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Comparative effectiveness of combination therapy with SGLT-2 inhibitors and GLP-1 RAs compared with SGLT-2 inhibitors

Gregor A Maier1, Beata Hennig2, Wolfgang Rathmann1

  • 1Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

Diabetes, Obesity & Metabolism
|February 23, 2026
PubMed
Abstract

Insights

Combination therapy with sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly reduced all-cause mortality in type 2 diabetes patients. This real-world evidence suggests combined SGLT-2 inhibitors and GLP-1 RAs offer substantial clinical benefits.

Area of Science:

  • Cardiology
  • Endocrinology
  • Pharmacology

Background:

  • Type 2 diabetes management often requires combination therapies to achieve glycemic control and reduce cardiovascular risk.
  • Sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used, but their combined effect in real-world settings needs evaluation.

Purpose of the Study:

  • To assess the effectiveness of combining SGLT-2 inhibitors with GLP-1 RAs versus continuing SGLT-2 inhibitors alone in type 2 diabetes patients.
  • To evaluate the impact of this combination therapy on all-cause mortality and key cardiorenal outcomes.

Main Methods:

  • A prevalent new-user design using nationwide health claims data (BARMER) from 2013-2023.
  • Matching individuals initiating GLP-1 RAs (with or without SGLT-2 inhibitors) to SGLT-2 inhibitor continuers using propensity scores.
  • Analysis of all-cause mortality, a modified cardiovascular composite, heart failure, nephropathy, and renal failure using Cox proportional hazards models.

Main Results:

  • The study included 21,664 matched pairs with a median follow-up of 1.3 years.
  • Combination therapy showed a 29% lower hazard of all-cause mortality (HR 0.71; 95% CI 0.63-0.80).
  • Significant hazard reductions were also observed for the cardiovascular composite (HR 0.81; 95% CI 0.74-0.88) and heart failure (HR 0.78; 95% CI 0.68-0.89).

Conclusions:

  • Combination therapy with SGLT-2 inhibitors and GLP-1 RAs is associated with reduced all-cause mortality in a real-world type 2 diabetes population.
  • While secondary cardiorenal outcomes were generally favorable, estimates were imprecise.
  • Sustained concurrent use of both drug classes may provide significant clinical benefits in routine practice, though residual confounding is possible.
Keywords:
GLP‐1 analogueSGLT2 inhibitorobservational studypharmacoepidemiologyreal‐world evidencetype 2 diabetes

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