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. 2022 Mar 16;21(1):42.
doi: 10.1186/s12933-022-01474-z.

The effect of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors on cardiorenal outcomes: a network meta-analysis of 23 CVOTs

Dario Giugliano  1 , Miriam Longo  2   3 , Simona Signoriello  4 , Maria Ida Maiorino  2   3 , Bruno Solerte  5 , Paolo Chiodini  4 , Katherine Esposito  2   3
Affiliations

The effect of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors on cardiorenal outcomes: a network meta-analysis of 23 CVOTs

Dario Giugliano et al. Cardiovasc Diabetol. .

Abstract

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose co-transporter-2 (SGLT-2) inhibitors reduce cardiorenal outcomes. We performed a network meta-analysis to compare the effect on cardiorenal outcomes among GLP-1 RAs, SGLT-2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors.

Methods: We searched the PUBMED, Embase and Cochrane databases for relevant studies published up until 10 December 2021. Cardiovascular and renal outcome trials reporting outcomes on GLP-1RA, SGLT-2 inhibitors and DPP-4 inhibitors in patients with or without type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE); other outcomes were cardiovascular and total death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure (HHF), and renal outcome.

Results: Twenty-three trials enrolling a total number of 181,143 participants were included. DPP-4 inhibitors did not lower the risk of any cardiorenal outcome when compared with placebo and were associated with higher risks of MACE, HHF, and renal outcome when compared with the other two drug classes. SGLT-2 inhibitors significantly reduced cardiovascular (RR = 0.88) and total (RR = 0.87) death, as compared with DPP-4 inhibitors, while GLP-1 RA reduced total death only (RR = 0.87). The comparison between GLP-1RA and SGLT-2 inhibitors showed no difference in their risks of MACE, nonfatal MI, nonfatal stroke, CV and total death; SGLT-2 inhibitors were superior to GLP-1RA in reducing the risk of HHF and the renal outcome (24% and 22% lower risk, respectively). Only GLP-1RA reduced the risk of nonfatal stroke (RR = 0.84), as compared with placebo. There was no head-to-head trial directly comparing these antidiabetic drug classes.

Conclusions: SGLT-2 inhibitors and GLP-1RA are superior to DPP-4 inhibitors in reducing the risk of most cardiorenal outcomes; SGLT-2 inhibitors are superior to GLP-1RA in reducing the risk of HHF and renal events; GLP-1RA only reduced the risk of nonfatal stroke. Both SGLT-2 inhibitors and GLP-1RA should be the preferred treatment for type 2 diabetes and cardiorenal diseases.

Keywords: Cardiovascular outcome trials; DPP-4 inhibitors; GLP-1 receptor agonists; Network meta-analysis; SGLT-2 inhibitors.

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Conflict of interest statement

DG received honoraria for speaking at meetings from Novartis, Sanofi, Eli Lilly and Company, AstraZeneca, and Novo Nordisk. MIM received honoraria for speaking at meetings from AstraZeneca, Novo Nordisk, Bruno Farmaceutici, Mundipharma, and Sanofi. KE received honoraria for speaking at meetings from Novartis, Sanofi Aventis, Eli Lilly and Company, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.

Figures

Fig. 1
Fig. 1
The network of comparisons for the outcomes. The numbers on the arrows indicate the number of comparisons with placebo for each outcome
Fig. 2
Fig. 2
Forest plot of the network meta-analysis of MACE, nonfatal myocardial infarction, and nonfatal stroke. DPP-4i: dipeptydil-peptidase-4 inhibitors; Pl: placebo; GLP-1RA: glucagon-like peptide-1 receptor agonists; SGLT-2i: sodium-glucose cotransporter-2 inhibitors
Fig. 3
Fig. 3
Forest plot of the network meta-analysis of cardiovascular death, total death, hospitalization for heart failure, and renal outcome. DPP-4i: dipeptydil-peptidase-4 inhibitors; Pl: placebo; GLP-1RA: glucagon-like peptide-1 receptor agonists; SGLT-2i: sodium-glucose cotransporter-2 inhibitors
Fig. 4
Fig. 4
Summary “at glance” of the network meta-analysis comparing the effects of SGLT-2 inhibitors, GLP-1RA and DPP-4 inhibitors on cardiorenal outcomes. The symbol = indicates non significantly different; the symbol > indicates significantly different
See this image and copyright information in PMC

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