Background: Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i), Dipeptyl Peptidase-4 inhibitors (DPP-4i) and Glucagon-Like Peptide-1 agonists (GLP-1a) effectively reduce HbA1c levels. Their long-term cardiovascular effects have been tested against placebo, but the comparative efficacy of individual drug types is unclear.

Aim: To compare the efficacy of SGLT2i, DPP-4i and GLP-1a for reducing cardiovascular outcomes by network meta-analysis.

Methods: Medline, Embase and the Cochrane Library Central Register of Controlled Trials were searched for randomised controlled trials (RCTs) of >12 weeks’ duration enrolling patients with type 2 diabetes and comparing drugs of SGLT2i, DPP-4i or GLP-1a classes with another included class or control. Comparative point estimates were synthesised by random effects frequentist network meta-analysis.

Results: In all, 236 RCTs were included, accounting for 176,310 patients across 20 interventions (DPP-4i: 6; GLP-1a: 7; SGLT2i: 7). Empagliflozin and liraglutide reduced cardiovascular mortality compared to control (RR 0.63; 95% CI 0.51-0.79; P<0.001; and RR 0.79, 95% CI 0.66-0.93, P=0.006, respectively). Empagliflozin was the highest-ranking drug for cardiovascular mortality (P-score=0.89) and significantly reduced fatal cardiovascular events compared to 5 other drug types in addition to control (DPP-4i: 2; GLP-1a: 2; SGLT2i: 1). Empagliflozin and canagliflozin reduced heart failure events compared to control (RR 0.66; 95% CI 0.51-0.86 and RR 0.70; 95% CI 0.54-0.90 respectively), while saxagliptin increased heart failure events (RR 1.23; 95% CI 1.04-1.46). Myocardial infarction and stroke were not affected by any drug of any class.

Conclusions: Empagliflozin and liraglutide demonstrate the greatest efficacy for cardiovascular mortality, while SGLT2i may exert additional benefits in heart failure. This study provides evidence to support clinical decisions in treatment of type 2 diabetes.


A.J. Roddick: None.S. Zheng: None.

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