The findings appeared on April 30, 2026 in Cardiovascular Diabetology – Endocrinology Reports.

Dr Simon Cork, Senior Lecturer in Physiology at Anglia Ruskin University in Cambridge, UK and lead author, said: “This is the most comprehensive review to date of long term cardiovascular outcome trials for GLP 1 receptor agonists. We know that one of the factors that weighs on people’s minds when considering going onto these drugs is the potential long-term side effects. Our results show that, when taken over a prolonged period of at least one year, these medications do much more than help control blood sugar or weight. They significantly reduce the risk of heart attacks, strokes and premature death in people who are already vulnerable.

The investigators conducted a review and meta-analysis of randomized, placebo-controlled cardiovascular outcome trials evaluating GLP-1RAs in adults at high cardiovascular risk.

Each trial had enrolled ≥ 3,000 subjects with a minimum follow-up of 12 months.

The primary outcome of this meta-analysis was major adverse cardiovascular events (MACE). Secondary outcomes included cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure, and adverse events.

Eleven trials enrolling a total of 91,490 subjects were included. The mean period of follow-up was 2.7 years.

The investigators reported that GLP-1RA treatment was associated with a significant 13% reduction in MACE compared with placebo. The analysis also showed significant reductions in cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure.

“We found the benefits to be consistent across different drugs, trial designs and patient groups. This has important implications for clinical practice and health policy, particularly given cardiovascular disease is the leading cause of death in the UK,” the authors concluded.

Individuals in Cluster 5 Remain at High Diabetes Risk Despite Lifestyle Changes

The study was based on data from the Tübingen Lifestyle Intervention Program (TULIP). Participants with an increased risk of type 2 diabetes completed a two-year lifestyle intervention and were subsequently followed for approximately nine years. The analysis focused on individuals who were able to achieve substantial and sustained long-term weight reduction.

“We were particularly interested in whether individuals in risk clusters 3 and 5 differed from those in other clusters with regard to improvements in blood glucose levels and the prevention of type 2 diabetes,” explains Professor Norbert Stefan, the lead author of the study. “We were very surprised to find that, despite a large and sustained weight loss of 8% and after a very long follow-up period of 9 years, individuals in risk cluster 5 showed increasing blood glucose levels, declining insulin secretion, and a persistently high risk of type 2 diabetes.”

Fatty Liver and Insulin Resistance May Explain the Findings

Why does lifestyle intervention protect individuals in risk cluster 5 less effectively against diabetes? The authors examined mechanisms that could explain the unfavorable metabolic trajectory observed in this group. Their data suggest that insulin resistance—most likely caused by pronounced fatty liver disease and fatty liver–related impairment of insulin secretion from pancreatic beta cells—led to rising blood glucose levels in individuals in cluster 5.

These findings are consistent with earlier observations showing that fatty liver disease and insulin resistance are the dominant pathophysiological mechanisms in individuals classified in Tübingen’s type 2 diabetes risk cluster 5, making them particularly susceptible to type 2 diabetes and cardiovascular disease.

Precision Prevention Strategies Are Needed

The present results indicate that individuals in risk cluster 5 do not benefit to the same extent from lifestyle interventions as those in other clusters, even with significant and sustained weight loss—particularly with respect to glucose metabolism. If these findings are confirmed in a prospective study, a more tailored approach to diabetes prevention will be required, in which high-risk phenotypes such as cluster 5 may need more intensive or targeted interventions.

* Wagner R, …, Häring HU, Fritsche A. Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes. Nat Med. 2021 Jan;27(1):49-57. doi: 10.1038/s41591-020-1116-9. Epub 2021 Jan 4. PMID: 33398163.

The results suggest that the five-year risk of major cardiovascular events such as heart attacks and the risk of end-stage kidney disease were reduced by 15% and 19%, respectively, for the patients taking GLP-1-RA drugs such as semaglutide (Ozempic) and tirzepatide (Mounjaro). For the study, the researchers analyzed electronic health records data on about 175,000 type 1 diabetes patients in the U.S.

About 2 million Americans, including 314,000 children and adolescents, have been diagnosed with type 1 diabetes, according to the Centers for Disease Control and Prevention. The autoimmune disorder destroys the pancreas’s insulin-producing cells and requires lifelong insulin injections to control blood sugar levels.

The risks of side effects of particular concern for type 1 diabetes patients taking GLP-1-RAs—severe hypoglycemia and diabetic ketoacidosis; a severe lack of insulin, causing acid accumulation in the blood—were not increased among the patients taking these drugs.

The findings were published online March 19 in Nature Medicine.

“These risk reductions for heart and kidney disease outcomes are comparable to what we’ve seen for type 2 diabetes patients taking GLP-1-RA drugs, and it’s reassuring that we saw no sign of any new safety issues,” says study senior author Jung-Im Shin, MD, PhD, an associate professor in the Bloomberg School’s Department of Epidemiology.

Patients with type 1 diabetes face high lifetime risks of cardiovascular and kidney disease. Chronic excess blood sugar promotes atherosclerosis that leads to heart attacks and strokes, and elevated blood-sugar levels can damage the kidney’s urine-filtering structures. There have been few GLP-1-RA clinical trials that measure these outcomes in patients with type 1 diabetes.

Landmark clinical trials have found that GLP-1-RA drugs lower the risks of major cardiovascular events and kidney failure in type 2 diabetes patients by roughly 20%. An estimated 29 million Americans have been diagnosed with type 2 diabetes, according to the CDC.

“The type 1 diabetes population, compared to the type 2 diabetes population, is relatively small and relatively young, so it is inherently difficult to conduct a large-scale clinical trial that can show clear differences in cardiovascular and kidney event rates in this population within a reasonable time,” Shin says.

Two small trials in type 1 diabetes patients a decade ago suggested that the combination of insulin treatment and a GLP-1-RA could cause potentially severe low blood sugar levels (hypoglycemia), and reducing insulin to minimize this risk could cause a different serious complication called diabetic ketoacidosis.

For the new study, the researchers used de-identified electronic health records from a large commercial database covering patients from more than 60 health systems across the U.S. The analysis included 174,678 type 1 diabetes patients and covered January 2013 through March 2024. The team used a “sequential target trial emulation” design—mimicking a clinical trial-type protocol—and accounted for baseline differences between those who began taking GLP-1-RAs and those who didn’t.

The average five-year risk of major cardiovascular events was 4.3% in the GLP-1-RA group vs. 5.0% in the non-GLP-1-RA group, a relative risk reduction of about 15%. The data also suggested a risk reduction of about 21% for heart attacks and 16% for all-cause mortality. The five-year risk of end-stage kidney disease was 1.6% for the GLP-1-RA group vs. 1.9% for the non-GLP-1-RA group, for an estimated relative risk reduction of 19% among those taking GLP-1-RA.

The analysis also found that the GLP-1-RA group had estimated risk reductions of 18% for heart failure, and 28% for major adverse liver events. Patients who initiated GLP-1-RAs also were about 22% more likely to achieve weight loss of at least 10% over five years.

Safety-related outcomes were similarly encouraging. Estimated risks of hospitalization for hypoglycemia and for diabetic ketoacidosis were significantly lower—18% and 17% respectively—in the GLP-1-RA group.

“These findings suggest that physicians are being relatively careful when selecting the type 1 diabetes patients who will receive these drugs, and that the patients are adjusting their insulin doses appropriately,” Shin says. “While our study fills a critical knowledge gap and informs clinical practice for type 1 diabetes patients, ultimately large clinical trials are needed to confirm these findings.”

This study has limitations, including unmeasured confounding due to the nature of observational study design despite the rigorous adjustment methods, and potential misclassification of type 1 diabetes. In addition, only hospitalized cases of hypoglycemia and diabetic ketoacidosis were captured in this study.

“Glucagon-Like Peptide-1 Receptor Agonists for Major Cardiovascular and Kidney Outcomes in Type 1 Diabetes” was co-authored by Yunwen Xu, Natalie Daya Malek, Alexander R. Chang, Justin B. Echouffo-Tcheugui, Elizabeth Selvin, Morgan E. Grams, Michael Fang, and Jung-Im Shin.

Support for the study was provided by the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK139324, R01 DK115534, K01 DK138273).

The Inflation Reduction Act of 2022 mandated an out-of-pocket cap of $35 for a 30-day insulin supply for Medicare Part D beneficiaries starting January 1, 2023. This is the first time the federal government has imposed caps on insulin prices for all Medicare beneficiaries.

For their study, the researchers analyzed Medicare claims data covering nearly 3.8 million patients who had at least one claim for insulin during the five-year period from 2019 to 2023.

The percentage of these patients who paid $35 or less out of pocket for a 30-day equivalent supply increased from 48% in 2019 to 75% in 2023.

The findings were published online in a peer-reviewed research letter March 19 in JAMA.

The study also showed that the mean out-of-pocket cost for that quantity of insulin dropped from $50.87 in 2019 to $21.98 in 2023. Cost decreases during 2019–2023 were seen in every U.S. state. The study is thought to be the first to analyze the Inflation Reduction Act’s insulin-cap impacts.

“This is compelling evidence that Medicare policies in recent years have done what they were meant to do—improve insulin access and affordability,” says study lead author Michael Fang, PhD, MHS, assistant professor in the Bloomberg School’s Department of Epidemiology. “Insulin costs are now at historically low levels for people on Medicare.”

The researchers note that the finding that about one-quarter of Medicare beneficiaries paid more than $35 for a 30-day supply of insulin in 2023 was unexpected. Their analysis found that these beneficiaries had at least one prescription that was not prorated to the Inflation Reduction Act limit.

Approximately 3.8 million Medicare beneficiaries use insulin as a treatment for type 1 or type 2 diabetes. Insulin replaces the natural metabolic hormone of the same name, whose production is virtually nonexistent in type 1 diabetes, and is also compromised in many cases of type 2 diabetes.

To help rein in insulin costs for beneficiaries, the Centers for Medicare & Medicaid Services (CMS) capped out-of-pocket cost at $35 for a 30-day supply in 2021 as a limited, voluntary initiative. The Inflation Reduction Act of 2022’s mandated $35 cap for out-of-pocket cost for a 30-day supply for Medicare Part D beneficiaries took effect January 1, 2023.

The study covered all Medicare Part D patients who had at least one claim for insulin during the study window and were not receiving Medicare low-income subsidies. The researchers grouped the claims data into five calendar years from 2019 to 2023 for their analysis.

As for the insulin-using Medicare Part D beneficiaries still paying more than $35 for a 30-day supply in 2023, Fang notes that CMS’s formal guidance is for the $35 rule to be applied only for full multiples of 30 days. “If the prescription falls in between, the patient can be charged up to the next full multiple of a month,” Fang says. “For example, health plans can treat a 45-day supply the same as a 60-day supply and charge up to $70.”

He adds that variations in average 30-day insulin costs by state—from $10.36 in Washington, D.C., to $31.09 in Minnesota in 2023—may partly reflect state-level differences in how pro-rating is handled by Medicare insurance plans.

The researchers are now exploring the issue of prorating prescriptions that fall outside the current 60- and 90-day supply window to see in more detail how average costs vary across plans, and whether policy changes are needed to close the gap.

“Trends in Insulin Out-of-Pocket Costs Among U.S. Medicare Beneficiaries” was co-authored by Michael Fang, Chen Dun, Dan Wang, Caitlin Hicks, Elizabeth Selvin, Jung-Im Shin, and Mariana Socal.

Support for the research was provided by the National Institute of Diabetes and Digestive and Kidney Diseases (K01DK138273, R01DK139324).

Diagnosis of Type 2 diabetes and prediabetes are on the rise in adults 40 years old and younger. Complications from Type 2 diabetes include heart disease, kidney disease and stroke, and it can also damage nerves in the brain, eyes and feet.

“We know that as a whole, people with prediabetes are at higher risk for progression to Type 2 diabetes and its complications. The U.S. Food and Drug Administration (FDA) has approved treatment with the new weight-loss medications, called GLP-1 Receptor Agonists (GLP-1RA), for select patients who meet certain criteria. We used these existing criteria to estimate the risk of developing Type 2 diabetes in young adults with glucose levels in the prediabetes range,” said Mary Rooney, Ph.D., M.P.H., lead author of the study and an assistant research professor in the department of epidemiology at the Johns Hopkins Bloomberg School of Public Health in Baltimore.

Some GLP-1 RA medications are FDA-approved for people with Type 2 diabetes and others to help facilitate weight loss when diet and exercise have not been effective. The eligibility criteria for prescribing GLP-1 RA medications for weight loss include obesity (body mass index of 30 kg/m² or higher), or overweight (body mass index of 27 kg/m²) plus at least one related condition, such as high blood pressure or high cholesterol. GLP-1 RA medications are not FDA-approved for the prevention of Type 2 diabetes in people with prediabetes.

For their analysis, investigators estimated the 5-year risk of progression from prediabetes to Type 2 diabetes in 662 young adults. Participants were followed for an average of seven years through one of three U.S.-based studies focused on young adult health and heart disease risk.

The analysis found:

• The 5-year risk of progression from prediabetes to Type 2 diabetes was 7.5% overall.
• The risk increased to 10.9% for individuals who met the criteria for treatment with a GLP-1RA medication for weight loss.
• In addition, the 5-year risk grew to 15.1% for those with higher levels of fasting glucose (110-125 mg/dL), and 24.8% for those with a higher fasting glucose and who met the criteria for treatment with a GLP-1 RA medication.

“Current approaches to Type 2 diabetes prevention are ‘one-size-fits-all.’ Our results signal that some people with prediabetes have a higher risk of progressing to Type 2 diabetes. These are the patients who may benefit from more targeted, intensive treatment than others,” said Rooney.

According to the American Heart Association, lifestyle changes, such as losing weight, eating healthy and engaging in regular, moderate physical activity, may reduce the progression of prediabetes to Type 2 diabetes, help manage Type 2 diabetes and mitigate other risk factors like high blood pressure, as well as heart attacks and stroke.

The study also raises the possibility that GLP-1 RA medications might be beneficial to prevent progression to Type 2 diabetes in people with prediabetes who meet the BMI measures for overweight or obesity and other weight-related health conditions.

“However, the cost-effectiveness of GLP-1 RA medications for Type 2 diabetes prevention, particularly in subgroups with the highest risk for Type 2 diabetes, is not yet known,” said Rooney.

“Different groups of people with Type 2 diabetes may need different prevention strategies based on their level of risk,” said Joshua J. Joseph, M.D., M.P.H., FAHA, ASCI, an American Heart Association volunteer expert and chair of the Lifestyle Diabetes Committee for the Association’s Council on Lifestyle and Cardiometabolic Health. “A next step would be to study a larger and more diverse group of people so we can better understand how factors like where someone lives, such as a rural or urban setting, their background and their community influence risk. These findings support the idea of acting early, before Type 2 diabetes and related heart or kidney conditions become more serious, using healthy lifestyle changes and, when needed, medications to lower risk, consistent with the cardiovascular-kidney-metabolic syndrome framework, which prioritizes early intervention.” Joseph, who was not involved in this study, is an associate professor of internal medicine and the endowed professor for research in internal medicine at The Ohio State University Wexner Medical Center in Columbus, Ohio.

Study details, background or design:

• The study included 662 young adults from three studies in the U.S.: the Hispanic Community Health Study/Study of Latinos, the Coronary Artery Risk Development in Young Adults study and the Framingham Heart Study Third Generation.
• Participants included adults ages 18-40 (mean age of 32 years) with prediabetes. 33% of all participants were women; 47% self-identified as Hispanic/Latino, 45% self-identified as non-Hispanic White and 7% self-identified as non-Hispanic Black.
• Health information, including fasting glucose levels, weight and body mass index, lipid levels and blood pressure, was measured during study visits between 1985 and 2011, all prior to the first FDA approval of GLP-1 RA medications for weight loss.
• During a median follow-up period of about seven years, researchers analyzed how the various risk factors influenced the 5-year risk of progressing from prediabetes to Type 2 diabetes.

The study’s findings are limited because participants’ hemoglobin A1c blood tests, which measure blood sugar levels over the past 2-3 months, were not available. Hemoglobin A1c can also be used to define prediabetes. Only fasting glucose tests were included in the analysis.

Co-authors, disclosures and funding sources are listed in the abstract.

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But people with high blood sugar often don’t achieve those benefits from exercise, especially the ability to use oxygen efficiently. They’re at higher risk for heart and kidney disease, but high blood sugar can prevent their muscles from taking up oxygen more effectively in response to exercise.

For them, a new study suggests the answer could be eating not less fat, but more.

The study by exercise medicine scientist Sarah Lessard, published Feb. 25 in Nature Communications, found that a high-fat, ketogenic diet reduced high blood sugar, or hyperglycemia, in mice, and their bodies were more responsive to exercise.

“After one week on the ketogenic diet, their blood sugar was completely normal, as though they didn’t have diabetes at all,” said Lessard, associate professor at the Fralin Biomedical Research Institute at VTC Center for Exercise Medicine Research. “Over time, the diet caused remodeling of the mice’s muscles, making them more oxidative and making them react better to aerobic exercise.”

The ketogenic diet is named for its ability to induce ketosis, a metabolic state that shifts the body to burning fat for fuel instead of sugar. The diet is controversial because it calls for eating high-fat, very low-carbohydrate foods, which is counter to the low-fat diet historically urged by health advocates.

However, the keto diet has been linked to benefits for people with some diseases, including epilepsy and Parkinson’s disease. In the 1920s, before the discovery of insulin, it was a way to manage diabetes because of its ability to lower blood sugar.

In earlier research, Lessard found that people with high blood sugar had lower exercise capacity. She wondered if the diet might improve the response to exercise, leading to higher exercise capacity.

Mice were fed a high-fat, low-carbohydrate diet and exercised on running wheels. The mice developed more slow-twitch muscle fibers, which give better endurance.

“Their bodies were more efficiently using oxygen, which is a sign of higher aerobic capacity,” Lessard said.

Lessard said exercise positively affects virtually every tissue in our body, even fat tissue, but she and others are seeing that the greatest health improvements won’t come with diet or exercise alone.

“What we’re really finding from this study and from our other studies is that diet and exercise aren’t simply working in isolation,” said Lessard, who also holds an appointment in the Department of Human Foods, Nutrition, and Exercise in Virginia Tech’s College of Agriculture and Life Sciences. “There are a lot of combined effects, and so we can get the most benefits from exercise if we eat a healthy diet at the same time.”

Next, Lessard would like to continue her research in human subjects to see if they gain the same benefits from the keto diet seen in mice.

She also notes that the keto diet is challenging to follow. A less restrictive regimen, such as the Mediterranean diet, might be easier for people to follow and still be effective. That diet can also keep blood sugar low, while including carbohydrates from unprocessed fruits, vegetables, and whole grains rather than restricting carbohydrates altogether.

“Our previous studies have shown that any strategy you and your doctor have arrived at to reduce your blood sugar could work,” she said.

Drawing on clinical data from more than 450,000 patients, the research adds to growing evidence that incretin-based therapies have protective benefits for the brain.

The study examined GLP-1 receptor agonists, which include such medications as Ozempic, as well as DPP-4 inhibitors.

“These are very promising results,” said Dr. Christel Renoux, associate professor in McGill’s Department of Neurology and Neurosurgery and senior investigator at the Lady Davis Institute. “By measuring factors that were unaccounted for in earlier studies, our results provide more reliable evidence of the potential cognitive benefits.”

Type 2 diabetes increases the risk of dementia by about 60 per cent, and there are few known strategies for reducing the risk, she added. The number of Canadians living with dementia is projected to reach one million by 2030.

Stronger associations with longer use

For about three years, researchers followed patients age 50 or older who were starting the incretin-based therapies and those taking another common diabetes medication, sulfonylureas.

DPP-4 inhibitors were associated with a 23-per-cent lower dementia risk compared with sulfonylureas, which served as a comparison group and are not known to offer cognitive protection. The longer people used the DPP-4 inhibitors, and the higher the dose, the stronger the association became. GLP-1 receptor agonists showed a similar pattern, though with less certainty because fewer patients were using these newer medications.

“While there has been enormous attention on GLP-1 drugs, these findings suggest DPP-4 inhibitors also deserve a closer look,” said Renoux.

Study designed to reduce bias

Earlier studies have pointed to cognitive benefits of incretin-based therapies, but many lacked detailed information on patient health, including the severity of diabetes, a major predictor of dementia on its own. Using richer clinical data from the U.K.’s Clinical Practice Research Datalink, the authors were able to control for these and other factors, yielding a more reliable comparison.

“These results give us solid evidence for something scientists have suspected for some time,” said Renoux. “These drugs may have benefits far beyond blood-sugar control that we are only beginning to understand.”

She noted that longer-term studies will be needed to confirm the results, including in people now using GLP-1 drugs for weight loss.

About the study

“Incretin‑Based Drugs and the Risk of Dementia Among Patients with Type 2 Diabetes” by Yun‑Han Wang and Christel Renoux et al., was published in Drug Safety. The study was funded by a grant from the Canadian Institutes of Health Research.

A research team including experts from IIASA and the Vienna University of Economics and Business (WU Vienna) has calculated the economic impact of diabetes across 204 countries from 2020 to 2050. The findings are striking: Excluding informal care provided by family members, global costs amount to approximately US$ 10 trillion – equivalent to 0.2% of the annual global GDP. When informal care is factored in, costs soar to as much as US$ 152 trillion, or 1.7% of GDP. This is particularly significant for diseases like diabetes.

“Caregivers often drop out of the labor market, at least partially, which creates additional economic costs,” explains WU economist Klaus Prettner, one of the study authors.

The high share of informal caregiving, ranging between 85% and 90% of the total economic burden, is explained by the fact that prevalence exceeds mortality by a factor of 30-50. Although diabetes is more common in lower-income countries, the United States bears the highest absolute costs, followed by China and India.

”To some extent, these rankings reflect the size of the economies included in our analysis in terms of GDP and population, but it is interesting to note that at 0.5% the Czech Republic has the highest burden as a percentage of GDP, followed by the United States and Germany at 0.4%. Ireland, Monaco, and Bermuda face the largest per capita economic burdens at $18,000, $12,000, and $8,000 dollars respectively,” notes coauthor Michael Kuhn, Acting Economic Frontiers Research Group Leader at IIASA.

One prime distinction between high- and low-income countries is the distribution of the burden across the treatment cost and lost labor channels, where the former makes up 41% of the economic burden (net of caregiving) for high-income countries as opposed to 14% for low-income countries.

“This is a stark illustration of how medical treatment regimes for chronic diseases such as diabetes are accessible to high income countries only,” Kuhn adds.

Role of COVID-19
Diabetes has proved to be one of the main risk factors for mortality from COVID-19. In a side analysis the authors explored how the economic burden of diabetes has been affected when factoring in morbidity and mortality from COVID-19 that can be attributed to diabetes. The effects are sizeable, where the economic burden increases from 0.16% to 0.22% per unit of GDP for China, from 0.4% to 0.65% per unit of GDP for the US, and from 0.4% to 0.45% per unit of GDP for Germany.

“Previous estimates of diabetes-related costs were often based on overly simplified assumptions and tended to ignore economic dynamics,” says Prettner. “This study’s innovative approach incorporates labor market effects, such as work absences due to caregiving responsibilities. It also recognizes that healthcare spending does not necessarily reduce economic output but often represents a shift from consumer spending toward health sector spending.”

Urgent need for policy action
When compared to other diseases over the same period, such as Alzheimer’s, dementia, or cancer, the economic impact of diabetes is enormous. The authors emphasize that the most effective way to prevent diabetes and reduce its economic impact lies in promoting healthier lifestyles. Regular physical activity combined with a balanced diet can significantly lower the risk of developing the disease.

In addition, early detection plays a crucial role: comprehensive diabetes screening programs for the entire population, along with rapid diagnosis and timely treatment for individuals showing symptoms or risk factors, are essential steps toward mitigating both health and economic consequences.

“Such steps are particularly relevant for low-income countries, where high levels of underdiagnosis and its role in raising mortality from infectious diseases render diabetes a severe risk factor for the stability of health care systems,” Kuhn concludes.

Reference
Chen, S., Cao, Z., Chen, W., Zhao, J., Jiao, L., Prettner, K., Kuhn, M., Pan, A., Bärnighausen, T.W., Bloom, D.E. (2025). The global macroeconomic burden of diabetes mellitus. Nature Medicine DOI: 10.1038/s41591-025-04027-5

The study, titled “Sodium-Glucose Cotransporter-2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, and Frailty Progression in Older Adults With Type 2 Diabetes,” and published in Diabetes Care, looked at older adults who had just started different types of diabetes medications and followed them for one year. They found that people taking SGLT-2 inhibitors or GLP-1 drugs were less likely to show signs of frailty, such as weakness, slowed movement, or fatigue, compared with those starting other diabetes medications. In other words, these treatments appeared to help patients with diabetes maintain strength and function as they aged. The benefit could not be fully explained by heart benefits, suggesting the medications may directly help protect against frailty.

Analyzing a national 7% sample of U.S. Medicare claims, researchers tracked one-year changes in a validated claims-based frailty index (CFI; range 0–1, with higher scores indicating greater frailty). Compared with new users of DPP-4 inhibitors, those starting GLP-1 receptor agonists saw a mean CFI change of –0.007 (95% CI: –0.011 to –0.004) and those starting SGLT-2 inhibitors saw a mean change of –0.005 (95% CI: –0.008 to –0.002), indicating slower frailty progression. Users of sulfonylureas showed no significant difference. Additional analyses found that cardiovascular or other safety events accounted for only a small portion of the effect, suggesting a potential direct benefit of these medications on frailty itself.

According to prior research, roughly 10–15% of adults over age 65 experience frailty, with higher rates in those with type 2 diabetes. People with diabetes are particularly at risk due to chronic inflammation, muscle loss, cardiovascular disease, and the cumulative burden of managing a complex condition. Frailty is associated with falls, disability, hospitalization, and reduced lifespan. Because it is difficult to reverse once established, slowing frailty progression has emerged as an important goal in geriatric care, making the findings of this study especially significant for older adults with diabetes.

“While SGLT-2 inhibitors and GLP-1 receptor agonists are primarily prescribed for blood sugar control and heart protection, our findings show they may also help older adults with diabetes stay stronger and less vulnerable to health setbacks,” said lead author of the study, Chanmi Park, MD, MPH, Assistant Scientist I, Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife. “Because frailty is common, serious, and hard to reverse, this could meaningfully change how clinicians think about medication choices for aging patients.”

In addition to Park, the other researchers were Saran Thanapluetiwong, MD, Visiting Research Fellow, Marcus Institute for Aging Research, Hebrew SeniorLife; Xiecheng Chen, PhD, Data Scientist I, Marcus Institute for Aging Research, Hebrew SeniorLife; Gahee Oh, MD, MPH, Daa Scientist II, Marcus Institute for Aging Research, Hebrew SeniorLife; Darae Ko, MD, MSc, Associate Scientist, Marcus Institute for Aging Research, Hebrew SeniorLife; and Dae Hyun Kim, MD, MOH, ScD, Associate Director & Senior Scientist, Marcus Institute for Aging Research, Hebrew SeniorLife.

Researchers from the ATTAIN-2 trial reported their findings on Nov. 20, 2025 in The Lancet.

“We know it is harder for individuals with diabetes to lose weight. It is exciting to have an oral medication that provides double-digit weight loss, which on average was 23 lbs. Once FDA approved, orforglipron is scheduled to be available in 2026 at a significantly decreased cost compared to current injectables. This could position it to be the ‘metformin’ of obesity and become widely covered by insurance plans, opening the door to treatment for all,” said Deborah Horn, DO, MPH, professor and director of obesity medicine at McGovern Medical School at UTHealth Houston and principal author of the study.

Orforglipron stimulates insulin release, reduces glucagon secretion, lowers blood sugar and helps control appetite. No refrigeration is needed.

The investigators conducted the 72-week, phase 3, double-blind, placebo-controlled trial across 136 sites in ten countries.

The primary endpoint was the mean percent change in bodyweight from baseline to week 72.

The investigators enrolled 1613 subjects (757 female) and randomized them, after a dose escalation phase, to receive orforglipron 6 mg (n=329), 12 mg (n=332), 36 mg (n=322), or placebo (n=630), as an adjunct to lifestyle modification.

Of the total group, 1444 (89·5%) completed the 72-week study.

At endpoint, subjects treated with up to 6 mg of orforglipron averaged a weight loss of 5.5%, those who received 12 mg averaged 7.8%, and those who received 36 mg averaged 10.5%.

The placebo group averaged just 2.2% in weight loss.

Orforglipron treatment significantly improved blood sugar and caused only mild to moderate gastrointestinal side effects.

The authors reported, “All prespecified weight and cardiometabolic measures including HbA_1c statistically significantly improved with orforglipron. Treatment discontinuations due to adverse events (mainly gastrointestinal-related) were higher for orforglipron (6·1–9·9%) versus placebo (4·1%). The most common adverse events with orforglipron were mild-to-moderate gastrointestinal events, predominantly occurring during dose escalation.”

The authors concluded, “In adults with obesity or overweight and type 2 diabetes, statistically superior reduction in bodyweight compared with placebo was demonstrated by once-daily orforglipron as an adjunct to lifestyle modification, with a safety profile similar to other GLP-1 receptor agonists.”

Horn added, “The opportunity for an oral GLP-1 medication with highly effective weight loss that is simpler to take may provide increased access and opportunities for better health for our patients with obesity and diabetes.”

That is the conclusion of a Rutgers-led study published in The Journal of Clinical Endocrinology & Metabolism, which found that metformin blunts critical improvements in blood vessel function, fitness and blood sugar control that normally come from working out.

Since 2006, doctors have been advised to tell patients with high blood sugar to take metformin while engaging in exercise. Two proven therapies should deliver better results together, they reasoned. But Rutgers researchers said the math doesn’t add up.

“Most health care providers assume one plus one equals two,” said Steven Malin, a professor in the Department of Kinesiology and Health in the School of Arts and Sciences and the lead author of the study. “The problem is that most evidence shows metformin blunts exercise benefits.”

To test the theory, Malin’s team recruited 72 adults at risk for metabolic syndrome. The syndrome is viewed as a cluster of conditions that raise the risk of diabetes and heart disease. They divided the trial participants into four groups: people performing high-intensity exercise while taking a placebo; high-intensity exercise with metformin; low-intensity exercise with placebo; and low-intensity exercise with metformin.

Over 16 weeks, researchers tracked changes in blood vessel function under insulin stimulation, a process that helps vessels dilate and deliver oxygen, hormones and nutrients after meals.

The results were clear: Exercise alone improved vascular insulin sensitivity, meaning blood vessels responded better to insulin and allowed more blood flow to muscles. This matters because insulin’s ability to open blood vessels helps shuttle glucose out of the bloodstream and into tissues, lowering blood sugar after meals.

But when metformin was added, the improvements shrank. The drug also diminished gains in aerobic fitness and reduced the positive effects on inflammation and fasting glucose.

“Blood vessel function improved with exercise training, regardless of intensity,” Malin said. “Metformin blunted that observation, suggesting one type of exercise intensity is not better either with the drug for blood vessel health.”

This matters because exercise is supposed to lower blood sugar and improve physical function, crucial goals of diabetes treatment. If metformin interferes with those benefits, patients may not get the protection they expect to help lower disease risk.

“If you exercise and take metformin and your blood glucose does not go down, that’s a problem,” Malin said. “People taking metformin also didn’t gain fitness. That means their physical function isn’t getting better and that could have long-term health risk.”

The implications go beyond lab measurements. Fitness gains translate into energy for daily life. This includes activities such as climbing stairs, playing with children and staying active with friends. If those improvements stall, quality of life suffers, Malin said.

The findings don’t mean people should stop taking metformin or exercising, Malin said. Instead, it raises urgent questions for doctors about how the two treatments can be combined and the need for close monitoring. Malin hopes future research will uncover strategies that preserve the benefits of both.

Why does metformin blunt exercise benefits? The answer is unclear but may lie in the drug’s mechanism of action, Malin said. Metformin works partly by blocking parts of the mitochondria, which reduces oxidative stress and improves blood sugar control. But that same inhibition may interfere with the cellular adaptations triggered by exercise, including improvements in mitochondrial function and aerobic capacity. In other words, the very process that makes metformin effective may block the body’s ability to respond fully to physical training.

Previous research has hinted at similar effects, but this trial is among the first to examine vascular insulin sensitivity, which is a key factor controlling glucose regulation and cardiovascular health, Malin said. By showing that metformin can blunt improvements in both large arteries and tiny capillaries regardless of exercise intensity, the study underscores the complexity of combining such treatments.

The stakes are high, Malin said. Type 2 diabetes affects nearly 35 million people in the United States, and prevention strategies often hinge on lifestyle changes combined with medication. If those strategies don’t work as expected, patients could face greater risks down the road.

“We need to figure out how to best recommend exercise with metformin,” Malin said. “We also need to consider how other medications interact with exercise to develop better guidelines for doctors to help people lower chronic disease risk.”

Other Rutgers researchers on the study include: Sue Shapses, professor in the Department of Nutritional Sciences at the School of Environmental and Biological Sciences; Andrew Gow, professor of pharmacology and toxicology at the Ernest Mario School of Pharmacy; Ankit Shah, assistant professor in the Department of Medicine at Robert Wood Johnson Medical School; Tristan Ragland, a former post-doctoral fellow in Department of Kinesiology and Health; Emily Heiston, project scientist and clinical coordinator in the Applied Metabolism and Physiology Laboratory; and Daniel Battillo, a former doctoral student in the Department of Kinesiology and Health.

Explore more of the ways Rutgers research is shaping the future

Prior placebo-controlled randomized controlled trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and tirzepatide have shown that these medications are associated with an increased risk for gastrointestinal-related adverse events; however, whether individual GLP-1 RAs and tirzepatide have different gastrointestinal safety among patients with type 2 diabetes in clinical practice remains unclear. Researchers from Brigham and Women’s Hospital and Harvard Medical School and colleagues used data from Optum’s deidentified Clinformatics Data Mart database to emulate three clinic trials of adults with T2D initiating dulaglutide, subcutaneous semaglutide, or tirzepatide between 1 January 2019 and 30 August 2024. They assessed 65,238 matched pairs in the semaglutide versus dulaglutide cohort, 20,893 in the tirzepatide versus dulaglutide cohort, and 46,620 in the tirzepatide versus semaglutide cohort. The primary outcome was a composite of severe gastrointestinal AEs resulting in an inpatient and/or emergency department encounter. The hazard ratio of gastrointestinal events was 0.96 (95% CI, 0.87 to 1.06) in the semaglutide versus dulaglutide cohort, 0.96 (CI, 0.77 to 1.20) in the tirzepatide versus dulaglutide cohort, and 1.07 (CI, 0.90 to 1.26) in the tirzepatide versus semaglutide cohort. These findings were consistent across subgroups and sensitivity analyses. The results align with those seen in head-to-head randomized clinical trials and may help physicians when determining the benefits and risks of prescribing these popular medications.

Abstract: https://www.acpjournals.org/doi/10.7326/ANNALS-25-01724