Background & Clinical Rationale
Heart failure (HF) affects more than 64 million people worldwide and is a leading cause of hospitalization and mortality. The intersection of HF with obesity, type 2 diabetes (T2D), and chronic kidney disease (CKD) defines a growing subset of patients with multiple metabolic comorbidities who are at especially high risk.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) — including semaglutide, liraglutide, exenatide, dulaglutide, and albiglutide, as well as the dual GIP/GLP-1 agonist tirzepatide — were developed initially for glycaemic control in T2D. Over time, large-scale cardiovascular outcome trials revealed profound reductions in major adverse cardiovascular events (MACE) well beyond glucose lowering. These agents have now become transformative tools in cardiometabolic medicine.
However, the relationship between GLP-1 RAs and heart failure is nuanced. Evidence strongly supports their use in HF with preserved ejection fraction (HFpEF), particularly in patients with obesity and/or T2D. In contrast, signals of potential harm in HF with reduced ejection fraction (HFrEF) have tempered enthusiasm, making phenotype-specific evidence crucial for clinical decision-making.
Mechanisms of Action in Heart Failure
GLP-1 receptors are expressed in the heart, vasculature, kidneys, brain, and adipose tissue. The cardioprotective effects of GLP-1 RAs arise through both direct and indirect pathways. The indirect metabolic effects — particularly weight loss — appear to be the dominant driver of HFpEF benefit.
10–15% body weight reduction with semaglutide; 11–21% with tirzepatide. Visceral adiposity reduction decreases pericardial fat, wall stress, and volume overload — the central drivers of obesity-phenotype HFpEF.
Modest reductions in systolic BP (~3–5 mmHg) through natriuresis and vasodilation. SUMMIT trial: −5 mmHg systolic with tirzepatide (p<0.001). Reduces afterload and cardiac wall stress.
Significant reductions in hs-CRP and IL-6. In SUMMIT, tirzepatide reduced CRP by 37.2%. Systemic inflammation drives myocardial fibrosis and diastolic dysfunction in HFpEF.
Tirzepatide reduced estimated blood volume significantly in SUMMIT secondary analysis (Nature Medicine, 2024), directly addressing circulatory overload driving end-organ damage in HFpEF.
SUMMIT CMR substudy (JACC 2025): tirzepatide reduced LV mass by 11g and paracardiac adipose tissue. Semaglutide reduced left atrial remodelling and improved LA volumes in STEP-HFpEF echocardiography substudies.
GLP-1 RAs reduce glomerular hyperfiltration and proteinuria, providing renal protective effects particularly relevant in the CKD-HF overlap. FLOW trial confirmed kidney outcomes benefit with semaglutide.
GLP-1 receptors on sinus node modulate heart rate (+6–8 bpm). Some pre-clinical data suggest enhanced myocardial glucose uptake and ischaemic preconditioning, though direct myocardial effects remain debated.
Reductions in LDL, triglycerides, endothelial activation markers, and plaque vulnerability. These effects explain the consistent ASCVD benefit even when direct HF benefits are less clear.
The Story So Far: A Historical Timeline
Cardiovascular Outcome Trials (CVOTs) with HF Data
All major GLP-1 RA CVOTs captured HF hospitalisation as a pre-specified secondary outcome. Together, they provide the foundation for understanding CV and HF effects in T2D populations.
| Trial | Drug | N (with HF) | HF Hosp. HR | MACE HR | Key HF Finding | Signal |
|---|---|---|---|---|---|---|
| ELIXA NEJM 2015 |
Lixisenatide | 6,068 (22% HF) | HR 0.96 (NS) | HR 1.02 (NS) | Neutral; post-ACS population | Neutral |
| LEADER NEJM 2016 |
Liraglutide | 9,340 (14.3% HF) | HR 0.87 (p=0.14) | HR 0.87 (p=0.01) | 13% numerical reduction in HHF; consistent across subgroups | Positive trend |
| SUSTAIN-6 NEJM 2016 |
Semaglutide s.c. | 3,297 (24% HF) | HR 1.11 (NS) | HR 0.74 (p<0.001) | Numerically higher HHF; powered for MACE not HF | Inconclusive |
| EXSCEL NEJM 2017 |
Exenatide ER | 14,752 (16% HF) | HR 0.94 (NS) | HR 0.91 (NS) | Subgroup: LVEF <40% — increased HHF (OR 1.49 in meta-analysis) | Mixed |
| HARMONY Lancet 2019 |
Albiglutide | 9,463 (20% HF) | HR 0.71 (p=0.03) | HR 0.78 (p<0.001) | Significant 29% reduction in HHF — strongest HHF signal among CVOTs | Positive |
| REWIND Lancet 2019 |
Dulaglutide | 9,901 (9% HF) | HR 0.93 (NS) | HR 0.88 (p=0.026) | Neutral for HHF; broader primary prevention population | Neutral |
| PIONEER-6 NEJM 2019 |
Semaglutide oral | 3,183 (9% HF) | HR 1.15 (NS) | HR 0.79 (p<0.001) | Not powered for HF; numerically higher HHF | Neutral |
| SELECT NEJM 2023 |
Semaglutide s.c. 2.4mg | 17,604 (24% HF at baseline) | HR 0.77 (p=0.002) | HR 0.80 (p<0.001) | Non-diabetic obesity + CVD; 23% reduction in HHF. HFpEF subgroup: significant benefit. HFrEF: less clear. | Positive |
| FLOW NEJM 2024 |
Semaglutide s.c. 1.0mg | 3,533 (T2D + CKD) | HR 0.71 (p=0.002) | HR 0.76 (p<0.001) | T2D + CKD; 29% reduction in HHF; HF outcomes in CKD-HF overlap confirmed | Positive |
HR = Hazard Ratio; NS = Not Statistically Significant; HHF = Heart Failure Hospitalisation; s.c. = subcutaneous; ER = Extended Release
Landmark Dedicated HF Trials
Unlike CVOTs, the following trials specifically enrolled HF patients as the primary population, providing the most direct evidence on GLP-1 RA efficacy and safety across HF phenotypes.
| Trial | Agent & Dose | Population | N | Primary Outcome | Result | Verdict |
|---|---|---|---|---|---|---|
| FIGHT JAMA 2016 |
Liraglutide 1.8mg | HFrEF, recent decompensation (mean EF 25%) | 300 | Death, HHF, or NT-proBNP change at 180 days | Neutral overall; numerically higher events (143 vs 96 in liraglutide arm). Trend to harm in T2D subgroup. | Concerning |
| LIVE Eur J HF 2017 |
Liraglutide 1.8mg | Stable HFrEF ± T2D (mean EF ~35%, BMI ~28) | 241 | Change in LVEF at 24 weeks | No improvement in LVEF. Increased serious cardiac events (12 vs 3, p<0.05) including VT, AF, ACS. HR increase +6 bpm. | Harmful signal |
| STEP-HFpEF NEJM Aug 2023 |
Semaglutide 2.4mg weekly | HFpEF (EF ≥45%), obesity (BMI ≥30), no T2D | 529 | Change in KCCQ-CSS & body weight at 52 weeks | KCCQ-CSS +16.6 pts (vs +8.7, p<0.001); weight −13.3% (vs −2.6%). Worsening HF events: HR 0.08 (92% reduction, 13 events total) | Landmark benefit |
| STEP-HFpEF DM NEJM 2024 |
Semaglutide 2.4mg weekly | HFpEF (EF ≥45%), obesity (BMI ≥30), T2D present | 616 | Change in KCCQ-CSS & body weight at 52 weeks | KCCQ-CSS +13.7 pts (vs +6.4, p<0.001); weight −9.8% (vs −3.7%). Confirms T2D subgroup benefits. | Confirmed benefit |
| SUMMIT NEJM Jan 2025, presented AHA Nov 2024 |
Tirzepatide up to 15mg weekly (dual GIP/GLP-1) | HFpEF (EF ≥50%), obesity (BMI ≥30), ±T2D | 731 | CV death or worsening HF event (time-to-first) & KCCQ-CSS at 52 weeks | CV death/HF event: HR 0.62 (p=0.026). Worsening HF events: HR 0.54. KCCQ-CSS +19.5 vs +12.7 (p<0.001). Weight −11.7%. CRP −37.2%. Blood volume reduced. | Game-changing |
GLP-1 RAs in HFrEF: A Cautionary Tale
The contrast between the robust benefit in HFpEF and the neutral-to-concerning signals in HFrEF is one of the most important distinctions in contemporary heart failure medicine. Understanding this requires reviewing multiple converging lines of evidence.
Stable HFrEF — Primary Safety Signal
241 patients with stable HFrEF (EF ≤45%, mean BMI 28 kg/m²). Liraglutide 1.8mg vs placebo for 24 weeks. Primary endpoint (change in LVEF) was neutral. However, serious cardiac events occurred in 12 liraglutide vs 3 placebo patients (p<0.05): 1 VT death, 3 VTs, 4 AFs requiring cardioversion, 1 worsening HF, 3 ACS events. Heart rate increased by 6 bpm.
Acute Decompensated HFrEF — Neutral with Trend
300 recently hospitalized HFrEF patients (mean EF 25%). Liraglutide neutral on primary composite (death, HHF, NT-proBNP), but numerically more events in liraglutide arm (143 vs 96). Post-hoc arrhythmia analysis: trend toward more arrhythmic events (IRR 1.76, p=0.088). In T2D subgroup: significantly worse outcomes.
LVEF <40% — Increased HF Hospitalisation
Neves et al. (J Card Fail 2023): meta-analysis combining EXSCEL LVEF <40% subgroup and FIGHT trial data showed OR 1.49 (95% CI 1.05–2.10, p=0.02) for HF hospitalisation with GLP-1 RA in patients with LVEF <40%. First formal meta-analytic evidence of potential harm in HFrEF.
Device-Monitored HFrEF Patients
Retrospective analysis of 106 HFrEF patients with implanted cardiac devices. GLP-1 RA use (vs non-use) significantly increased heart rate by +7 bpm (p<0.01) and was associated with increased nonsustained ventricular events and total shock/ATP therapies (33 vs 3, p=0.01). Real-world corroboration of arrhythmia concerns.
HFrEF: Most Up-to-Date Synthesis
Neves, Vale, Leite et al. (JACC HF 2025): systematic meta-analysis of RCTs evaluating GLP-1 RAs specifically in HFrEF. Confirmed no mortality benefit and signal of increased HF events. Authors conclude data do not support GLP-1 RA initiation for HFrEF without a compelling co-indication (e.g., obesity, T2D with ASCVD).
Non-Diabetic Obesity — Some Reassurance
Deanfield et al. (Lancet 2024): SELECT prespecified HF subgroup analysis showed that semaglutide 2.4mg improved HF outcomes in HFpEF, but effects in HFrEF were less robust and not significant. No clear safety signal in non-diabetic obese patients, possibly because obesity phenotype modifies risk.
GLP-1 RAs in HFpEF: A New Standard of Care?
The convergence of data from STEP-HFpEF, STEP-HFpEF DM, SUMMIT, SELECT, and FLOW, together with multiple meta-analyses, now provides robust, consistent, and mechanistically coherent evidence that GLP-1 RAs — particularly semaglutide and tirzepatide — significantly benefit patients with HFpEF and obesity.
Pooled Analysis: SELECT, FLOW, STEP-HFpEF, STEP-HFpEF DM
Kosiborod et al. (Lancet 2024) pooled data from these four trials in patients with HFpEF (EF ≥45%). Semaglutide produced consistent, significant benefits in worsening HF events, quality of life (KCCQ-CSS), exercise capacity (6MWD), and body weight. Benefits were consistent regardless of T2D status, confirming a class effect in obesity-related HFpEF beyond glucose lowering.
KCCQ-CSS Improvement
Semaglutide: +16.6 pts (STEP-HFpEF), +13.7 pts (STEP-HFpEF DM). Tirzepatide: +19.5 pts (SUMMIT). A minimum clinically important difference is ~5 pts — all trials exceeded 2× this threshold. Patients report meaningful improvements in symptom burden and functional limitations.
6-Minute Walk Distance
Semaglutide increased 6MWD by +21.5m (STEP-HFpEF) and +14.3m (STEP-HFpEF DM) vs placebo. Tirzepatide improved exercise tolerance significantly in SUMMIT. Benefits scale with degree of weight loss (each 10% loss = +14.4m improvement).
Hospitalisation Prevention
SUMMIT: HR 0.54 for worsening HF events. Meta-analysis of 6 RCTs (J Card Fail 2025): HR 0.56 [0.38–0.82] for worsening HF events alone. RCT meta-analysis of obese HFpEF (Diabetes Obes Metab 2025): RR 0.40 [0.22–0.73] for HF events with GLP-1 RAs vs placebo.
Mechanistic Corroboration
Consistent reductions in hs-CRP across all trials — a direct marker of the inflammatory milieu driving HFpEF. NT-proBNP improvements observed in multiple studies. Blood volume and pressure overload directly addressed by tirzepatide (SUMMIT Nature Medicine 2024).
Effect Modification: Who Benefits Most?
Evidence consistently shows the greatest benefit in patients with:
- BMI ≥30 kg/m² — obesity is the central driver of the phenotype GLP-1 RAs most effectively modify
- Elevated baseline hs-CRP — inflammatory phenotype responds most to anti-inflammatory mechanisms
- Concomitant T2D or pre-diabetes — metabolic benefits compound structural benefits
- EF ≥45% — spectrum of HFpEF and HFmrEF (≥40%) show benefit; HFrEF remains contraindicated-equivalent
- Higher KCCQ symptom burden at baseline — greater absolute room for improvement
Key Meta-Analyses & Systematic Reviews (2023–2025)
| Citation | Population | N / Trials | Key Result | Conclusion |
|---|---|---|---|---|
| Ferreira et al. Diabetes Obes Metab 2023 |
T2D with/without CHF (CVOTs) | ~60,000 / 7 RCTs | GLP-1 RAs reduced HHF in those without CHF but not in those with established CHF. HFrEF subgroup showed potential harm. | Critical phenotype distinction: GLP-1 RAs prevent HF onset but may not benefit — and could harm — established HFrEF. |
| Waqas et al. J Card Fail July 2025 |
HFpEF/HFmrEF (RCTs) | 8,788 / 6 RCTs | CV death or worsening HF: HR 0.68 [0.51–0.89], p=0.006. Worsening HF alone: HR 0.56 [0.38–0.82], p=0.003. CV death alone: HR 0.86 (NS). | GLP-1 RAs significantly reduce worsening HF and composite events in HFpEF, particularly with obesity/T2D. |
| Talavera et al. Diabetes Obes Metab Dec 2025 |
Obese HFpEF (RCTs only) | 1,876 / 3 RCTs | HF events: RR 0.40 [0.22–0.73], p=0.003. KCCQ-CSS: +7.23 pts. Mortality: NS. Serious AEs: NS. | In obese HFpEF, GLP-1 RAs significantly reduce HF events and improve QoL without increasing mortality. |
| Neves et al. JACC HF July 2025 |
HFrEF (RCTs) | Pooled / multiple | No mortality benefit; signal of increased HF events in HFrEF. Confirmed LIVE and FIGHT findings. | GLP-1 RAs should not be initiated for HFrEF treatment based on current evidence. Safety concern persists. |
| Kosiborod et al. Lancet 2024 (Pooled) |
HFpEF (SELECT, FLOW, STEP programs) | ~25,000 pooled | Semaglutide consistently improved KCCQ-CSS, weight, 6MWD, and worsening HF events regardless of T2D status. | Establishes semaglutide's broad efficacy across the HFpEF spectrum, with and without T2D. |
| Sattar et al. Lancet Diabetes Endocrinol 2021 |
T2D (CVOTs meta-analysis) | ~60,000 / 7 CVOTs | GLP-1 RAs: 18% reduction in HHF across all CVOTs. MACE HR 0.88. Renal outcomes: HR 0.82. | Class effect for MACE and HHF prevention in T2D; cardiorenal protection confirmed. |
Real-World Evidence
Real-world studies complement trial data by capturing broader, more heterogeneous populations with longer follow-up, variable adherence, and clinical practice variation. Several important datasets have emerged through 2025.
Reduction in HF hospitalisation rates in T2D patients initiating GLP-1 RAs vs other antihyperglycaemics in propensity-matched cohorts (~100,000+ patients). Findings consistent with trial data but confounded by channelling bias and indication.
Jiang et al. (ESC Heart Failure 2025): GLP-1 RA use associated with improved pulmonary artery pressure trajectories in HF patients with implanted hemodynamic monitors, consistent with reduced volume overload and pulmonary venous pressures. Real-world mechanistic corroboration of SUMMIT data.
JACC HF 2025: 53 HFrEF patients initiating GLP-1 RAs vs 53 matched non-users. Heart rate increased by +7 bpm (p<0.01). Significant increase in nonsustained VT events and total shock/ATP therapies (33 vs 3, p=0.01). Largest real-world HFrEF safety dataset to date.
Cross-sectional study of cardiology prescribing found significant under-utilisation of GLP-1 RAs and SGLT2i in eligible HFpEF patients, despite growing evidence base. Barriers include cost, limited awareness of HFpEF-specific evidence, and lack of formal guideline recommendations.
Meta-analyses of real-world cohort studies in T2D consistently confirm ~15–20% reduction in new-onset HF incidence with GLP-1 RA use, irrespective of diabetes duration, consistent with the CV prevention paradigm.
Pharmacovigilance analysis of adverse event databases confirms known GI side effects as dominant. Psychiatric adverse events being studied (Tobaiqy et al. 2024). No new unexpected cardiovascular safety signals in HFpEF patients emerging from spontaneous reporting, but HFrEF data underrepresented.
Clinical Decision-Making Framework
Patient Selection Algorithm: GLP-1 RAs in Heart Failure (2026)
Determine ejection fraction: HFpEF (EF ≥50%), HFmrEF (EF 41–49%), or HFrEF (EF ≤40%). This single step is the most important determinant of GLP-1 RA suitability.
Is BMI ≥30 kg/m²? The strongest evidence exists in obese HFpEF. In non-obese HFpEF, evidence is less robust and use should be considered on a case-by-case basis.
T2D? ASCVD/high CV risk? CKD? Each of these provides independent evidence base supporting GLP-1 RA use (and potentially modifying HFrEF risk). SGLT2i remains preferred first-line for T2D + HFrEF.
Personal/family history of medullary thyroid carcinoma or MEN2 syndrome. Pancreatitis history. Current severe gastroparesis. Decompensated HF requiring IV therapy (delay initiation).
Strong evidence base (STEP-HFpEF, SUMMIT). Choose semaglutide 2.4 mg weekly (preferred based on evidence) or tirzepatide 2.5–15 mg weekly. Start low, uptitrate. Target weight loss ≥10% for maximal HF benefit.
If obesity or T2D + ASCVD mandates a GLP-1 RA, use with extreme caution. Ensure optimised HFrEF therapy (ACEi/ARNi, beta-blocker, MRA, SGLT2i) is in place. Monitor heart rate, arrhythmias (consider Holter), and HF symptoms closely. Discuss risks explicitly.
Agent Comparison: Semaglutide vs Tirzepatide in HFpEF
| Feature | Semaglutide 2.4mg weekly | Tirzepatide 5–15mg weekly |
|---|---|---|
| Mechanism | GLP-1 RA (selective) | Dual GIP + GLP-1 RA |
| Evidence in HFpEF | STEP-HFpEF, STEP-HFpEF DM, SELECT, FLOW (pooled) | SUMMIT (N Engl J Med 2025) |
| Weight Loss (RCT) | ~13% (HFpEF trial) | ~11–12% (SUMMIT); 20%+ in SURMOUNT |
| HF Events | HR ~0.08 (worsening HF events, STEP-HFpEF — small numbers) | HR 0.54 for worsening HF events (SUMMIT) |
| CV Death/HF Composite | SELECT: HR 0.77 for HHF | SUMMIT: HR 0.62 (p=0.026) |
| LV Mass Reduction | Not significant (echocardiography) | −11g reduction (CMR substudy) |
| CRP Reduction | Significant (multiple trials) | −37.2% (SUMMIT) |
| T2D Approved | Yes (Ozempic/Rybelsus) | Yes (Mounjaro) |
| Obesity Approved | Yes (Wegovy) | Yes (Zepbound) |
| HFpEF Formal Approval | Pending in most regions (2025–2026) | Pending (anticipated 2026) |
Side Effects & Monitoring Essentials
GI Adverse Events
Nausea (20–40%), vomiting, diarrhoea — particularly during dose escalation. Usually transient and manageable with slower uptitration. Rare but important: acute pancreatitis (precaution in prior history); gallbladder disease (~1.5% higher risk vs placebo).
Chronotropy — Watch in All HF
Consistent +4–8 bpm increase across all agents. Clinically meaningful in HFrEF where every 5 bpm above target worsens outcomes. Monitor resting HR at each visit. In HFpEF patients on beta-blockers, interaction may be complex.
Sarcopenia Concern
Significant weight loss includes a lean mass component (up to 30–40% of total weight lost). In elderly HFpEF patients, encourage resistance exercise and ensure adequate protein intake ≥1.2g/kg/day. Sarcopenia and frailty could offset functional benefits in some patients.
Practical Guidance
Baseline: KCCQ, weight, HR, BNP/NT-proBNP, renal function. At 4 weeks: GI tolerability, BP, HR. At 12 weeks: repeat weight, KCCQ, labs. At 6 months: 6MWD, echocardiography if clinical change. Annual: HbA1c, lipids, comprehensive metabolic panel.
Ongoing Research & The Future Landscape
The therapeutic frontier for GLP-1 RAs in HF is rapidly expanding. Several critical trials are underway or in late planning that will reshape guidelines and clinical practice through 2027.
CagriSema in HFpEF
Cagrisema (combined GLP-1 RA semaglutide + amylin analogue cagrilintide) in HFpEF and obesity. Anticipated greater weight loss (~24%) than semaglutide alone. Will test whether amplified weight loss further improves HF outcomes.
Long-Term Tirzepatide Outcomes
Extended follow-up of SUMMIT cohort and additional HFpEF patients. Will provide longer-term mortality data and assess whether sustained weight loss maintains or augments HF benefits. Mortality signal should clarify by 2027.
GLP-1 RA Safety in HFrEF
Dedicated safety trial of a GLP-1 RA in HFrEF patients with obesity, incorporating cardiac device monitoring and holter analysis. Designed to definitively characterize arrhythmia risk and determine if the obesity phenotype modifies HFrEF safety.
Retatrutide, Mazdutide & Others
Triple receptor agonists offer up to 24% weight loss in phase 2 trials. Retatrutide entering cardiovascular outcomes trial. If weight loss is the dominant mechanism, these agents could offer even greater HFpEF benefit — or reveal divergence from GLP-1–specific effects.
GLP-1 RA + SGLT2i Combination
Whether dual therapy with GLP-1 RA and SGLT2i in HFpEF provides additive benefit over either alone. Both independently improve symptoms and events; the combination is widely used clinically but formal RCT evidence is awaited.
Biomarker-Guided Patient Selection
Ongoing efforts to identify biomarkers (hs-CRP, IL-6, adiponectin, epicardial fat volume on imaging) that predict GLP-1 RA response in HFpEF. May allow targeting therapy to the inflammatory-obesity phenotype most likely to respond.
Formal HFpEF Indication Expected
FDA/EMA submissions for semaglutide in HFpEF were advanced following STEP-HFpEF and SUMMIT. Guideline committees are expected to incorporate GLP-1 RAs into HFpEF management recommendations in 2025–2026 updates. Class IIa recommendation anticipated.
Post-Marketing Surveillance
European HF Registry, Get With the Guidelines HF, and national prescribing datasets will accumulate GLP-1 RA data in routine HFpEF practice. Will provide data on underrepresented groups: elderly (>75), frail, non-obese HFpEF, and combined HFrEF-obesity populations.
- Can GLP-1 RAs safely be used in HFrEF with concomitant severe obesity? Does obesity phenotype override the EF-based harm signal?
- What is the mortality impact of GLP-1 RAs in HFpEF with longer follow-up (3–5 years)?
- Does dual therapy (GLP-1 RA + SGLT2i) offer additive benefit over either agent alone in HFpEF?
- Can non-obese HFpEF patients benefit from GLP-1 RAs via anti-inflammatory mechanisms alone?
- What is the optimal agent, dose, and duration for HFpEF? When should therapy be stopped?
- Will triple GIP/GLP-1/glucagon agonists (retatrutide) further improve HF outcomes through amplified weight loss?
Current Guideline Status (as of February 2026)
Supported by Evidence
Strong evidence from STEP-HFpEF DM, SUMMIT, and multiple meta-analyses. Multiple professional societies now acknowledge GLP-1 RAs as appropriate therapy in this phenotype. Anticipated formal Class IIa or IIb recommendation in upcoming 2025/2026 guideline updates from AHA/ACC and ESC.
Supported by Evidence
STEP-HFpEF and SUMMIT included patients without T2D; evidence is robust. Semaglutide FDA-approved for weight management (Wegovy). Off-label use for HFpEF in obese non-diabetic patients is increasingly endorsed by expert opinion pending formal HFpEF-specific approval (anticipated 2026).
Standard of Care
Established in ADA, ESC/EASD 2023 guidelines for CV risk reduction in T2D with established ASCVD. GLP-1 RAs preferred alongside SGLT2i for MACE prevention. This indication indirectly prevents incident HF (~18% reduction in HHF across CVOTs).
No Recommendation / Caution
No guideline currently recommends GLP-1 RAs for HFrEF treatment. Current AHA/ACC and ESC HF guidelines are silent or cautionary. If a patient with HFrEF requires GLP-1 RA for T2D/obesity with high ASCVD risk, proceed with extreme caution and in specialist context only.