SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs

Abstract

Background: It has been suggested that sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduce the cardiorenal risk in patients with type 2 diabetes (T2D). The purpose of this study is to provide an update of all large cardiovascular outcome trials (CVOTs) with SGLT-2 inhibitors to assess their cardiorenal efficacy in patients with and without T2D.

Methods: An electronic search up to 30 September 2021 was conducted in PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. to determine eligible trials. We included CVOTs comparing any SGLT-2 inhibitor with placebo, reporting desired cardiovascular or renal outcomes and with a follow-up duration of at least 6 months.

Results: Eleven CVOTs, with data from five SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) and 77,541 participants, were included. In the overall analysis, the risk of the composite CV mortality or hospitalization for heart failure (HF) was reduced by 23% (HR = 0.77, 95% CI 0.73-0.82, P < 0.001) compared with placebo, with not significant heterogeneity (I² = 26%, P = 0.20), and irrespective of the presence of T2D (P for interaction = 0.81) and age (> 65 vs ≤ 65 years, P for interaction = 0.78). The risk of CV mortality, total mortality and hospitalization for HF was significantly reduced by 16%, 13%, and 32%, respectively; similarly, the risk of the composite renal outcome was reduced by 35% (HR = 0.65, 95% CI 0.56-0.75), with moderate heterogeneity (I² = 32%). In the analysis of 6 CVOTs reporting the data, the risk of major cardiovascular events (MACE) was reduced by 12%, with low heterogeneity (I² = 21.2%, P = 0.19) and irrespective of the presence of established CV disease at baseline (P for interaction = 0.46).

Conclusions: Therapy with SGLT-2 inhibitors in patients with cardiometabolic and renal diseases results in a sustained to moderate reduction of the composite CV death or hospitalization for HF, robust reduction of HF and renal outcomes, moderate reduction of CV mortality, total mortality and MACE.

Keywords: Cardiorenal outcomes; Cardiovascular outcome trials; SGLT-2 inhibitors; Type 2 diabetes.

Fig. 1

Forest plots examining the first outcome of CV death or hospitalization for heart failure in participants of 11 CVOTs irrespective of the presence of type 2 diabetes. There is a low and not significant heterogeneity in the analysis (I² = 23%, P = 0.20)

Fig. 2

Forest plots examining the kidney outcome in participants of ten CVOTs irrespective of the presence of type 2 diabetes and diabetic kidney disease. There is a moderate and borderline significant heterogeneity in the analysis (I² = 35%, P = 0.10)

Fig. 3

Forest plots examining the composite outcome of cardiovascular death or hospitalization for heart failure in participants of four CVOTs with (top) or without (bottom) type 2 diabetes. There is no heterogeneity in the analyses (I² = 0%) and difference between the two groups (P interaction = 0.81)

Fig. 4

Forest plots examining the composite outcome of cardiovascular death or hospitalization for heart failure in participants of three CVOTs with age > 65 years (top) or ≤ 65 years (bottom). There is no heterogeneity in the analyses (I² = 0–2%) and difference between the two groups (P interaction = 0.78)

Fig. 5

Forest plots examining the outcome cardiovascular mortality in participants of 11 CVOTs. There is moderate heterogeneity in the analyses (I² = 42% of borderline significance)

Fig. 6

Forest plots examining the outcome cardiovascular mortality in participants of 11 CVOTs. There is moderate and significant heterogeneity in the analyses (I² = 45%)

Fig. 7

Forest plots examining the outcome hospitalization for heart failure in participants of ten CVOTs. There is a null heterogeneity in the analyses (I² = 0%)