Systematic review of sodium-glucose cotransporter 2 inhibitors: a hopeful prospect in tackling heart failure-related events

Abstract

In modern cardiology, sodium-glucose cotransporter 2 (SGLT2) inhibitors are critical components of heart failure (HF) treatment algorithms and exert their effects primarily by preventing glucose reabsorption and facilitating its urinary excretion. The objective was to systematically review randomized controlled trials (RCTs) assessing the effects of SGLT2 inhibitors, particularly canagliflozin, empagliflozin, dapagliflozin, ertugliflozin, sotagliflozin (dual SGLT inhibitor), and their use in HF. Systematic searches of PubMed/Medline, The Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases were performed. There were no restrictions imposed on the date and status of publication; however, there were restrictions on language for the searched studies. A total of 1139 records were identified in the bibliographic searches from both databases and the register of choice for this systematic review. Following duplicate removal, screening for titles and abstracts, and thorough assessment of full-text articles, 12 RCTs met the inclusion criteria. Altogether, 83 878 patients were included in this review. Among the included studies, two RCTs, with six respective reports, investigated canagliflozin, four RCTs with 13 derived reports investigated dapagliflozin, three RCTs with 12 separate reports studied the effects of empagliflozin, one RCT and its three respective reports assessed ertugliflozin's effects, and two RCTs with one added report investigated the dual inhibitor sotagliflozin. Pooled meta-analytic effects of SGLT2 inhibitors were as follows: on atrial fibrillation odds ratio (OR) = 0.83, 95% confidence interval (CI): 0.68-1.01, prediction interval (PI): 0.57-1.19; on HF hospitalization OR = 0.69, 95% CI: 0.60-0.78, PI: 0.60-0.78; on cardiovascular death OR = 0.82, 95% CI: 0.58-1.15, PI: 0.42-1.60; and on major adverse cardiovascular events OR = 0.90, 95% CI: 0.77-1.06, PI: 0.71-1.15. SGLT2 inhibitors significantly improve the quality of life in HF patients. Their beneficial effects on HF, especially in left ventricular dysfunction, have made their use possible irrespective of diabetes mellitus or atrial fibrillation status.

Keywords: Diabetes mellitus; Heart failure; Hypoglycaemic agents; Sodium-glucose transporter 2 inhibitors.

Figure 1

PRISMA 2020 Flow Diagram.

Figure 2

Risk of bias summary. Review authors' judgements about each risk of bias item for each of the 12 included RCTs. Created with Revman Software (Review Manager 5.4.1), upon completion of quality assessment for each study.

Figure 3

(A) Forest plot of placebo‐controlled randomized trials examining the pooled effects of SGLT2 inhibitors therapy on AF occurrence in heart failure patients. The meta‐analytic results (lines 4) consist of two intervals, both around the same bullet, which represent the weighted average effect or the combined effect size. CI is represented by the smaller, black interval, whereas prediction interval is represented by the larger green interval. (B) Funnel plot of placebo‐controlled randomized trials examining the effects of SGLT2 inhibitors therapy on AF in heart failure patients, depicting effect sizes against their standard errors. (C) L'Abbé plot showing the AF event rate in the intervention group (SGLT2 inhibitors) against the AF event rate in the placebo group.

Figure 4

(A) Forest plot of placebo‐controlled randomized trials examining the pooled effects of SGLT2 inhibitors‐related common side effects. The meta‐analytic results (lines 11) consist of two intervals, both around the same bullet, which represent the weighted average effect or the combined effect size. Confidence interval is represented by the smaller, black interval, whereas prediction interval is represented by the larger green interval. (B) Funnel plot of placebo‐controlled randomized trials examining the side effects of SGLT2 inhibitors, depicting effect sizes against their standard errors. (C) L'Abbé plot showing the side effects in the intervention group (SGLT2 inhibitors) against the side effects in the placebo group.

Figure 5

Forest plot of placebo‐controlled randomized trials comparing the pooled effects of SGLT2 inhibitors, GLP‐1 agonists, and DPP‐4 inhibitors on HHF. The meta‐analytic results (lines 5) consist of two intervals, both around the same bullet, which represent the weighted average effect or the combined effect size. Confidence interval is represented by the smaller, black interval, whereas prediction interval is represented by the larger green interval.

Figure 6

Forest plot of placebo‐controlled randomized trials comparing the pooled effects of SGLT2 inhibitors, GLP‐1 agonists, and DPP‐4 inhibitors on cardiovascular death. The meta‐analytic results (lines 5) consist of two intervals, both around the same bullet, which represent the weighted average effect or the combined effect size. Confidence interval is represented by the smaller, black interval, whereas prediction interval is represented by the larger green interval.

Figure 7

Forest plot of placebo‐controlled randomized trials comparing the pooled effects of SGLT2 inhibitors, GLP‐1 agonists, and DPP‐4 inhibitors on MACE. The meta‐analytic results (lines 5) consist of two intervals, both around the same bullet, which represent the weighted average effect or the combined effect size. Confidence interval is represented by the smaller, black interval, whereas prediction interval is represented by the larger green interval.

Figure 8

(A) Forest plot of placebo‐controlled randomized trials examining the pooled effects of SGLT2 inhibitors effects on end‐stage renal disease. The meta‐analytic result (line 8) consists of two intervals, both around the same bullet, which represent the weighted average effect or the combined effect size. Confidence interval is represented by the smaller, black interval, whereas prediction interval is represented by the larger green interval. (B) Funnel plot of placebo‐controlled randomized trials examining the effects of SGLT2 inhibitors on end‐stage renal disease, depicting effect sizes against their standard errors. (C) L'Abbé plot showing the side effects in the intervention group (SGLT2 inhibitors) against the side effects in the placebo group.