Comparative cardiovascular benefits of individual SGLT2 inhibitors in type 2 diabetes and heart failure: a systematic review and network meta-analysis of randomized controlled trials

Front Endocrinol (Lausanne). 2023 Dec 20:14:1216160. doi: 10.3389/fendo.2023.1216160. eCollection 2023.

Abstract

Background: In patients with type 2 diabetes (T2D) and a history of heart failure (HF), sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated cardiovascular (CV) benefits. However, the comparative efficacy of individual SGLT2is remains uncertain. This network meta-analysis (NMA) compared the efficacy and safety of five SGLT2is (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin) on CV outcomes in these patients.

Materials and methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched up to September 23, 2022, to identify all randomized controlled trials (RCTs) comparing SGLT2is to placebo in T2D patients with HF. The main outcomes included composite CV death/heart failure hospitalization (HFH), HFH, CV death, all-cause mortality, and adverse events. Pairwise and NMA approaches were applied.

Results: Our analysis included 11 RCTs with a total of 20,438 patients with T2D and HF. All SGLT2is significantly reduced HFH compared to standard of care (SoC) alone. "Add-on" SGLT2is, except ertugliflozin, significantly reduced composite CV death/HFH relative to SoC alone. Moreover, canagliflozin had lower composite CV death/HFH compared to dapagliflozin. Based on the surface under the cumulative ranking curve (SUCRA), the top-ranked SGLT2is for reducing HFH were canagliflozin (95.5%), sotagliflozin (66.0%), and empagliflozin (57.2%). Head-to-head comparisons found no significant differences between individual SGLT2is in reducing CV death. "Add-on" SGLT2is reduced all-cause mortality compared with SoC alone, although only dapagliflozin was statistically significant. No SGLT2is were significantly associated with serious adverse events. A sensitivity analysis focusing on HF-specific trials found that dapagliflozin, empagliflozin, and sotagliflozin significantly reduced composite CV death/HFH, consistent with the main analysis. However, no significant differences were identified from their head-to-head comparisons in the NMA. The SUCRA indicated that sotagliflozin had the highest probability of reducing composite CV death/HFH (97.6%), followed by empagliflozin (58.4%) and dapagliflozin (44.0%).

Conclusion: SGLT2is significantly reduce the composite CV death/HFH outcome. Among them, canagliflozin may be considered the preferred treatment for patients with diabetes and a history of heart failure, but it may also be associated with an increased risk of any adverse events compared to other SGLT2is. However, a sensitivity analysis focusing on HF-specific trials identified sotagliflozin as the most likely agent to reduce CV death/HFH, followed by empagliflozin and dapagliflozin.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022353754.

Keywords: cardiovascular disease; congestive heart failure; diabetes mellitus; network meta-analysis; sodium-glucose cotransporter 2 inhibitor (SGLT2 inhibitor); systematic review.

Publication types

  • Meta-Analysis
  • Systematic Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Canagliflozin / therapeutic use
  • Diabetes Mellitus, Type 2* / complications
  • Heart Failure* / complications
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Network Meta-Analysis
  • Randomized Controlled Trials as Topic
  • Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use

Substances

  • Canagliflozin
  • dapagliflozin
  • empagliflozin
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2 Inhibitors

Grants and funding

This work is part of the training towards a PhD degree in Health Technology Assessment (HTA), for which a scholarship was provided by Mahidol University and the International Decision Support Initiative (iDSI) through a grant awarded to UC (OPP1087363). This study was conducted as part of the International Decision Support Initiative (www.idsihealth.org), which supports countries in obtaining the best value of money from health spending. The iDSI receives funding support from the Bill & Melinda Gates Foundation, the UK Department for International Development, and the Rockefeller Foundation. In addition, this work was also supported by the Medicine Regulations Division, Food and Drug Administration, Ministry of Public Health, Thailand. This study was conducted at the request of the National List of Essential Medicine (NLEM). This manuscript is a part of the project “Economic evaluation of add-on SGLT2 inhibitor to standard treatment in type 2 diabetes with congestive heart failure in Thailand” which was used to support the policy-making process under the Subcommittee for the Development of the NLEM in Thailand through the Health Economic Working Group (HEWG) but the HEWG is not responsible for the study findings or their dissemination. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.