Patients with cardiometabolic heart failure with preserved ejection fraction and type 2 diabetes who initiated semaglutide or tirzepatide had markedly lower 1-year risks of heart failure hospitalization or all-cause mortality compared with sitagliptin, used as a placebo proxy, according to a five-cohort, real-world analysis of three US claims databases (N=58,333 for semaglutide vs sitagliptin; N=11,257 for tirzepatide vs sitagliptin; N=28,100 for tirzepatide vs semaglutide). Findings were published in JAMA and presented at the European Society of Cardiology Congress 2025.

Tirzepatide showed no meaningful benefit over semaglutide.

By the numbers (expanded routine-care cohorts)

• Semaglutide vs sitagliptin: 1-year risk 5.5% vs 8.6% (absolute risk reduction 3.2%; NNT 31); HR 0.58 (95% CI 0.51–0.65) → 42% relative risk reduction.

• Tirzepatide vs sitagliptin: 1-year risk 3.6% vs 7.5% (absolute risk reduction 3.9%; NNT 26); HR 0.42 (95% CI 0.31–0.57) → 58% relative risk reduction.

• Head-to-head: 1-year risk 3.3% vs 3.4%; risk difference 0.1%; HR 0.86 (95% CI 0.70–1.06) → no meaningful difference.

Follow-up (as-treated, up to 52 weeks) Median on-treatment follow-up ranged 128–141 days across cohorts (e.g., 133 for semaglutide vs 141 for sitagliptin; 137 vs 133 for tirzepatide vs sitagliptin; 139 vs 128 for tirzepatide vs semaglutide). Treatment discontinuation was the most common reason for censoring (~37%–45%).

Safety & secondary outcomes

No substantially increased risks were seen for gastrointestinal adverse events, serious bacterial infections, or urinary-tract infections with semaglutide or tirzepatide vs sitagliptin; notably, serious bacterial infections were lower with semaglutide vs sitagliptin (HR 0.70). The broader composite secondary endpoint— heart-failure (HF) hospitalization, urgent IV diuretics, or all-cause mortality—also favored both agents vs sitagliptin.

What the study did (and why it matters)

Five active-comparator, new-user cohorts using Medicare A/B/D (2018–2020), Optum Clinformatics (2018–Nov 2024), and Merative MarketScan (2018–2022). Primary endpoint: HF hospitalization or all-cause mortality; as-treated follow-up to 52 weeks; propensity-score overlap weighting to balance baseline characteristics; prespecified protocols and registration on ClinicalTrials.gov.

Before broadening to routine care, researchers benchmarked database emulations against STEP-HFpEF DM (semaglutide) and SUMMIT (tirzepatide) using the RCT-DUPLICATE framework; both emulations met all agreement metrics. Real-world effects were directionally concordant with trials (RWE HR 0.57 vs STEP-HFpEF DM HR 0.40; RWE HR 0.39 vs SUMMIT HR 0.62).

Who was studied

Mean ages 66.7–70.8 years; 53–55% women; mean BMI 36.6–40.2 (where available); 4.1–5.8% had a prior 12-month HF hospitalization. Covariates were well balanced after overlap weighting (SMDs <0.01 on displayed characteristics).

Methods notes & guardrails

The primary composite used claims-validated definitions (HF hospitalization PPV 98%; death sensitivity >99% vs National Death Index). Negative controls (lumbar radiculopathy, abdominal hernia) showed no associations, supporting validity. Prespecified subgroup analyses by age, sex, and BMI showed no meaningful heterogeneity of treatment effect.

Eligibility nuance

In the expanded "routine-care" analyses, participants with a BMI of 27 or higher were included (compared to STEP-HFpEF DM's requirement of a BMI of 30 or higher). A post-hoc cohort restricted to those with a BMI of 30 or higher showed similar results for the primary endpoint—providing useful context for readers curious about the weight criteria.

Limitations

Observational design with potential residual confounding (despite overlap weighting); adherence inferred from dispensing; outcomes rely on claims algorithms; and the sitagliptin "placebo proxy" assumption—supported by TECOS, prior database work, and benchmarking with similar outcome rates.

Disclosures can be found in the study.

Source: JAMA