ArticleTherapeutic advances in endocrinology and metabolism2026
Associations of mortality and sepsis after GLP-1 receptor agonist initiation versus SGLT2 inhibitor or metformin initiation in people with HIV, overweight or obesity, and type 2 diabetes: A target trial emulation.
Article in Therapeutic advances in endocrinology and metabolism, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: People living with HIV (PLWH) with overweight or obesity and type 2 diabetes (T2D) carry elevated cardiometabolic and infectious morbidity. Comparative effectiveness data for glucagon-like peptide-1 receptor agonists (GLP-1 RAs)against active comparators are scarce in this population. Objectives: To estimate associations between GLP-1 RA initiation andclinical outcomes compared withsodium-glucose cotransporter-2 inhibitors (SGLT2i) or metformin. Design: Target trial emulation of new-user, active-comparator cohorts in the TriNetX US Collaborative Network (2017 to 2025), with pre-specified replication in the Global Collaborative Network. Methods: Adults with HIV, overweight or obesity (ICD-10-CM E66 or body mass index 27 kg/m2 or higher), and T2D newly starting a GLP-1 RA, SGLT2i, or metformin after a 6-month washout were eligible. The primary endpoint was all-cause mortality within 3 years of the index date; secondary endpoints were A41.9-coded sepsis, candidiasis, major adverse cardiovascular events, major adverse kidney events, other or unspecified encephalopathy, and three nested exploratory code-based neurocognitive definitions (definitions 1, 1 to 2, and 1 to 3). We built 1:1 propensity score matched cohorts and fitted Cox models with Benjamini-Hochberg correction within each comparator stratum. Results: Analyses included 2,720 matched pairs vs SGLT2i and 4,604 vs metformin. GLP-1 RA initiation was associated with a lower estimated hazard of all-cause mortality during up to 3 years of follow-up vs SGLT2i (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.49-0.81) and vs metformin (HR 0.65, 0.53-0.81). Kaplan-Meier estimated 3-year mortality risk was 6.7% versus 9.4% against SGLT2i and 5.4% versus 7.4% against metformin. A41.9-coded sepsis showed a lower hazard vs SGLT2i (HR 0.71, 0.53-0.94) and metformin (HR 0.75, 0.60-0.94). Cardiovascular and kidney composites differed less clearly, with renal outcomes directionally favoring SGLT2i. Code-based neurocognitive endpoints were lower vs metformin, but were exploratory and limited by administrative coding; reported significance reflects adjusted Conclusion: GLP-1 RA initiation was associated with a lower observed hazard of all-cause mortality and of A41.9-coded sepsis than SGLT2i or metformin in PLWH with overweight or obesity and T2D. These associations remainvulnerable to residual confounding and require prospective confirmation. Emulation is not equivalent to randomization.
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