Association of sodium-glucose cotransporter 2 inhibitors with cardiovascular outcome and safety events: A meta-analysis of randomized controlled clinical trials

Abstract

Background: The clinical benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors for preventing and treating cardiovascular events remains controversial. We aimed to study the effect of SGLT2 inhibitors on cardiovascular outcomes and safety events, giving particular attention to the benefits in subgroups of patients with different diseases.

Method: Randomized controlled trials (RCTs) reporting cardiovascular outcomes following the administration of SGLT2 inhibitors and placebo were included in this study. Cardiovascular outcomes included all-cause death, major adverse cardiovascular events (MACEs), cardiovascular (CV) death, myocardial infarction (MI), stroke, and hospitalization for heart failure (HHF). We also focused on the cardiovascular benefits of SGLT2 inhibitor application in subgroups of patients with different diseases, including type 2 diabetes (T2D), heart failure (HF), high risk of atherosclerotic cardiovascular disease (ACD), diagnosed ACD, and chronic kidney disease (CKD). Safety events associated with SGLT2 inhibitors, including acute kidney injury (AKI), diabetic ketoacidosis (DKA), hypoglycemia, urinary tract infection, thromboembolic event, bone fracture, volume depletion, and amputation, were also reported.

Results: This meta-analysis included 15 RCTs with 78,212 participants. SGLT2 inhibitors reduced the risk of all-cause death (RR 0.89; 95% CI: 0.85-0.94; I2 = 32%; p < 0.01), CV death (RR 0.87; 95% CI: 0.82-0.93; I2 = 11%; p < 0.01), MACEs (RR 0.89; 95% CI: 0.84-0.94; I2 = 46%; p < 0.01), HHF (RR 0.70; 95% CI: 0.66-0.74; I2 = 0%; p < 0.01), and AKI (RR 0.81; 95% CI: 0.73-0.90; I2 = 0%; p < 0.01) but increased the risk of DKA (RR 2.56; 95% CI: 1.72-3.80; I2 = 0%; p < 0.01). However, no apparent benefit in MI and stroke was observed between the SGLT2 inhibitor and control groups. SGLT2 inhibitors reduced the risk of all-cause death, MACEs, CV death, and HHF in diabetic patients; reduced the risk of all-cause death, MACEs, CV death, MI, and HHF in primary prevention; reduced the risk of all-cause death, CV death, and HHF in patients with ACD and HF; and reduced the risk of MACEs, CV death, and HHF in patients with CKD.

Conclusion: SGLT2 inhibitors have a positive effect in reducing the risk of all-cause death, CV death, MACE, HHF, and AKI and increasing the risk of DKA. The application of SGLT2 inhibitors in the primary prevention of ACD also has certain clinical benefits in reducing MI.

Systematic review registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022306490].

Keywords: atherosclerotic cardiovascular disease; cardiovascular risks; diabetes; heart failure; sodium-glucose cotransoporter-2 inhibitors.

FIGURE 1

Flow diagram of the study selection process.

FIGURE 2

Risk of bias plot. (A) Risk of bias summary; (B) risks of bias of each included study.

FIGURE 3

Forest plot of all-cause death and the detection of publication bias. (A) Forest plot of all-cause death; (B) funnel chart of trimming and filling.

FIGURE 4

Comparison of SGLT2 inhibitor vs. control group on the risks of (A) MACE; (B) CV death; (C) HHF. SGLT2, Sodium-glucose cotransporter 2; MACEs, major adverse cardiac events; CV death, cardiovascular death; HHF, hospitalization for heart failure.

FIGURE 5

Forest plot of subgroup of subjects with diabetes, HF, ACD, high risks of ACD, and CKD. SGLT2, Sodium-glucose cotransporter 2; MACEs, major adverse cardiac events; CV death, cardiovascular death, MI, myocardial infarction; HF, heart failure; HHF, hospitalization for heart failure. *Random-effects model.

FIGURE 6

Comparison of SGLT2 inhibitor vs. control group on the risks of (A) AKI; (B) DKA; (C) Volume Depletion. SGLT2, sodium-glucose cotransporter 2; AKI, acute kidney injury; DKA, diabetic ketoacidosis.