Comparative Effectiveness of SGLT2i Versus DPP4i on Cardiovascular, Kidney and Hyperkalemia Outcomes in Individuals from Routine Clinical Practice: Observational Cohort Study

Background: While clinical trials have demonstrated efficacy for SGLT2 inhibitors (SGLT2i) on preventing cardiovascular and kidney damage, few high-quality studies have expanded to routine-care settings of low-risk patients. Previous observational studies were limited by immortal time bias or did not adjust for laboratory measurements. Methods: We compared clinical outcomes of adults who started SGLT2i or DPP4i therapy in Stockholm, Sweden, during 2013-2019. The primary outcome was a composite of cardiovascular (CV) death and hospitalization for heart failure (HHF). Secondary outcomes included major adverse cardiovascular events (MACE), all-cause mortality, atrial fibrillation, hyperkalemia and kidney disease progression (composite kidney failure and doubling of serum creatinine). Propensity score weighted Cox regression was used to estimate hazard ratios and balance 56 covariates. Results: We included 16,537 individuals (5526 SGLT2i; 11,011 DPP4i users), followed for median 1.9 years. Median age was 64 years (36% women), median estimated glomerular filtration rate 87 ml/min/1.73m2 and 31% had albuminuria. After weighting, patients starting SGLT2i therapy were at lower risk for the composite of CV death/HHF (HR 0.65; 95% CI 0.47-0.89) and hyperkalemia (HR 0.41; 95% CI 0.20-0.83) compared with DPP4i, without an increase in hypokalemia (HR 0.98; 95% CI 0.72-1.34). The adjusted HRs (95% CI) were 0.82 (0.64-1.06) for MACE, 0.74 (0.52-1.06) for all-cause mortality, 0.95 (0.68-1.33) for atrial fibrillation and 0.54 (0.27-1.08) for kidney disease progression. Conclusions: SGLT2i use compared with DPP4i was associated with a reduction in cardiovascular and kidney outcomes similar in magnitude to trials, as well as a lower risk of hyperkalemia. Funding: Research reported in this publication was supported by the Swedish Research Council (#2019-01059), the Swedish Heart and Lung Foundation and the Westman Foundation. ELF acknowledges support by a Rubicon Grant of the Netherlands Organization for Scientific Research (NWO). Declaration of Interests: JC acknowledges consultancy for Baxter and AstraZeneca, and grant support to Karolinska Institutet from AstraZeneca, Viforpharma and Astellas, all outside the submitted work. CMC has received consultation, advisory board membership or research funding from the Ontario Ministry of Health, Sanofi, Johnson & Johnson, Pfizer, Leo Pharma, Astellas, Janssen, Amgen, Boehringer-Ingelheim and Baxter, all outside the submitted work. None of the other authors declare relevant financial interests that would represent a conflict of interest. MJJ is responsible for research programs that have received unrestricted funding from Gambro, Baxter, Commonwealth Serum Laboratories (CSL), Amgen, Eli Lilly, and Merck; has served on advisory boards and steering committees sponsored by Akebia, Baxter, Boehringer Ingelheim, CSL, Janssen, and Vifor; and spoken at scientific meetings sponsored by Janssen, Amgen, and Roche, with any consultancy, honoraria, or travel support paid to her institution. Ethics Approval Statement: The study utilized only de-identified data and thus was deemed not to require informed consent, being approved by the regional ethical review boards and the Swedish National Board of Welfare.