An Endocrine News roundup of the week’s pharmaceutical news, breakthroughs, and general information. *
New Study Shows that Ozempic® Reduces the Risk of Heart Attack, Stroke, and Death by 23% Compared to Dulaglutide
On September 18, Novo Nordisk announced results from the REACH real-world study, which demonstrated that compared to dulaglutide, Ozempic® (once-weekly injectable semaglutide) was associated with a reduced risk of major adverse cardiovascular events such as a heart attack or stroke by 23%.
The data span nearly 60,000 U.S. Medicare patients (aged ≥66 years) living with type 2 diabetes, atherosclerotic cardiovascular disease (ASCVD) – a condition where fatty deposits build up in blood vessels, reducing blood flow and increasing the risk of heart attacks, strokes and related problems – and multiple health conditions. The results were presented at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting on 15–19 September in Vienna, Austria.
“As we age, the risk of experiencing a heart attack, stroke, or dying from a cardiovascular event increases. At the same time, there are limited clinical data for people living with diabetes and cardiovascular disease aged 66 years or older. These data, showing a 23% risk reduction of a heart attack, stroke and death, fill an important gap and reinforce the well-established clinical evidence of semaglutide,” says Filip Krag Knop, senior vice president and incoming chief medical officer at Novo Nordisk. “This is great news for older patients as well as healthcare professionals, as these results build on the importance of our randomized clinical trial data assessing the effectiveness of treatments in a real-life setting. This also supports what we already know from our clinical development programs that not all GLP-1 RAs are the same.”
Beyond these essential benefits, once-weekly semaglutide was also associated with a 25% risk reduction of heart attack, stroke, hospitalization for unstable angina or heart failure, and death from any cause (five-point MACE).
Ozempic® is the only GLP-1 RA that has proven risk reduction of cardiovascular and kidney events in people with type 2 diabetes. These results provide the first direct comparison of cardiovascular outcomes between Ozempic® and dulaglutide in US Medicare beneficiaries and add to the body of evidence for Ozempic®.
About REACH
REACH is a comprehensive series of studies assessing the cardiovascular disease-related outcomes of the once-weekly GLP-1 RA class, including semaglutide, compared to glucose-lowering therapies such as DPP4 inhibitors, SGLT2 inhibitors and others. It also includes within-class comparisons of GLP-1 RAs from multiple administrative claims and electronic health record databases.
The study presented at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting is a real-world evidence analysis evaluating cardiovascular risk reduction with GLP-1 RAs – semaglutide and dulaglutide – in people with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD). This study draws from Medicare fee-for-service claims data, using a target-trial emulation framework, including 58,336 matched patients (29,168 patients in each treatment group) aged ≥66 years with type 2 diabetes and ASCVD who initiated once-weekly semaglutide or dulaglutide. Direct cardiovascular outcome comparisons between GLP-1 RAs are lacking. These results address a critical gap for insights, particularly in an older Medicare population with multiple comorbidities underrepresented in randomised clinical trials.
Results from Phase 2 COURAGE Trial Demonstrate Potential to Improve Quality of GLP-1 Receptor Agonist-Induced Weight Loss by Preserving Lean Mass
On Sept. 17, Regeneron Pharmaceuticals, Inc. announced updated analyses from the ongoing Phase 2 COURAGE trial investigating novel combinations of semaglutide (GLP-1 receptor agonist) and trevogrumab (anti-GDF8/anti-myostatin) with or without garetosmab (anti-activin A) for the treatment of obesity.
The complete 26-week results were consistent with interim data previously reported, demonstrating that the addition of trevogrumab with or without garetosmab could significantly reduce the loss of lean mass associated with semaglutide-induced weight loss; the results confirmed that 33% of weight loss induced by semaglutide was due to loss of lean mass, and that adding trevogrumab could prevent about half of this lean mass loss. The results were presented as a late-breaking oral session at the 61st Annual Meeting of the European Association for the Study of Diabetes (EASD) in September 2025.
“These complete 26-week COURAGE results demonstrate a meaningful opportunity to preserve muscle mass while enhancing fat loss,” said Endocrine Society member Julio Rosenstock, MD, lead PI and senior scientific advisor Velocity Clinical Research at Medical City and clinical professor of medicine, University of Texas Southwestern Medical Center, Dallas. “These encouraging early data, with positive trends in lipid parameters, warrant further studies to confirm the potential of trevogrumab’s role in preserving lean muscle mass during weight loss, especially in combination with incretin-related therapies.”
COURAGE was designed to investigate the quality of weight loss in patients with obesity (BMI ³30 kg/m2). Treatment is divided into two 26-week periods comprised of a weight-loss phase and a weight-maintenance phase. The three primary efficacy endpoints were assessed in this analysis at week 26 (end of weight-loss phase), and included percent change from baseline at week 26 in lean mass, fat mass and body weight. During the weight-loss phase, patients were randomized to receive semaglutide 2.4 mg alone or in combination with trevogrumab 200 mg (lower dose), trevogrumab 400 mg (higher dose) or higher-dose trevogrumab plus garetosmab 10 mg/kg (triplet).
At this analysis, 33% of semaglutide-induced weight loss was due to lean mass loss, while patients in all combination groups had improvement in body composition including lean mass preservation and greater fat loss compared to semaglutide alone.
Detailed results of this analysis from baseline to week 26 include:
| Semaglutide monotherapy (n=151) | Lower-dose combo (n=149) | Higher-dose combo (n=152) | Triplet (n=147) | |
| Lean mass | ||||
| Percent change from baseline (SE) | -6.5 (0.5) | -3.3 (0.5) | -3.8 (0.5) | -2.0 (0.6) |
| Change in kg from baseline (% of total weight loss) | -3.3 kg (33.0%) | -1.5 kg*** (16.8%) | -1.9 kg*** (18.1%) | -0.9 kg*** (7.4%) |
| Fat mass | ||||
| Percent change from baseline (SE) | -15.7 (0.9) | -17.3 (0.9) | -19.1 (0.9) | -27.1 (1.1) |
| Change in kg from baseline (% of total weight loss) | -6.7 kg (67.0%) | -7.6 kg (83.2%) | -8.5 kg* (81.9%) | -11.8 kg*** (92.6%) |
| Body weight | ||||
| Percent change from baseline (SE) | -10.6 (0.5) | -9.9 (0.5) | -11.1 (0.5) | -13.4*** (0.6) |
SE= Standard Error
NOTE: Lean mass and fat mass was calculated using dual-energy X-ray absorptiometry (DXA) scan, while body weight was measured using a scale; as a result, the lean and fat mass numbers may not exactly sum to body weight. Total weight loss is defined as the sum of lean mass loss and fat mass loss. Results are based on least-squares means derived from MMRM analysis using efficacy estimand that excludes data after the treatment discontinuation.
***p<0.001; *p<0.05; p-values are for the primary endpoints of % change from baseline at week 26 in each category, and were not corrected for multiplicity.
Numerical improvements in metabolic and lipid parameters, secondary and exploratory endpoints, were seen across all treatment groups, including improvements in waist circumference, blood pressure, cholesterol, triglycerides and A1C.
The combination of semaglutide with trevogrumab was generally well-tolerated; Adverse events that occurred in ≥5% of participants in any treatment group included muscle spasms, nausea, constipation, fatigue, diarrhea, headache, vomiting, gastroesophageal reflux disease, upper respiratory tract infection, nasopharyngitis, UTI, influenza and COVID-19. Most of these events were mild to moderate in severity.
As previously reported, the triplet combination of semaglutide with both antibodies had a substantially higher rate of discontinuations due to tolerability issues and other adverse events. Two deaths occurred in the triplet group, one due to an undetermined cause in a patient with multiple cardiovascular risk factors and the second due to a cardiac arrest in a person with a history of cardiovascular disease. Regeneron has not identified a causal association between treatment and these events.
After 26 weeks, patients enter into the weight-maintenance phase in which they receive either higher-dose trevogrumab monotherapy or placebo through the end of the trial (week 52).
The safety and efficacy of trevogrumab and garetosmab have not been evaluated by any regulatory authority.
Rezolute Announces Alignment with FDA on Streamlined Design for Ongoing Phase 3 Trial of Ersodetug in Tumor Hyperinsulinism
On Sept. 2, Rezolute, Inc., announced that it has gained alignment with the U.S. Food and Drug Administration (FDA) on a significantly streamlined clinical development path for its ongoing Phase 3 study (upLIFT) of ersodetug for the treatment of hypoglycemia caused by tumor HI. Rezolute, Inc. is a late-stage rare disease company focused on treating hypoglycemia caused by hyperinsulinism.
At a meeting held with FDA on August 19, 2025, the agency agreed to modifications to the design of the study including removing the need to conduct a double-blind randomized placebo-controlled trial. The truncated study will include as few as 16 participants and will be limited to the single-arm open-label portion of the upLIFT study, which has been the focus of the Company’s patient recruitment efforts. FDA also confirmed that Rezolute’s pivotal sunRIZE trial in congenital HI, which is on track to report topline results in December 2025, would serve as confirmatory clinical evidence, and is demonstrative of FDA’s recognition of the broad applicability of ersodetug in multiple forms of HI.
“We are absolutely delighted with this regulatory outcome,” said Nevan Charles Elam, CEO and founder of Rezolute. “The FDA’s staff and leadership have been very vocal about the desire to responsibly simplify clinical development for rare diseases, particularly when there is real-world evidence of benefit combined with mechanistic plausibility. We believe that the alignment we have achieved with the agency exemplifies this innovative approach and is substantially based upon the favorable outcomes that we have observed over the last two years treating more than 10 patients with tumor HI under our Expanded Access Program.”
Endocrine Society member Brian Roberts, MD, chief medical officer at Rezolute went on to say, “This revised and simplified plan for the upLIFT study and approval pathway marks an important development for us as well as the community of healthcare providers, patients, and families living with serious hypoglycemia caused by tumor HI. By focusing on an open-label study in upLIFT, while building upon the robust clinical foundation established in the congenital HI indication, we are expediting development with the goal of making this therapy available as efficiently as possible.”
About upLIFT
The Phase 3 registrational study is a single-arm, open-label, pivotal trial in approximately 16 participants with insulinoma or non-islet cell tumors who have uncontrolled hypoglycemia caused by tumor hyperinsulinism (HI). Eligible participants requiring continuous intravenous (IV) glucose will receive ersodetug 9 mg/kg per week for 8 weeks, as an add-on to standard of care. Following this 8-week pivotal treatment period, all participants may receive ersodetug in long-term extension. The primary endpoint is the number of participants achieving at least a 50 percent reduction from baseline in IV glucose requirements (glucose infusion rate; GIR). Additional endpoints include the number of participants and time to discontinuation of GIR, time to discharge from the hospital, extent of hypoglycemia events and hypoglycemia time in the outpatient setting by self-monitored blood glucose and continuous glucose monitor, respectively, and patient reported quality of life.
About Tumor Hyperinsulinism
Tumor hyperinsulinism (HI) is a rare disease that may be caused by two distinct types of tumors: islet cell tumors (ICTs) and non-islet cell tumors (NICTs), both of which lead to hypoglycemia as a result of over-activation of the insulin receptor. Insulinomas are the most common type of ICT and cause hypoglycemia by stimulating the over production of insulin. A variety of different NICTs, particularly hepatocellular carcinoma, can cause hypoglycemia by producing and secreting insulin-like paraneoplastic substances such as IGF-2 that bind to and activate the insulin receptor. With high morbidity and mortality rates within tumor HI, there remains a significant unmet need for new therapies directed at hypoglycemia treatment. Ersodetug has shown real-world benefit in patients with insulinoma and NICTs.
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