GLP-1 receptor agonists beyond obesity and diabetes: HFpEF, PAD, and PCOS

Key takeaways

• STEP-HFpEF (Kosiborod 2023 NEJM, n=529, 52 weeks) showed semaglutide 2.4 mg improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score by 7.8 points more than placebo (95 percent CI 4.8 to 10.9, P less than 0.001), with a body-weight difference of -10.7 percentage points and a 6-minute walk distance difference of 20.3 m .
• STEP-HFpEF DM (Kosiborod 2024 NEJM, n=616, 52 weeks) extended the same signal to HFpEF plus type 2 diabetes, with a KCCQ-CSS difference of 7.3 points (95 percent CI 4.1 to 10.4), a body-weight difference of -6.4 percentage points, and a 6-minute walk difference of 14.3 m .
• SUMMIT (Packer 2025 NEJM, n=731, median 104 weeks of follow-up) is the first GLP-1-class HFpEF trial with a hard composite endpoint: tirzepatide cut adjudicated cardiovascular death or worsening heart failure events to 9.9 percent versus 15.3 percent on placebo (hazard ratio 0.62, 95 percent CI 0.41 to 0.95, P 0.026), with a KCCQ-CSS between-group difference of 6.9 points .
• STRIDE (Bonaca 2025 Lancet, n=792, 52 weeks) is the first Phase 3 trial of a GLP-1 receptor agonist in symptomatic peripheral artery disease with type 2 diabetes. Semaglutide 1.0 mg improved the ratio of week-52 maximum walking distance to baseline by an estimated treatment ratio of 1.13 (95 percent CI 1.06 to 1.21, P 0.0004) .
• PCOS evidence is meta-analytic, not registrational. A 2025 network meta-analysis of 27 randomized trials in 1,642 participants reported that GLP-1 receptor agonists improve menstrual frequency and anthropometric parameters in women with PCOS . A semaglutide-specific 2025 meta-analysis of 8 trials in 526 patients reported a mean BMI reduction of 2.20 kg/m^2 (95 percent CI -2.42 to -1.97) .
• Regulatory status as of publication: the FDA expanded Wegovy (semaglutide 2.4 mg) in March 2024 to include cardiovascular risk reduction in adults with established cardiovascular disease and obesity or overweight, based on SELECT . No HFpEF, PAD, or PCOS indication has been approved for any GLP-1 receptor agonist at the time of writing.

What counts as a new indication

GLP-1 receptor agonists started as glycemic drugs and matured into cardio-renal-metabolic drugs. The next bar is whether the same molecules move outcomes in conditions where weight, inflammation, and metabolic stress have downstream effects beyond glucose and atherosclerotic cardiovascular disease. Heart failure with preserved ejection fraction (HFpEF), peripheral artery disease (PAD), and polycystic ovary syndrome (PCOS) are the three indications where the most useful trial readouts have actually landed. Substance use is a fourth signal with thinner trial backing.

This piece is an indication-by-indication scan, not a unified thesis. For each indication, we walk what trial generated the signal, what endpoint moved, and where the regulatory posture sits at the time of writing.

A note on framing. A signal is not the same as an approval. Phase 3 efficacy data in HFpEF and PAD now exist. Phase 3 outcome data, beyond surrogates, exist only for tirzepatide HFpEF in the SUMMIT trial . Everything else is symptom and function endpoints, meta-analytic synthesis, or signal-finding work. For research and educational purposes only. Not medical advice.

HFpEF, the largest and best-studied new indication

Heart failure with preserved ejection fraction has historically lacked effective drug therapy. The STEP-HFpEF program tested whether semaglutide 2.4 mg, the same dose used for obesity, would also benefit adults with obesity-driven HFpEF.

STEP-HFpEF (ClinicalTrials.gov NCT04788511) randomized 529 patients with HFpEF, a body mass index of 30 or higher, and no diabetes to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary endpoints were change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS, a symptom and physical-function score where higher numbers mean fewer symptoms and limitations) and change in body weight .

At 52 weeks, KCCQ-CSS rose 16.6 points on semaglutide and 8.7 points on placebo, an estimated difference of 7.8 points (95 percent CI 4.8 to 10.9, P less than 0.001). Body weight fell 13.3 percent on semaglutide and 2.6 percent on placebo, an estimated difference of -10.7 percentage points (95 percent CI -11.9 to -9.4, P less than 0.001). 6-minute walk distance improved by 21.5 m on semaglutide and 1.2 m on placebo, a difference of 20.3 m (95 percent CI 8.6 to 32.1, P less than 0.001). CRP fell 43.5 percent on semaglutide and 7.3 percent on placebo (estimated treatment ratio 0.61, 95 percent CI 0.51 to 0.72). Serious adverse events were less frequent on semaglutide (13.3 percent) than placebo (26.7 percent) .

STEP-HFpEF DM extended the same protocol to 616 patients who also had type 2 diabetes. The KCCQ-CSS difference was 7.3 points (95 percent CI 4.1 to 10.4, P less than 0.001), the weight difference was -6.4 percentage points (95 percent CI -7.6 to -5.2, P less than 0.001), and the 6-minute walk difference was 14.3 m (95 percent CI 3.7 to 24.9, P 0.008). The diabetes context reduced the absolute weight effect, but the symptom and function effect was preserved .

SUMMIT (NCT04847557) raised the bar. The trial randomized 731 patients with HFpEF, an ejection fraction of at least 50 percent, and a body mass index of at least 30 to tirzepatide (titrated up to 15 mg subcutaneously weekly) or placebo for at least 52 weeks, with a median 104 weeks of follow-up. The dual primary endpoints were a composite of adjudicated death from cardiovascular causes or a worsening heart-failure event, and change in KCCQ-CSS at 52 weeks .

The primary composite occurred in 36 of 364 patients (9.9 percent) on tirzepatide and 56 of 367 (15.3 percent) on placebo (hazard ratio 0.62, 95 percent CI 0.41 to 0.95, P 0.026). Worsening heart-failure events alone were lower on tirzepatide (hazard ratio 0.54, 95 percent CI 0.34 to 0.85). KCCQ-CSS at 52 weeks was 19.5 points on tirzepatide and 12.7 on placebo, a between-group difference of 6.9 points (95 percent CI 3.3 to 10.6, P less than 0.001). Cardiovascular death alone was not significantly reduced in this trial size (8 versus 5 events). SUMMIT is the first GLP-1-class HFpEF trial to move a clinical-event composite, not just symptoms . The broader cardio-renal-metabolic case for GLP-1 receptor agonists (SELECT, FLOW, and the earlier glycemic-era outcome trials) sits in the related pepSmart article on GLP-1 cardiovascular outcomes.

PAD, STRIDE makes the first Phase 3 case

Peripheral artery disease is atherosclerosis of the leg arteries that limits walking distance through claudication, the cramping pain that comes on with exertion and goes away with rest. Few drug therapies meaningfully improve walking distance. STRIDE is the first Phase 3 trial of a GLP-1 receptor agonist for the indication .

STRIDE (NCT04560998) enrolled 792 adults with type 2 diabetes and symptomatic PAD with intermittent claudication (Fontaine stage IIa, able to walk more than 200 m) and an ankle-brachial index of 0.90 or below or a toe-brachial index of 0.70 or below. Patients were randomized 1:1 to subcutaneous semaglutide 1.0 mg once weekly or placebo for 52 weeks. The primary endpoint was the ratio to baseline of maximum walking distance on a constant-load treadmill (fixed speed 3.2 km/h, fixed inclination 12 percent) at week 52 .

396 patients were assigned to each arm. Median age was 68.0 years (IQR 61.0 to 73.0), and 75 percent were male. The estimated median ratio to baseline in maximum walking distance was 1.21 on semaglutide (IQR 0.95 to 1.55) and 1.08 on placebo (IQR 0.86 to 1.36), with an estimated treatment ratio of 1.13 (95 percent CI 1.06 to 1.21, P 0.0004). Six serious adverse events in five (1 percent) semaglutide-treated patients and nine in six (2 percent) placebo patients were possibly or probably treatment related, mostly gastrointestinal. There were no treatment-related deaths .

PCOS, meta-analytic rather than registrational

Polycystic ovary syndrome is a common endocrine condition that combines hyperandrogenism, irregular ovulation, and metabolic features such as insulin resistance and obesity. The pharmacology question is whether GLP-1 receptor agonists, by acting on weight and insulin resistance, also improve menstrual regularity and reproductive markers.

A 2025 systematic review and network meta-analysis (Sridharan and Sivaramakrishnan 2025, Diabetology and Metabolic Syndrome) pooled 27 randomized controlled trials with 1,642 participants. GLP-1 receptor agonists, alone or combined with metformin, improved menstrual frequency. GLP-1 agents also reduced anthropometric parameters across the pooled trials. SGLT2 inhibitors moved waist-hip ratio and android-gynoid fat ratio more than GLP-1 agents did in head-to-head comparison, but the two drug classes are typically used for different parts of the PCOS phenotype .

A semaglutide-specific 2025 meta-analysis (Chen 2025, Gynecological Endocrinology) pooled 8 randomized trials with 526 patients. Semaglutide reduced BMI by a mean of 2.20 kg/m^2 (95 percent CI -2.42 to -1.97, P less than 0.001) versus placebo or conventional treatment, with comparable reductions in total cholesterol, triglycerides, and LDL cholesterol. HDL cholesterol did not change. Subgroup analysis suggested a larger effect at doses of 1.0 mg per week or higher and in patients with baseline BMI above 28 kg/m^2 .

PCOS readouts are heterogeneous. Trials vary in inclusion criteria, dosing, comparator (placebo, metformin, or lifestyle), and outcome definitions. Effect sizes for menstrual frequency, ovulation, and pregnancy are reported in the meta-analyses, but the underlying primary trials are mostly small and short. The honest framing is that GLP-1 receptor agonists improve weight and metabolic endpoints in women with PCOS and may improve reproductive endpoints, but the registrational case for a PCOS-specific GLP-1 label is not yet built.

Substance use, the thinnest of the four signals

A separate research thread tracks whether GLP-1 receptor agonists reduce craving and intake of alcohol, nicotine, and other substances of misuse. The early human randomized work has so far focused on alcohol use disorder. pepSmart covers this evidence in a dedicated article, with primary citations to the original trials.

This section is intentionally short. The brief for this article cross-links to the alcohol cravings piece rather than restating its claims. See the related-articles rail below.

Regulatory context as of publication

As of the publication date, the FDA has issued one obesity-anchored cardiometabolic GLP-1 labeling expansion: the March 2024 update to Wegovy (semaglutide 2.4 mg) to include reducing the risk of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in adults with established cardiovascular disease and either obesity or overweight, based on the SELECT outcomes trial .

No HFpEF-, PAD-, or PCOS-specific GLP-1 indication has been approved for any GLP-1 receptor agonist at the time of writing. The trial data summarized in this piece are the foundation for any future labeling claim, not the claim itself. Under review and submitted mean different things, and approved means something else again. None of those statuses currently apply to a GLP-1 HFpEF, PAD, or PCOS indication.

Compounded semaglutide and compounded tirzepatide preparations sold outside FDA-approved manufacturing do not inherit any of these trial results. Identity, purity, and dose accuracy of compounded vials cannot be assumed from sponsor-run Phase 3 data. For research and educational purposes only. Not medical advice.

Editorial summary

HFpEF is the clearest case where GLP-1 receptor agonists have moved beyond surrogate endpoints. STEP-HFpEF and STEP-HFpEF DM established symptom and function benefit with semaglutide. SUMMIT moved a composite of cardiovascular death and worsening heart failure event with tirzepatide. PAD has one Phase 3 readout (STRIDE), in patients with type 2 diabetes and symptomatic claudication. PCOS has meta-analytic improvements in weight and metabolic markers, with weaker primary-trial data on reproductive endpoints. Substance use signals are the thinnest of the four, and pepSmart covers alcohol cravings separately.

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