The efficacy and safety of novel classes of glucose-lowering drugs for cardiovascular outcomes: a network meta-analysis of randomised clinical trials

Diabetologia. 2021 Dec;64(12):2676-2686. doi: 10.1007/s00125-021-05529-w. Epub 2021 Sep 18.


Aims/hypothesis: Several cardiovascular outcome trials on sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been released recently, including trials enrolling patients with congestive heart failure (CHF) and chronic kidney disease (CKD). Comparisons of the efficacy and safety of SGLT2i, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) thus require an update. Assessments in patient subgroups, i.e., as stratified by age or the presence of CHF, CKD or atherosclerotic cardiovascular disease (ASCVD), are also currently lacking.

Methods: We searched the PubMed, Embase and Cochrane databases for relevant studies published up until 5 December 2020. RCTs comparing SGLT2i, GLP-1RA and DPP-4i with placebo (or other controls) or with each other with cardiovascular (CV) or renal outcomes were eligible for inclusion. The primary efficacy endpoint was 3-point major adverse cardiovascular events (3P-MACE), which are defined as CV death, non-fatal myocardial infarction and non-fatal ischaemic stroke. All-cause mortality, hospitalisation for heart failure (HHF) and composite renal outcomes were also analysed. Pre-specified subgroup analyses of 3P-MACE were also performed.

Results: A total of 21 trials with 170,930 participants were included in this network meta-analysis. Both GLP-1RA and SGLT2i were associated with lower risks of 3P-MACE than placebo (RR 0.89, 95% CI 0.84, 0.94 and RR 0.88, 95% CI 0.83, 0.94, respectively). GLP-1RA and SGLT2i were also associated with lower risks of 3P-MACE than DPP-4i (RR 0.89, 95% CI 0.82, 0.98 and RR 0.89, 95% CI 0.81, 0.97, respectively). A comparison between SGLT2i and GLP-1RA demonstrated no difference in their risks of 3P-MACE (RR 0.99, 95% CI 0.91, 1.08). Only GLP-1RA was associated with a lower risk of stroke compared with placebo (RR 0.85, 95% CI 0.76, 0.94). SGLT2i is superior to GLP-1RA in reducing HHF (RR 0.76, 95% CI 0.68, 0.84) and renal outcomes (RR 0.78, 95% CI 0.65, 0.93). Subgroup analyses indicated that the benefits of SGLT2i and GLP-1RA were more pronounced in elderly patients, white and Asian patients, those with established ASCVD and those with longer durations of diabetes mellitus and worse glycaemic control.

Conclusions/interpretation: SGLT2i and GLP-1RA are superior to DPP-4i in terms of CV and renal outcomes. GLP-1RA is the only drug class that reduces the risk of stroke. SGLT2i is superior in reducing HHF and renal outcomes. Therefore, the choice between SGLT2i and GLP-1RA should be individualised according to patient profiles.

Prospero registration number: CRD42020206600.

Keywords: CVOT; Cardiovascular outcome trial; Composite renal outcome; DPP4; Meta-analysis; SGLT-2.

Publication types

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

MeSH terms

  • Aged
  • Brain Ischemia* / chemically induced
  • Brain Ischemia* / complications
  • Brain Ischemia* / drug therapy
  • Cardiovascular Diseases*
  • Diabetes Mellitus, Type 2* / complications
  • Dipeptidyl-Peptidase IV Inhibitors* / therapeutic use
  • Glucagon-Like Peptide-1 Receptor / agonists
  • Glucose
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Network Meta-Analysis
  • Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use
  • Stroke* / drug therapy


  • Dipeptidyl-Peptidase IV Inhibitors
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2 Inhibitors
  • Glucose