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 back semaglutide because a patient with obesity-related HFpEF looks too frail. They’re the ones who stand to benefit most. In our analysis, the frailest patients saw the largest symptom gains, were far more likely to improve their frailty status, and experienced fewer serious adverse events on semaglutide than on placebo. If you’ve been hesitant because a patient seems fragile, reconsider. That’s exactly who should be getting this therapy.” – Ambarish Pandey, MD, MSCS, Divisions of Cardiology and Geriatrics, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas These results are striking for another important reason — they counter what Pandey dubs “therapeutic nihilism.” Returning to the “nagging question” at the heart of this study, he says that the concern makes sense on the surface. “With GLP-1RAs, 25% to 40% of total weight loss can come from muscle rather than fat. Picture a 70-year-old with HFpEF who already has sarcopenia. The natural worry is that you’re speeding up their decline. But there’s a deeper issue. Frail patients routinely get undertreated because clinicians fear they won’t tolerate medications well.” With such promising findings, Pandey says the team’s next step is confirming these results with objective physical measures: the Fried frailty phenotype, Short Physical Performance Battery, grip strength, gait speed. “We also want detailed body composition imaging through MRI to understand whether the muscle patients retain is actually healthier. Longer follow-up will tell us whether improvements in frailty lead to fewer hospitalizations and better survival. That’s the ultimate question.” He has some strong advice for clinicians: “Don’t hold back semaglutide because a patient with obesity-related HFpEF looks too frail. They’re the ones who stand to benefit most. In our analysis, the frailest patients saw the largest symptom gains, were far more likely to improve their frailty status, and experienced fewer serious adverse events on semaglutide than on placebo. If you’ve been hesitant because a patient seems fragile, reconsider. That’s exactly who should be getting this therapy.” Targeting Alström Syndrome In “ E ffectiveness of the Dual GIP/GLP1-Agonist Tirzepatide in 2 Cases of Alström Syndrome, a Rare Obesity Syndrome ,” published in JCEM in April, Thomas Scherer, MD, of the Medical University of Vienna, in Vienna, Austria, and team showed tirzepatide’s efficacy even in the particularly difficult-to-treat Alström syndrome (AS), a rare, genetic, multisystemic disorder, characterized by, among other conditions, diabetes with profound insulin resistance due to marked hyperphagia. Scherer cares for patients living with rare obesity syndromes and recounts a recent particular struggle to treat two male patients ages 20 and 23 years with AS, who did not respond to multimodal obesity therapy including GLP-1RAs. “We tried the mono agonists available on the European market at that time, which were dulaglutide, liraglutide, and semaglutide,” he explains, “but hyperphagia was unaffected and body weight only temporarily mildly dipped and eventually stagnated.” Scherer explains that the situation was particularly critical for one of the men who was experiencing obesity-related metabolic complications including MASLD, dyslipidemia, and type 2 diabetes requiring insulin doses greater than 100 IU/day despite maximal antidiabetic therapy with metformin 1,000 mg bid, dapagliflozin 5 mg bid, pioglitazone 45 mg qd, and semaglutide 1 mg once weekly. “We decided to start the patient on tirzepatide (imported from the United States at that time) as a final option before considering bariatric surgery,” he says. “The second patient followed shortly after, since we saw a marked weight response in our first patient (body weight –27%) and massive reductions in insulin doses (–83%) and resolution of insulin resistance upon starting tirzepatide.” Their choice stands to reason. As described in the first study mentioned here, dual (and triple agonists) work in complementary and synergistic ways. In the case of tirzepatide, Scherer believes the mechanism may relate to its GIPR action: “Since tirzepatide is an imbalanced dual agonist with stronger GIPR action and weaker binding to GLP-1R compared to classic GLP-1 agonists, a GIP-mediated mechanism seems likely. Studies in rodents showed, for example, that GIPR agonism mediates weight-independent insulin sensitization by improving glucose disposal into white adipose tissue (WAT). This suggests that maybe tirzepatide ameliorates WAT function in AS, thereby improving overall metabolism and insulin sensitivity (also demonstrated by the rapid decline insulin demand). This is particularly interesting since, in contrast to GLP-1Rs, only GIPRs are expressed in WAT. In addition, loss of function of the ALMS1 gene in adipose tissue or preadipocytes recapitulates the metabolic phenotype of a global ALMS1 loss of function, suggesting that adipose tissue failure is a major pathophysiologic component of AS. Ultimately, rodent studies in ALMS1 knockout mice are needed to get at the exact mechanism at work.” “Patients and caregivers should be instructed to be mindful of below-target fasting and postprandial glucose readings and be instructed to make adjustments to the insulin doses in close contact with the treatment center. Using a continuous glucose monitor (CGM) device with alarm function and the possibility of remote monitoring of CGM data would also help mitigate hypoglycemic events in this context.” – Thomas Scherer, MD, deputy chief, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria For Scherer’s two patients, uptitration of tirzepatide to the maximal dose of 15 mg a week was necessary, but in addition to the weight they lost, they did achieve significant improvements in insulin resistance (which can be quite pronounced in the setting of AS) as well as reduced hyperphagia. This success prompts future studies to not only confirm the findings in larger cohorts but also to explore similar avenues. “It would be great to undertake studies with the newer dual agonists and polyagonists also in rare obesity syndromes such as AS, Prader-Willi syndrome, and Bardet-Biedl syndrome (just to name a few) as the clinical need for effective obesity/hyperphagia therapies in these patients is especially high,” says Scherer. “This is an effort where industry and academia need to closely collaborate to find the right patient cohorts, which is not an easy task in rare disease.” Meanwhile, he wants clinicians to know that tirzepatide is a good option for treating obesity, hyperphagia, MASLD, and type 2 diabetes in AS, but because of the rapid therapeutic response it produces, patients require careful monitoring. “Care should be taken in patients with insulin therapy as rapid adjustments in insulin doses should be anticipated,” he says. “Therefore, close meshed control intervals during the uptitration phase of tirzepatide with biweekly to monthly visits are merited to avoid hypoglycemia. Furthermore, patients and caregivers should be instructed to be mindful of below-target fasting and postprandial glucose readings and be instructed to make adjustments to the insulin doses in close contact with the treatment center. Using a continuous glucose monitor (CGM) device with alarm function and the possibility of remote monitoring of CGM data would also help mitigate hypoglycemic events in this context.” Discontinuation As mentioned, the news is not all perfectly rosy, as “ Reasons for Discontinuation of Obesity Pharmacotherapy With Semaglutide or Tirzepatide in Clinical Practice ” shows. Even in this study published in Obesity in August and written by Hamlet Gasoyan, PhD, of the Center for Value-Based Care Research at the Cleveland Clinic and the Department of Medicine, at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, in Cleveland, Ohio, and team, however, researchers have reason to be hopeful. “Discontinuation of injectable semaglutide and tirzepatide for obesity is common in clinical practice,” says Gasoyan. “Although potential causes of this have been speculated by clinicians and third-party payers, no U.S.-based study to date has quantified the reasons for it. We believe that a better understanding of the reasons could help address the barriers to continued use of these medications.” Their cross-sectional study examined electronic health record (EHR) data of 288 patients with overweight or obesity and without type 2 diabetes who initiated injectable semaglutide or tirzepatide and discontinued treatment within the first year, 145 of whom received semaglutide, and 143 tirzepatide. The researchers found that 137 patients (47.6%) discontinued their medication due to cost or insurance-related issues, 42 (14.6%) due to side effects, 34 (11.8%) due to shortages, 7 (2.4%) due to switching to a compounded medication, and 5 (1.7%) due to unsatisfactory weight loss. Another 31 (10.8%) discontinued for other reasons, and the discontinuation reason was not specified in the EHR for 32 (11.1%) patients. “Our findings are in line with studies that examined the association of insurance type, copayment amount, and socioeconomic factors with the initiation and persistence with novel obesity medications,” says Gasoyan. “Discontinuation due to factors typically irrelevant in clinical trial settings (i.e., cost or insurance-related issues and medication shortages) could contribute to the substantial discrepancy between discontinuation rates in pivotal phase 3 trials and those reported in real-world studies.” Regarding discontinuation due to side effects, Gasoyan says we do not currently know of patient-level predictors that would help identify who might experience side effects and why. “The most helpful recommendation for patients would be to work closely with their clinician on gradual dosing and making specific dietary and lifestyle adjustments,” he says. “Discontinuation of injectable semaglutide and tirzepatide for obesity is common in clinical practice. Although potential causes of this have been speculated by clinicians and third-party payers, no U.S.-based study to date has quantified the reasons for it. We believe that a better understanding of the reasons could help address the barriers to continued use of these medications.” – Hamlet Gasoyan, PhD, Center for Value-Based Care Research, Cleveland Clinic; Department of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, Ohio Indeed, the team’s next steps involve individualizing therapy. “In our future work, we will be generating evidence on what alternative obesity treatment works best for whom, to help patients and providers make evidence-based decisions when continuing with a specific novel obesity medication is not possible,” says Gasoyan. Helpfully, recent policy changes regarding cost may make having a variety of options to readily choose from more possible from an affordability perspective. “These are positive developments that will improve access and treatment persistence among patients needing obesity medications, particularly those covered by Medicare, state Medicaid programs in states that will choose to participate, and those who can afford the cash pay option.” Meanwhile, he says, “recognizing the primary reasons for discontinuation may facilitate more informed discussions between clinicians and their patients, helping to address challenges in long-term persistence with these highly effective medications.” Horvath is a freelance writer based in Baltimore, Md. In the January issue, she wrote about a number of new directions for treating patients with thyroid cancer. The post Beyond the Scale: What Else Glucagon-like Peptide-1 Receptor Agonists Can Do appeared first on Endocrine News .