GLP-1 Receptor Agonists Beyond Diabetes: What the Evidence Shows
Synthesising evidence from 10 landmark trials — including SELECT, FLOW, STEP-HFpEF, and ESSENCE — on the expanding cardiovascular, renal, heart failure, and hepatic indications for GLP-1 receptor agonists in patients with and without diabetes. Evidence level: high (multiple large RCTs).
This is an original evidence synthesis. See References for source studies.
One-Minute Takeaway
One-Minute Takeaway
- GLP-1 receptor agonists beyond diabetes now have high-quality RCT evidence supporting a 20% reduction in major adverse cardiovascular events in patients with obesity and established CVD but without diabetes (SELECT trial, HR 0.80; 95% CI 0.72–0.90).
- The FLOW trial demonstrated a 24% reduction in major kidney disease events with semaglutide in patients with type 2 diabetes and CKD (HR 0.76; 95% CI 0.66–0.88), including a 29% reduction in cardiovascular death — leading to early trial termination for efficacy.
- In the STEP-HFpEF programme, semaglutide produced clinically meaningful improvements in heart failure symptoms (KCCQ-CSS +7.8 points vs placebo), 6-minute walk distance, and CRP levels in patients with obesity-related HFpEF, with and without type 2 diabetes.
- The phase 3 ESSENCE trial showed that semaglutide achieved resolution of metabolic dysfunction-associated steatohepatitis (MASH) in a significantly greater proportion of patients than placebo, though long-term clinical outcome data remain pending.
- Key gaps persist: most trials enrolled predominantly male, white participants; whether cardiovascular benefit is driven by weight loss or independent pleiotropic mechanisms is unresolved; and long-term safety beyond 4 years requires further surveillance.
Why GLP-1 Receptor Agonists Beyond Diabetes Matter for Internists
Initially developed for glycaemic control in type 2 diabetes, GLP-1 receptor agonists have undergone a remarkable transformation in clinical scope. A convergence of large-scale cardiovascular outcomes trials has established these agents — particularly semaglutide — as therapies with broad cardiometabolic benefits that extend well beyond glucose management. The 2023 World Obesity Atlas projects that over half the global population will have overweight or obesity by 2035, driving parallel increases in cardiovascular disease, heart failure, chronic kidney disease, and metabolic liver disease.
For internists, the clinical implications are substantial. Patients with obesity-related cardiovascular disease, heart failure with preserved ejection fraction (HFpEF), diabetic kidney disease, and MASH are among the most complex and frequently encountered populations in internal medicine. The evidence reviewed here suggests that GLP-1 receptor agonists may represent a single therapeutic platform capable of addressing multiple comorbidities simultaneously — a paradigm shift from organ-specific treatment toward integrated cardiometabolic management.
What Evidence Was Reviewed
This synthesis draws on 10 landmark studies published between 2021 and 2025, including four large-scale RCTs with hard clinical endpoints, two HFpEF trials, one dedicated kidney outcomes trial, one liver histology trial, and supporting prespecified subgroup analyses. All primary trials enrolled >500 participants and were randomised, double-blind, and placebo-controlled. Evidence through 2025.
| Study | Design | n | Population | Key Finding | Quality |
|---|---|---|---|---|---|
| SELECT (Lincoff 2023) | Multicentre RCT | 17,604 | Obesity + CVD, no diabetes | Semaglutide 2.4 mg reduced MACE 20% (HR 0.80; 95% CI 0.72–0.90) | High |
| SELECT HF Prespecified (Deanfield 2024) | Prespecified RCT analysis | 4,286 | Subset with prevalent HF | Semaglutide reduced MACE by 28% and composite HF endpoint by 21% in HF patients | High |
| FLOW (Perkovic 2024) | Multicentre RCT | 3,533 | T2D + CKD (eGFR 25–75) | 24% reduction in major kidney events (HR 0.76; 95% CI 0.66–0.88); stopped early | High |
| STEP-HFpEF (Kosiborod 2023) | Multicentre RCT | 529 | Obesity + HFpEF, no diabetes | KCCQ-CSS +7.8 pts vs placebo; body weight −13.3% vs −1.8% | High |
| STEP-HFpEF DM (Kosiborod 2024) | Multicentre RCT | 616 | Obesity + HFpEF + T2D | Similar HF symptom and weight improvements in diabetic HFpEF | High |
| ESSENCE Phase 3 (Sanyal 2025) | Multicentre RCT | 800 (Part 1) | Biopsy-proven MASH, fibrosis F2/F3 | MASH resolution significantly greater with semaglutide vs placebo | High |
| Phase 2 NASH (Newsome 2021) | Double-blind RCT | 320 | NASH, fibrosis F1–F3 | NASH resolution: 59% semaglutide 0.4 mg vs 17% placebo (p<0.001) | High |
| SELECT Weight (Ryan 2024) | Prespecified RCT analysis | 17,604 | Full SELECT cohort | Mean −10.2% weight loss sustained to 4 years; consistent across subgroups | High |
| FLOW HF Analysis (Mahaffey 2024) | Prespecified RCT analysis | 3,533 | Full FLOW cohort | 27% reduction in HF events or CV death; benefit in both HFpEF and HFrEF | High |
| FLOW + SGLT2i (Perkovic 2024b) | Prespecified RCT analysis | 3,533 | FLOW cohort ± SGLT2i at baseline | Semaglutide benefits on kidney/CV outcomes maintained regardless of baseline SGLT2i use | High |
Key Findings: GLP-1 Receptor Agonists Across Organ Systems
1. Cardiovascular Protection Without Diabetes: The SELECT Paradigm Shift
The SELECT trial represents a watershed moment for GLP-1 receptor agonist therapeutics. By enrolling 17,604 patients with established atherosclerotic CVD (prior MI, stroke, or symptomatic PAD) and obesity (BMI ≥27) but explicitly excluding those with diabetes, the trial isolated the cardiovascular effects of semaglutide from its glycaemic benefits. Over a mean follow-up of 39.8 months, semaglutide 2.4 mg weekly reduced the composite primary endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke by 20% compared with placebo (HR 0.80; 95% CI 0.72–0.90; p <0.001).
This represents the first demonstrated pharmacological cardiovascular risk reduction specifically attributable to an anti-obesity medication in a non-diabetic population. Concurrent weight loss averaged 9.4% in the semaglutide group versus 0.9% with placebo, but prespecified analyses suggest the cardiovascular benefit may not be fully explained by weight reduction alone — pointing to additional anti-inflammatory and anti-atherosclerotic mechanisms. Notably, the benefit was observed despite widespread concurrent statin use, indicating that semaglutide addresses residual cardiovascular risk not adequately controlled by standard lipid-lowering therapy.
2. Kidney Protection: FLOW Establishes a Fourth Pillar
The FLOW trial is the first dedicated kidney outcomes trial of a GLP-1 receptor agonist. Among 3,533 participants with type 2 diabetes and CKD (eGFR 25–75 mL/min/1.73 m², albuminuria), semaglutide 1.0 mg weekly reduced the composite of kidney failure, sustained ≥50% eGFR decline, or kidney/cardiovascular death by 24% compared with placebo (HR 0.76; 95% CI 0.66–0.88; p = 0.0003). The trial was stopped early at a prespecified interim analysis owing to overwhelming efficacy — a signal of robust clinical benefit.
The kidney-specific components alone were reduced by 21% (HR 0.79; 95% CI 0.66–0.94), and the annual rate of eGFR decline was 1.16 mL/min/1.73 m² slower in the semaglutide group, indicating meaningful preservation of kidney function. Cardiovascular death was reduced by 29% (HR 0.71; 95% CI 0.56–0.89) and all-cause mortality by 20%. A prespecified analysis found that these benefits were maintained irrespective of baseline SGLT2 inhibitor use, suggesting additive or complementary mechanisms rather than therapeutic redundancy. These data position GLP-1 receptor agonists as a potential fourth pillar of diabetic kidney disease management, alongside RAS inhibitors, SGLT2 inhibitors, and nonsteroidal mineralocorticoid receptor antagonists.
Of the 3,533 FLOW participants, 550 (approximately 15%) were receiving an SGLT2 inhibitor at baseline. While the primary outcome showed consistent benefit of semaglutide overall, the subgroup on concurrent SGLT2 inhibitors had a numerically non-significant result (HR 1.07; 95% CI 0.69–1.67), contrasting with a clear benefit in those not on SGLT2 inhibitors (HR 0.73). The p-value for interaction did not reach significance, and the subgroup was underpowered. These findings do not support withholding either agent, but head-to-head and formal combination studies are needed to define optimal sequencing and stacking strategies. The lack of harm in the combination group is reassuring regarding safety.
A prespecified analysis of the FLOW trial examined heart failure events in this high-risk CKD population. Semaglutide reduced the composite of HF events or cardiovascular death by 27%, HF events alone by 27%, and cardiovascular death by 29% compared with placebo. These reductions were consistent in participants with and without baseline heart failure and in those with HFpEF or HFrEF. Background SGLT2 inhibitor and MRA use did not attenuate these benefits. These findings complement the STEP-HFpEF data and suggest that GLP-1 receptor agonists address HF risk across a broad spectrum of cardiorenal disease.
3. Heart Failure With Preserved Ejection Fraction: Symptom and Function Gains
The STEP-HFpEF programme (two trials: one without diabetes, n = 529; one with diabetes, n = 616) targeted the specific phenotype of obesity-related HFpEF — a condition with limited prior pharmacological options. In both trials, 52 weeks of semaglutide 2.4 mg produced substantial improvements in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), a validated patient-reported measure of HF symptoms and physical limitations. In the non-diabetic STEP-HFpEF trial, the treatment difference was 7.8 points (95% CI 4.8–10.9; p <0.001), well above the established minimum clinically important difference of 5 points.
Body weight decreased by 13.3% with semaglutide versus 1.8% with placebo, and the 6-minute walk distance improved by 21.5 metres more in the semaglutide group. CRP levels — a marker of systemic inflammation — declined by 38% more with semaglutide than placebo. NT-proBNP levels fell by 22% more in the treatment group. These combined improvements in symptoms, functional capacity, biomarkers, and body composition represent the most comprehensive therapeutic response observed for this difficult-to-treat condition. Efficacy was consistent across age groups, sex, obesity class, and baseline symptom severity.
4. Metabolic Liver Disease: From Histological Proof-of-Concept to Phase 3
Metabolic dysfunction-associated steatohepatitis (MASH) affects an estimated 5% of adults globally and is projected to drive a two- to three-fold increase in liver-related mortality by 2030. A phase 2 RCT (Newsome et al. 2021, n = 320) first demonstrated that daily subcutaneous semaglutide achieved histological resolution of NASH in 59% of treated patients versus 17% with placebo among those with stage F2/F3 fibrosis (p <0.001). These promising results were subsequently confirmed in the phase 3 ESSENCE trial.
The ESSENCE trial enrolled patients with biopsy-proven MASH and fibrosis stage F2 or F3. In the first 800 participants completing 72 weeks of treatment, semaglutide 2.4 mg weekly met both co-primary endpoints: resolution of steatohepatitis without fibrosis worsening and improvement in fibrosis without steatohepatitis worsening were both significantly superior to placebo. Additionally, 32.8% of semaglutide-treated patients achieved both MASH resolution and fibrosis improvement simultaneously, compared with 16.2% on placebo. Mean weight loss of 10.5% was also observed. Hepatic safety was favourable, with no treatment discontinuations due to liver enzyme elevations. Part 2 of the ESSENCE trial, evaluating long-term clinical liver outcomes, is ongoing.
Resmetirom, a thyroid hormone receptor-β agonist, became the first FDA-approved treatment specifically for non-cirrhotic MASH in March 2024. Semaglutide subsequently received conditional approval for this indication based on the ESSENCE data. A cross-trial comparison (acknowledging its inherent limitations) suggests similar rates of fibrosis improvement over placebo — approximately 14–15% absolute improvement with both agents. However, semaglutide appears to produce higher absolute rates of MASH resolution, potentially driven by its greater weight loss effects. Notably, a recent meta-analysis suggests that diabetes status may modify the fibrosis response: semaglutide showed a stronger fibrosis benefit in non-diabetic MASH patients, while resmetirom's fibrosis benefit appeared more consistent in diabetic patients. These data may ultimately guide personalised treatment selection.
Across all trials reviewed, gastrointestinal adverse effects — primarily nausea, diarrhoea, vomiting, and constipation — were the most common side effects and the leading cause of treatment discontinuation. In SELECT, permanent discontinuation was twice as common in the semaglutide group (16.6%) compared to placebo (8.2%), almost entirely driven by GI intolerance. However, these events were generally mild to moderate and most frequent during dose escalation. In clinical practice, slower up-titration schedules and proactive patient counselling may improve tolerability. Serious adverse events were actually less frequent with semaglutide in most trials, and the ESSENCE trial reported a favourable hepatic safety profile with no liver-related treatment discontinuations.
Quality & Consistency of Evidence
What the Evidence Does Not Show
Despite the breadth of evidence, several clinically important questions remain unanswered.
The SELECT trial enrolled only 27.7% women — far lower than the 74% female representation in prior obesity trials with semaglutide. Whether the 20% MACE reduction applies equally to women with obesity-related CVD is uncertain, as the trial was not powered for sex-specific subgroup analysis. Similarly, representation of Black and Hispanic participants was limited across most trials, constraining generalisability to diverse populations.
The FLOW trial did not enrol patients with CKD in the absence of diabetes — a critical gap given that obesity itself is an independent risk factor for kidney disease progression. Whether GLP-1 receptor agonists provide kidney protection in non-diabetic CKD is unknown and requires dedicated investigation. For HFpEF, while the STEP-HFpEF trials demonstrated impressive symptom and biomarker improvements, they were insufficiently powered to detect reductions in hard outcomes such as HF hospitalisation or cardiovascular death. Larger, event-driven HFpEF trials are needed.
Regarding MASH, the critical question of whether histological improvement translates into reduced cirrhosis, hepatocellular carcinoma, or liver transplantation need will not be answered until ESSENCE Part 2 reports, which is expected to require several years of additional follow-up. Finally, the contribution of weight-independent anti-inflammatory mechanisms versus weight loss per se to the observed cardiovascular and organ-protective benefits remains incompletely characterised — a mechanistic distinction with implications for whether non-GLP-1 weight-loss strategies might achieve similar outcomes.
Practical Implications
Based on the current evidence, the following considerations may inform clinical decision-making for internists managing patients across the cardiometabolic spectrum. These represent evidence-based observations, not directive clinical recommendations.
The SELECT trial provides the first evidence that a GLP-1 receptor agonist reduces MACE in patients with obesity and established CVD without diabetes. For internists managing secondary prevention in obese patients whose residual risk is not fully addressed by statins and antihypertensives, semaglutide represents an evidence-based therapeutic option.
FLOW data support adding semaglutide to the CKD management toolkit for patients with type 2 diabetes and albuminuric kidney disease, potentially alongside RAS inhibitors, SGLT2 inhibitors, and finerenone. The 24% kidney event reduction and slowed eGFR decline were clinically meaningful and maintained across CKD severity strata.
STEP-HFpEF evidence supports semaglutide as a treatment for the obesity-HFpEF phenotype, producing improvements in symptoms, functional capacity, and inflammatory biomarkers that exceeded the minimum clinically important difference. Clinicians should note that few patients in these trials were on background SGLT2 inhibitors — combination effects are not yet well characterised.
Phase 2 and phase 3 data consistently demonstrate histological MASH resolution with semaglutide. For internists co-managing patients with obesity, metabolic syndrome, and suspected or biopsy-proven MASH, these findings may support GLP-1 receptor agonist use — particularly when addressing multiple comorbidities simultaneously.
Evidence Grade + Bottom Line
Overall Evidence Grade: Strong
The evidence for GLP-1 receptor agonists beyond diabetes is supported by multiple large, well-designed RCTs with hard clinical endpoints. The SELECT and FLOW trials provide the highest-quality evidence for cardiovascular and kidney protection respectively. HFpEF data are strong for symptoms and function, with event-driven trials ongoing. MASH evidence is strong for histological endpoints but awaits long-term outcome confirmation.
A "strong" grade indicates that the core cardiovascular and kidney findings are unlikely to change substantially with additional research. However, specific questions about sex-stratified efficacy, combination therapy optimisation, long-term safety, and mechanistic pathways remain open and may refine clinical application.
- Semaglutide reduces MACE by 20% in patients with obesity and CVD without diabetes — the first pharmacotherapy to achieve this in a non-diabetic population.
- In diabetic CKD, semaglutide reduced major kidney events by 24%, with trial stopped early for efficacy, supporting its role as a fourth pillar alongside RAAS blockade, SGLT2i, and nsMRAs.
- Obesity-related HFpEF symptoms and functional capacity improve substantially with semaglutide, though hard outcome data from event-driven trials are still needed.
- MASH histological resolution is achievable with semaglutide, with phase 3 confirmation, though prevention of cirrhosis and liver-related mortality requires longer follow-up.
- Key limitation: Under-representation of women (27.7% in SELECT) and racial minorities across trials limits the generalisability of current evidence to all patient populations.
Article Information
For Educational Purposes Only. This is an original evidence synthesis informed by the studies listed below. It does not replace clinical judgement. Drug dosages should be verified against current prescribing information.
References
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