitors” in patients with type 1 diabetes ahead of the events, he said.

Dr. Angoulvant had no conflicts of interest to disclose.

While type 2 diabetes is associated with a greater risk for cardiovascular events than type 1 diabetes, the latter is more associated with chronic kidney complications, according to data from a French observational study.

That’s not to say that type 1 diabetes isn’t also associated with poor heart health that is of concern, according to Denis Angoulvant, MD, of Tours (France) Regional University Hospital and Trousseau Hospital in Paris.

“The difference is that, in the middle or older ages, we suddenly see a surge of cardiovascular events in type 1 diabetic patients,” he said at the annual meeting of the European Association for the Study of Diabetes. “As a cardiologist, I must say that we are barely see these patients ahead of those complications, so we advocate that there’s a gap to be filled here to prevent these events in these patients.”

Few studies have looked at the comparative risks for cardiovascular and renal outcomes between patients with type 1 and type 2 diabetes, Dr. Angoulvant said, so the aim of the study he presented was to look at this in more detail.
 

Comparing cardiovascular and renal outcomes

Data from the French hospital discharge database (PMSI), which covers more than 98% of the country’s population, were used to find all adults with type 1 or type 2 diabetes who had at least 5 years of follow-up data starting from 2013.

Not surprisingly, there were eight times as many individuals with type 2 diabetes (425,207) than those with type 1 diabetes (50,623), and patients with type 2 diabetes tended to be older than those with type 1 diabetes (mean age, 68.6 vs. 61.4 years).

There were many significant differences between the two groups of patients in terms of clinical variables, such as patients with type 2 diabetes having more cardiovascular risk factors or preexisting heart problems, and those with type 1 diabetes more likely to have diabetic eye disease.

Indeed, Dr. Angoulvant pointed out that those with type 2 diabetes were significantly more likely (all P < .0001) than those with type 1 diabetes to have: hypertension (70.8% vs. 50.5%), heart failure (35.7% vs. 16.4%), valvular heart disease (7.2% vs. 3.5%), dilated cardiomyopathy (5.5% vs. 2.7%), coronary artery disease (27.6 vs. 18.6%), previous MI (3.0% vs. 2.4%), peripheral vascular disease (22.0% vs. 15.5%), and ischemic stroke (3.3 vs. 2.2%).

“Regarding more specific microvascular diabetic complications, we had a higher incidence of chronic kidney disease in type 2 diabetes patients [10.2% vs. 9.1%], but a higher incidence of diabetic retinopathy in type 1 diabetes patients [6.6% vs. 12.2%],” Dr. Angoulvant said.

Considering more than 2 million person-years of follow-up, the annual rates of MI, new-onset heart failure, ischemic stroke, and chronic kidney disease for the whole study population were respective 1.4%, 5.4%, 1.2%, and 3.4%. The annual rates for death from any cause was 9.7%, and for a cardiovascular reason was 2.4%.
 

Cardiovascular disease prevalence and event rates

The mean follow-up period was 4.3 years, and over this time the age- and sex-adjusted prevalence of cardiovascular disease was found to be highest in individuals with type 2 diabetes, especially after the age of 40 years.

Looking at the rates of different cardiovascular events showed that both younger (18-29 years) and older (60+ years) people with type 1 diabetes had a 1.2-fold higher risk for MI than similarly aged individuals with type 2 diabetes.

Furthermore, younger and older type 1 diabetes individuals had a 1.1- to 1.4-fold greater risk of new-onset heart failure than those with type 2 diabetes.

“Interestingly, regarding the incidence of ischemic stroke in our population, we found no significant difference between patients with type 1 diabetes, and patients with type 2 diabetes,” Dr. Angoulvant said.
 

Chronic kidney disease and risk for death

Chronic kidney disease was most common in individuals with type 1 diabetes who were aged between 18 and 69 years, with a greater prevalence also seen in those with type 2 diabetes only after age 80.

The risk of new chronic kidney disease was significantly increased in patients with type 1 diabetes, compared with patients with type 2 diabetes, with a 1.1- to 2.4-fold increase seen, first in individuals aged 18-49 years, and then again after the age of 60 years.

Dr. Angoulvant reported that the risk of dying from any cause was 1.1-fold higher in people with type 1 diabetes, compared with those with type 2 diabetes, but after the age of 60 years.

The risk of death from cardiovascular events was also increased in people with type 1 diabetes, but between the ages of 60 and 69 years.

Asked what his take-home message might be, Dr. Angoulvant stressed the importance of heart failure, in all patients with diabetes but particularly in those with type 1 diabetes.

“I think there is room for improvement in terms of assessing who is going to have heart failure, how to assess heart failure, and more importantly, how to prevent heart failure,” perhaps by “introducing those drugs that have shown tremendous benefit regarding hospitalization, such as [sodium-glucose transporter 2] inhibitors” in patients with type 1 diabetes ahead of the events, he said.

Dr. Angoulvant had no conflicts of interest to disclose.

Low androgen levels appear to be linked to the development of posttransplantation diabetes mellitus (PTDM) in male kidney transplant recipients, new research suggests.

London_England/Thinkstock

Among 243 men who did not have diabetes prior to undergoing kidney transplantation, levels of both dihydrotestosterone (DHT) and testosterone were inversely related to the risk for developing diabetes the next 5 years.

“These results suggest that androgen insufficiency could play a role in the frequent deterioration of the glucose metabolism after kidney transplantation,” Suzanne P. Stam and colleagues wrote in Diabetes Care.

However, “our study has unfortunately no direct clinical findings as it was of an observational nature,” Ms. Stam told this news organization. “As a result, we can say that we have observed an association and have not established a causal relationship. So based on our study alone there is not a reason to start screening for low androgen values.”

Previous data have suggested that failure of pancreatic beta cell secretion of insulin plays a role in PTDM. In addition, DHT appears to act on the androgen receptor in pancreatic beta cells to enhance insulin secretion, while testosterone deficiency has been shown to play a role in the development of type 2 diabetes in aging males and in men receiving androgen-deprivation therapy. And, randomized clinical trials have found favorable metabolic effects of testosterone replacement therapy in hypogonadal men with type 2 diabetes.

The current post hoc analysis of a prospective single-center cohort study is the first longitudinal epidemiological investigation of the role of androgens in PTDM in kidney transplant recipients. The subjects, all men, had functioning grafts for at least a year posttransplantation. Androgen levels were assessed by liquid chromatography–tandem mass spectrometry.

At a median follow-up duration of 5.3 years, 28 (11.5%) of the men had developed PTDM. By DHT tertile, the proportions developing diabetes were 19% (15) for the lowest, 12% (10) for the middle, and 4% (3) for men with the highest DHT tertile (P = .008). A similar relationship was seen with tertiles of testosterone, with 17% (14), 14% (11), and 4% (3) developing diabetes in the lowest, middle, and highest tertiles, respectively (P = .01).

In unadjusted analysis, every doubling of DHT was linked to a 27% increased risk for PTDM (P < .001). The association remained significant after adjustments for age, estimated glomerular filtration rate, time between transplantation and baseline, body mass index, high sensitivity C-reactive protein, medication use, and baseline hemoglobin A1c (all P < .001). Similar results were found with total testosterone.

Ms. Stam, of the division of nephrology at the University Medical Center Groningen, the Netherlands, noted in an interview that, in the Netherlands, about 15% of those with kidney failure have preexisting diabetes, compared with about 50% in other western countries, including the United States.

She said that her team is currently working on a study to investigate the association between androgens and the development of PTDM in female kidney transplant recipients.

The study was funded by the TransplantLines Food and Nutrition Biobank and Cohort Study, Top Institute Food and Nutrition, and partly by the European Union’s Horizon 2020 research and innovation program. Ms. Stam and the other authors have no further disclosures.

Low androgen levels appear to be linked to the development of posttransplantation diabetes mellitus (PTDM) in male kidney transplant recipients, new research suggests.

London_England/Thinkstock

Among 243 men who did not have diabetes prior to undergoing kidney transplantation, levels of both dihydrotestosterone (DHT) and testosterone were inversely related to the risk for developing diabetes the next 5 years.

“These results suggest that androgen insufficiency could play a role in the frequent deterioration of the glucose metabolism after kidney transplantation,” Suzanne P. Stam and colleagues wrote in Diabetes Care.

However, “our study has unfortunately no direct clinical findings as it was of an observational nature,” Ms. Stam told this news organization. “As a result, we can say that we have observed an association and have not established a causal relationship. So based on our study alone there is not a reason to start screening for low androgen values.”

Previous data have suggested that failure of pancreatic beta cell secretion of insulin plays a role in PTDM. In addition, DHT appears to act on the androgen receptor in pancreatic beta cells to enhance insulin secretion, while testosterone deficiency has been shown to play a role in the development of type 2 diabetes in aging males and in men receiving androgen-deprivation therapy. And, randomized clinical trials have found favorable metabolic effects of testosterone replacement therapy in hypogonadal men with type 2 diabetes.

The current post hoc analysis of a prospective single-center cohort study is the first longitudinal epidemiological investigation of the role of androgens in PTDM in kidney transplant recipients. The subjects, all men, had functioning grafts for at least a year posttransplantation. Androgen levels were assessed by liquid chromatography–tandem mass spectrometry.

At a median follow-up duration of 5.3 years, 28 (11.5%) of the men had developed PTDM. By DHT tertile, the proportions developing diabetes were 19% (15) for the lowest, 12% (10) for the middle, and 4% (3) for men with the highest DHT tertile (P = .008). A similar relationship was seen with tertiles of testosterone, with 17% (14), 14% (11), and 4% (3) developing diabetes in the lowest, middle, and highest tertiles, respectively (P = .01).

In unadjusted analysis, every doubling of DHT was linked to a 27% increased risk for PTDM (P < .001). The association remained significant after adjustments for age, estimated glomerular filtration rate, time between transplantation and baseline, body mass index, high sensitivity C-reactive protein, medication use, and baseline hemoglobin A1c (all P < .001). Similar results were found with total testosterone.

Ms. Stam, of the division of nephrology at the University Medical Center Groningen, the Netherlands, noted in an interview that, in the Netherlands, about 15% of those with kidney failure have preexisting diabetes, compared with about 50% in other western countries, including the United States.

She said that her team is currently working on a study to investigate the association between androgens and the development of PTDM in female kidney transplant recipients.

The study was funded by the TransplantLines Food and Nutrition Biobank and Cohort Study, Top Institute Food and Nutrition, and partly by the European Union’s Horizon 2020 research and innovation program. Ms. Stam and the other authors have no further disclosures.

Low androgen levels appear to be linked to the development of posttransplantation diabetes mellitus (PTDM) in male kidney transplant recipients, new research suggests.

London_England/Thinkstock

Among 243 men who did not have diabetes prior to undergoing kidney transplantation, levels of both dihydrotestosterone (DHT) and testosterone were inversely related to the risk for developing diabetes the next 5 years.

“These results suggest that androgen insufficiency could play a role in the frequent deterioration of the glucose metabolism after kidney transplantation,” Suzanne P. Stam and colleagues wrote in Diabetes Care.

However, “our study has unfortunately no direct clinical findings as it was of an observational nature,” Ms. Stam told this news organization. “As a result, we can say that we have observed an association and have not established a causal relationship. So based on our study alone there is not a reason to start screening for low androgen values.”

Previous data have suggested that failure of pancreatic beta cell secretion of insulin plays a role in PTDM. In addition, DHT appears to act on the androgen receptor in pancreatic beta cells to enhance insulin secretion, while testosterone deficiency has been shown to play a role in the development of type 2 diabetes in aging males and in men receiving androgen-deprivation therapy. And, randomized clinical trials have found favorable metabolic effects of testosterone replacement therapy in hypogonadal men with type 2 diabetes.

The current post hoc analysis of a prospective single-center cohort study is the first longitudinal epidemiological investigation of the role of androgens in PTDM in kidney transplant recipients. The subjects, all men, had functioning grafts for at least a year posttransplantation. Androgen levels were assessed by liquid chromatography–tandem mass spectrometry.

At a median follow-up duration of 5.3 years, 28 (11.5%) of the men had developed PTDM. By DHT tertile, the proportions developing diabetes were 19% (15) for the lowest, 12% (10) for the middle, and 4% (3) for men with the highest DHT tertile (P = .008). A similar relationship was seen with tertiles of testosterone, with 17% (14), 14% (11), and 4% (3) developing diabetes in the lowest, middle, and highest tertiles, respectively (P = .01).

In unadjusted analysis, every doubling of DHT was linked to a 27% increased risk for PTDM (P < .001). The association remained significant after adjustments for age, estimated glomerular filtration rate, time between transplantation and baseline, body mass index, high sensitivity C-reactive protein, medication use, and baseline hemoglobin A1c (all P < .001). Similar results were found with total testosterone.

Ms. Stam, of the division of nephrology at the University Medical Center Groningen, the Netherlands, noted in an interview that, in the Netherlands, about 15% of those with kidney failure have preexisting diabetes, compared with about 50% in other western countries, including the United States.

She said that her team is currently working on a study to investigate the association between androgens and the development of PTDM in female kidney transplant recipients.

The study was funded by the TransplantLines Food and Nutrition Biobank and Cohort Study, Top Institute Food and Nutrition, and partly by the European Union’s Horizon 2020 research and innovation program. Ms. Stam and the other authors have no further disclosures.