Beyond the Scale: What Else Glucagon-like Peptide-1 Receptor Agonists Can Do

In the United States, American Heart Month is observed in February to raise awareness about cardiovascular disease, the leading cause of death worldwide. To a similar end, Endocrine News focuses on a few recent journal studies that take a closer look at the impacts of incretin-based therapies in the setting of obesity and impaired cardiovascular health, as well as how they affect the liver, quality of life, insulin resistance, and much more. February is heart month at Endocrine News , making it an opportune time to examine four recent studies that explore various aspects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and related incretin-based therapies, given obesity’s profound impact on cardiovascular health. Recent advances in obesity pharmacotherapy have shown unprecedented efficacy in weight reduction and cardiometabolic improvement. GLP-1RAs (and their offshoots that add agonists of other key metabolic regulation substances) have shown particular promise in patients with obesity-related cardiovascular and metabolic complications, offering synergistic benefits that extend beyond weight loss. The picture is not yet perfect, however, and a substantial proportion of patients discontinue treatment within the first year due to barriers related to cost, access, and tolerability. Nevertheless, evidence suggests these therapies may be especially valuable for high-risk patient populations who have been underserved or excluded from aggressive treatment approaches. At a Glance • The dual and triple agonists GLP-1/glucagon, GLP-1/GIP, GLP-1/GDF15, and GLP-1/GIP/glucagon demonstrate distinct yet complementary and synergistic profiles in glycemic control, weight reduction, and metabolic improvements with added benefits in cardioprotection, anti-inflammation, and hepatic health. • Semaglutide is not only an effective, safe therapy in the high-risk group of frail patients with obesity-related HFpEF, it may even significantly reduce their frailty burden and improve their overall quality of life. • The dual GLP1/GIP agonist tirzepatide markedly improves body weight, MASLD, insulin resistance, and hyperphagia in people living with Alström syndrome, but monitoring for potential resulting hypoglycemia should be vigilant. • High cost or insurance-related issues are the most common reasons for treatment discontinuation with semaglutide or tirzepatide for obesity, highlighting the need for policies to address cost and informing discussions between healthcare providers and patients concerning cost and side effects. Novel Agents Published in Endocrinology in August, “ Novel Dual and Triple Agonists Targeting GLP-1, GIP, Glucagon, and GDF15 for Type 2 Diabetes and Obesity Management ” sets the stage for how remarkably these agents have transformed the treatment landscape and what additional benefits may lie on the horizon. Chao Zheng, PhD, from The Second Affiliated Hospital, School of Medicine, Zhejiang University in Hangzhou, China, and team sought to expand the potential patient populations who can benefit by exploring novel peptide-based therapies, citing GLP-1RAs’ lack of effectiveness in a significant proportion of patients. While it is as yet premature to integrate these agents into clinical practice, the researchers undertook a comprehensive overview of what we know so far about dual and triple agonists that target glucose-dependent insulinotropic polypeptide (GIP), another incretin; glucagon; and/or growth differentiation factor 15 (GDF15) in addition to GLP-1. As the team points out, strong, sustained agonists at the GIP receptor (GIPR) inhibit appetite and stimulate insulin secretion. And, since GIPRs and GLP-1 receptors belong to a related family, the logical next step was to develop a coagonist that targets both — enter tirzepatide. With its demonstrated superior potency and efficacy compared to the single GLP-1RAs such as semaglutide, tirzepatide paved the way for continued experimentation with combined agents. Dual and triple incretin-based agonists show remarkable potential to more effectively treat the intertwined metabolic problems of type 2 diabetes and obesity, with all the cardiovascular and other comorbidities they confer. These multitarget drugs are designed to create synergy across pathways that regulate appetite, insulin secretion, hepatic metabolism, and energy expenditure, producing broader metabolic benefits than single-receptor therapies. For example, pairing GLP-1 with glucagon aims to merge GLP-1’s strong appetite-suppressing and glucose-lowering effects with glucagon’s lipolytic and thermogenic actions (possibly mediated indirectly through factors such as FGF21). Early coagonists showed improved glucose tolerance and lipid metabolism alongside weight loss driven by both reduced food intake and increased energy expenditure, such as cotadutide, a daily injectable, improves liver metabolism and has reduced HbA1c in clinical trials while also showing kidney-protective effects (e.g., reduced albumin-to-creatinine ratio). Another, efinopegdutide, produces dose-dependent weight loss and may reduce liver fat more than semaglutide, but has shown more adverse events and less consistent glycemic benefit. Bamadutide improved weight and glycemic measures and sometimes outperformed liraglutide, although its activity appears biased toward GLP-1R. Other dual agonists include survodutide, mazdutide, and pemvidutide, with evidence of meaningful weight loss and cardiometabolic improvements. GLP-1R/GIPR dual agonists like the aforementioned tirzepatide enhance glycemic control by increasing insulin secretion, suppressing glucagon, and slowing gastric emptying — while potentially improving satiety via central mechanisms. Triple GLP-1/GIP/glucagon agonists aim for even more comprehensive metabolic control. Long-acting retatrutide, for example, produced substantial HbA1c and weight reductions and showed promise for reducing hepatic fat and improving metabolic dysfunction–associated steatotic liver disease (MASLD)-related biomarkers. Efocipegtrutide shows potential benefits in obesity, MASLD/fibrosis, dyslipidemia, and even neuroinflammation in preclinical models. Despite their demonstrated potential in preclinical and clinical studies, challenges persist with these agents. The research team cites mechanistic complexities, long-term safety uncertainties, and the need for optimized dosing regimens, all of which require further investigation. Personalized approaches, guided by patient-specific biomarkers and phenotypes, may maximize therapeutic efficacy. “Future research must prioritize head-to-head trials (e.g., tirzepatide versus retatrutide) and validate predictive biomarkers (e.g., GDF15 for anti- inflammatory responses) to advance precision medicine. Collaborative efforts across research, clinical, and pharmaceutical domains are essential to translate these innovations into transformative therapies, ultimately improving outcomes for the global diabetes population,” say the study authors. Targeting Frailty In “ Frailty and Effects of Semaglutide in Obesity-Related HFpEF: Findings From the STEP-HFpEF Program ,” published in JACC: Heart Failure in September, Ambarish Pandey, MD, MSCS of the Divisions of Cardiology and Geriatrics in the Department of Internal Medicine at the University of Texas Southwestern Medical Center, in Dallas, Texas, and team demonstrated just how effective semaglutide can be in the setting of heart failure with preserved ejection fraction (HFpEF) and accompanying frailty. Based on the results in 1,145 participants from the Research Study to Investigate How Well Semaglutide Works in People Living with Heart Failure and Obesity (STEP-HFpEF), Pandey and team sought to answer a nagging question. “This question has been on our minds since the completion of the STEP-HFpEF trial,” says Pandey. “Over 60% of participants fell into the ‘most frail’ category. That’s a striking number. And it raised a concern we kept hearing: if someone is already frail, won’t a medication that causes significant weight loss, particularly muscle loss, make things worse? We needed real data to settle that question.” Semaglutide was the logical choice for this specific patient population he explains: “The STEP-HFpEF trials were built around semaglutide from the start. But there’s a broader rationale. GLP-1RAs do more than promote weight loss. They tamp down inflammation, improve cardiac hemodynamics, and offer metabolic benefits we’re still learning about. In obesity-related HFpEF, where inflammation and metabolic dysfunction sit at the center of the disease, semaglutide was a natural fit.” So, while weight loss across the board was anticipated (about 8% to 9% of body weight compared to placebo), the results this team found intriguing were semaglutide’s stratum-dependent ability to reduce frailty burden (strata = less frail, more frail, most frail). “Symptom improvements were far more pronounced in the frailest patients,” says Pandey. “That disconnect tells us something important. The benefit isn’t coming from weight loss alone.” He further explains that obesity-related HFpEF and frailty share common ground at the biological level: chronic inflammation, skeletal muscle dysfunction, depleted metabolic reserve. “Semaglutide seems to act on these overlapping pathways. There’s also growing evidence that GLP-1RAs improve muscle quality by clearing out the fat that infiltrates muscle tissue. Frail patients start with the most dysfunction, so they have the most to gain.” In fact, after one year, patients on semaglutide demonstrated an 11-point improvement on the Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score, which represented a shift into a less-frail stratum for many. “That’s enormous,” says Pandey. “It’s the kind of change patients actually feel in their daily lives. We may not just be managing symptoms here. We may be changing the trajectory of the disease itself.” “Don’t hold bac…