High‐dose sodium‐glucose co‐transporter‐2 inhibitors are superior in type 2 diabetes: A meta‐analysis of randomized clinical trials

Abstract

Aim To determine the overall efficacy of high‐ versus low‐dose sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D). Material and Methods A literature search using MEDLINE, EMBASE and the Cochrane Library was performed from 1 January 2006 to 23 September 2020. Random effects models were used to calculate mean differences (MDs) and pooled relative risk (RR). Prespecified subgroup analyses for each SGLT2 inhibitor, follow‐up and controls were performed. Leave‐one‐out sensitivity and meta‐regression analyses were conducted. Results A total of 51 randomized controlled trials involving 23 989 participants (weighted mean age, 58.9 years; men, 58.8%) were eligible for our meta‐analysis. For glycaemic regulation ability, a significant reduction in HbA1c (MD −0.080%, 95% confidence interval [CI] −0.100 to −0.060), fasting plasma glucose (MD −0.227 mmol/L, 95% CI −0.282 to −0.173) and postprandial plasma glucose (MD −0.834 mmol/L, 95% CI −1.268 to −0.400) levels was observed in the high‐dose SGLT2 inhibitor group. Treatment with high‐dose SGLT2 inhibitors enabled easier achievement of the target (HbA1c <7%) than low‐dose SGLT2 inhibitors (RR 1.148, 95% CI 1.104 to 1.193). High‐dose SGLT2 inhibitor‐based treatment resulted in more efficient regulation of body weight and blood pressure (body weight: MD −0.346 kg, 95% CI −0.437 to −0.254; systolic blood pressure: MD −0.583 mmHg, 95% CI −0.903 to −0.263; diastolic blood pressure: MD −0.352 mmHg, 95% CI −0.563 to −0.142). The results were similar in sensitivity analyses. Conclusions The overall efficacy of SGLT2 inhibitors, mainly canagliflozin, dapagliflozin and empagliflozin, was found to be dose dependent.

Are High- or Low-dose SGLT2 Inhibitors Associated With Cardiovascular and Respiratory Adverse Events? A Meta-analysis

“…Two meta-analyses 17,29 revealed that the efficacy of SGLT2 inhibitors was dose dependent and high-dose SGLT2 inhibitors were superior to low-dose SGLT2 inhibitors in treating diabetes mellitus. Two other meta-analyses 13,14 assessed the noncardiovascular safety of SGLT2 inhibitors versus placebo and identified that SGLT2 inhibitors were generally safe but were associated with the increased risks of some adverse events, such as genital infections and volume depletion.…”

“…High-dose SGLT2 inhibitors included canagliflozin (300 mg), empagliflozin (25 mg), dapagliflozin (10 mg), and ertugliflozin (15 mg), whereas low-dose SGLT2 inhibitors included canagliflozin (100 mg), empagliflozin (10 mg), dapagliflozin (5 mg), and ertugliflozin (5 mg). 16,17 Those trials evaluating sotagliflozin were excluded because sotagliflozin is a dual SGLT1 and SGLT2 inhibitor and so were those trials that enrolled less than 1000 participants in at least 1 study arm, to prevent small-study effects. We evaluated the quality of included trials according to the Cochrane risk of bias assessment tool.…”

“…However, there are no related meta-analyses that have evaluated the impact of high-dose or low-dose SGLT2 inhibitors on the risks of various cardiovascular and respiratory adverse events so far. Given that the effects of SGLT2 inhibitors on efficacy outcomes such as HbA1c and body weight are dose dependent, 17 it is essential to determine whether there are significant differences in risks of cardiopulmonary adverse events between high-dose and low-dose SGLT2 inhibitors.…”

Sodium-glucose co-transporter-2 inhibitors reduce the risk of new-onset stroke in patients with type 2 diabetes: A population-based cohort study

“…As evidence of the efficacy of SGLT-2 inhibitors continued to grow, many trails and meta-analysis on these drugs have expanded their prescriptions from diabetes patients only to also include patients with HF without type 2 DM (28)(29)(30)(31)(32). Furthermore, the safety and dose-response relationship of SGLT2 inhibitors were recommended in the clinical practice (33)(34)(35).…”

Mechanistic View on the Effects of SGLT2 Inhibitors on Lipid Metabolism in Diabetic Milieu

“…Another clinical trial demonstrated that after 12 weeks of canagliflozin treatment, HDL-cholesterol levels were increased, thus providing cardiovascular benefits in patients with T2DM [ 79 ]. This benefit occurred at high-dose therapy [ 80 ]. Shi et al reported that high dose of SGLT2, inhibitors of canagliflozin and dapagliflozin, increased HDL-cholesterol and decreased TG levels in patients with diabetes [ 80 ].…”