Effects of Sodium/Glucose Cotransporter 2 (SGLT2) Inhibitors and Combined SGLT1/2 Inhibitors on Cardiovascular, Metabolic, Renal, and Safety Outcomes in Patients with Diabetes: A Network Meta-Analysis of 111 Randomized Controlled Trials.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of anti-hyperglycemic drugs that has been steadily increasing in popularity due to its cardiovascular and renal benefits. Dual SGLT1/SGLT2 (SGLT1/2) inhibitors have potentially augmented anti-hyperglycemic action due to additional SGLT1 inhibition. This network meta-analysis aimed to compare the treatment effect across various outcomes between pure SGLT2 inhibitors and combined SGLT1/2 inhibitors in patients with diabetes. METHODOLOGY: Four electronic databases (PubMed, Embase, Cochrane, and Scopus) were searched for randomized controlled trials published from inception to 15th January 2022. Frequentist network meta-analysis was conducted to summarize the treatment effects reported in individual trials, stratified by type 1 (T1DM) and type 2 diabetes mellitus (T2DM). This meta-analysis was registered on PROSPERO (CRD42020222031). RESULTS: Our meta-analysis included 111 articles, comprising a combined cohort of 103,922 patients. SGLT2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, and luseogliflozin) and SGLT1/2 inhibitors (licogliflozin and sotagliflozin) were compared. Frequentist network meta-analysis demonstrated that in T2DM patients, SGLT1/2 inhibitors led to a decreased hazard rate of myocardial infarction (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.56-0.98) and stroke (HR 0.65, 95% CI 0.47-0.92) compared with SGLT2 inhibitors. SGLT2 inhibitors achieved a greater hemoglobin A1c (HbA1c) reduction than SGLT1/2 inhibitors (0.16%, 95% CI 0.06-0.26). In patients with T2DM, the risk of diarrhea (risk ratio [RR] 1.42, 95% CI 1.07-1.88) and severe hypoglycemia (RR 5.89, 95% CI 1.41-24.57) were found to be higher with SGLT1/2 inhibitor use compared with SGLT2 inhibitor use. No differences were observed for cardiovascular, metabolic, and safety outcomes between SGLT1/2 inhibitors and SGLT2 inhibitors in patients with T1DM. CONCLUSIONS: In patients with T2DM, compared with pure SGLT2 inhibitors, combined SGLT1/2 inhibitors demonstrated a lower risk of myocardial infarction and of stroke, but were associated with a higher risk of diarrhea and severe hypoglycemia.

Effects of Sodium/Glucose Cotransporter Inhibitors on Atrial Fibrillation and Stroke: A Meta-Analysis.

OBJECTIVES: Recent clinical trials have shown the potential of sodium glucose cotransporter (SGLT) 2 inhibitors to reduce the risk of atrial fibrillation but not stroke. We conducted a systematic review and meta-analysis to clarify if SGLT2 or combined SGLT1/2 inhibitors affect the risk of atrial fibrillation and stroke in patients regardless of diabetic status. MATERIALS AND METHODS: Four electronic databases were searched on 21st November 2020 for studies evaluating outcomes of stroke and atrial fibrillation with SGLT2 or combined SGLT1/2 inhibitors in both diabetic and non-diabetic patients. Both random and fixed effect, pair-wise meta-analysis models were used to summarize the results of the studies. RESULTS: A total of 13 placebo-controlled, randomized-controlled trials were included. Eight trials comprising 35,702 patients were included in the analysis of atrial fibrillation outcomes and eight trials comprising 47,910 patients were included in the analysis of stroke outcomes. Patients on SGLT inhibitors, particularly SGLT2 inhibitors, had lower odds of atrial fibrillation (Peto odds ratio [95% confidence interval] = 0.76 [0.63-0.92]) compared to placebo. This effect remained significant with a follow-up duration longer than 1 year, in studies utilizing dapagliflozin, patients with type 2 diabetes mellitus, and patients with cardiovascular disease. No difference was observed in the odds of atrial fibrillation in patients with baseline heart failure. No effect was seen on the risk of stroke in patients taking SGLT inhibitors. CONCLUSIONS: SGLT2 inhibitors significantly reduced the odds of atrial fibrillation in diabetic patients. However, SGLT inhibitors did not significantly affect the risk of stroke.

SGLT inhibitors on weight and body mass: A meta-analysis of 116 randomized-controlled trials.

OBJECTIVE: Multiple trials have demonstrated the metabolic effects of sodium/glucose cotransporter 2 (SGLT2) inhibitors in patients regardless of diabetes status, and recent trials have been conducted on the combined sodium/glucose cotransporter 1 and sodium/glucose cotransporter 2 (SGLT1/SGLT2) inhibitors. Therefore, a meta-analysis was conducted to investigate the weight reduction effects and dose-response relationship of SGLT inhibitors and to assess the relative efficacy of SGLT1/SGLT2 inhibitors. METHODS: Four electronic databases (PubMed, Embase, Cochrane, and Scopus) were searched on November 21, 2020, for articles published from January 1, 2000, up to November 21, 2020. RESULTS: In total, 116 randomized-controlled trials were included, with a combined cohort of 98,497 patients. Overall, patients had a mean weight reduction of -1.79 kg (95% CI: -1.93 to -1.66, p < 0.001) compared with placebo. This effect was observed across diabetes status, duration of follow-up, various comorbidities, and all SGLT drug types. Mean BMI changes were -0.71 kg/m2 (95% CI: -0.94 to -0.47, p < 0.001) compared with placebo. Canagliflozin, empagliflozin, sotagliflozin, and licogliflozin showed a dose-response relationship for mean weight change. Compared with SGLT2 inhibitors, SGLT1/SGLT2 inhibitors had a significantly larger reduction in weight. CONCLUSIONS: SGLT inhibitors demonstrated weight reduction benefits in this meta-analysis. Further studies are needed to clarify their role in weight management.