Efficacy and safety of empagliflozin at different doses in patients with type 2 diabetes mellitus: A network meta‐analysis based on randomized controlled trials

Abstract

What is Known and Objective: As an oral hypoglycaemic drug that significantly reduces cardiovascular risk, empagliflozin is often used in patients with type 2 diabetes mellitus (T2DM). However, the dosage and administration of empagliflozin are still controversial clinically. To determine the most appropriate dose, we performed this network meta-analysis. Methods:We identified randomized controlled trials (RCTs) about empagliflozin from eight databases. We analysed the pharmacodynamics, adverse effects (AEs), and pharmacokinetics of empagliflozin at different doses. Results:We identified 8264 articles, of which 23 RCTs with 10518 patients were included. Regarding haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), highdaily doses (10, 25, 50 mg) were significantly better than low doses (1, 2.5, 5 mg). For total AEs, there was a dose-response trend in which safety decreased with increasing doses. According to SUCRA sequencing, the order for lowering HbA1c was 25 > 50 > 10 > 5 > 1 mg, for lowering FPG was 50 > 25 > 10 > 5 > 2.5 > 1 mg and for safety was 1> 5 > 10 > 25> 2.5 > 50 mg. When considering HbA1c, FPG and total AEs, we performed a hierarchical cluster analysis and network meta-analysis to find that 25 mg performed best among different doses, which was more significant after long-term use (≥ 12 weeks). Pharmacokinetic parameters exhibited significant dose-response relationships. What is New and Conclusion:High-daily doses (10, 25, 50 mg) had better efficacy than low doses (1, 2.5, 5 mg). When considering HbA1c, FPG and total AEs, 25 mg performed best among the different doses in patients with T2DM.

Clinical Benefit of Switching from Low-Dose to High-Dose Empagliflozin in Patients with Type 2 Diabetes

“…On the other hand, there are two reports of network meta-analyses based on randomized control trials of empagliflozin. Wu et al reported that the reduction of HbA1c by 25 mg empagliflozin was greater than that caused by 10 mg empagliflozin, but this was not a significant difference [25 mg vs. 10 mg: effect size − 0.04%; 95%CI − 0.19 to 0.10)] [ 27 ]. They also reported that the reduction of BW by 25 mg empagliflozin was significantly greater than that caused by 10 mg empagliflozin [25 mg vs. 10 mg: effect size − 0.24 kg; 95%CI − 0.39 to − 0.09)] [ 27 ].…”

“…Wu et al reported that the reduction of HbA1c by 25 mg empagliflozin was greater than that caused by 10 mg empagliflozin, but this was not a significant difference [25 mg vs. 10 mg: effect size − 0.04%; 95%CI − 0.19 to 0.10)] [ 27 ]. They also reported that the reduction of BW by 25 mg empagliflozin was significantly greater than that caused by 10 mg empagliflozin [25 mg vs. 10 mg: effect size − 0.24 kg; 95%CI − 0.39 to − 0.09)] [ 27 ]. Zaccardi et al reported in the other network meta-analysis that the reduction of HbA1c by 25 mg empagliflozin was greater than that caused by 10 mg empagliflozin, but, as in the above reports, the difference was not significant [25 mg vs. 10 mg: effect size − 0.05%; 95%CI − 0.13 to 0.02)] [ 28 ].…”

Risk of acute pancreatitis among new users of empagliflozin compared to sulfonylureas in patients with type 2 diabetes: A post‐authorization safety study

“…1 Overall, the safety profile of empagliflozin is well established; it is generally well tolerated, with a low risk of serious adverse events. [2][3][4] The safety profile of empagliflozin is supported by the findings of a recent pooled analysis of 20 randomized clinical trials and four extension studies of patients with T2D. The pooled analysis showed that empagliflozin, at doses of 10 or 25 mg, was well tolerated in patients with T2D and was not associated with a higher rate of confirmed hypoglycemia versus placebo, except in patients receiving concurrent insulin and/or a sulfonylurea (SU).…”

“…7 For empagliflozin, current data indicate that urinary tract, but not genital, infections are more frequent compared with placebo, although these events are generally mild to moderate in severity and do not usually lead to treatment discontinuation. [2][3][4][5] Several potential adverse events have been associated with SGLT2 inhibitors following safety signals from case reports and large clinical trials of SGLT2 inhibitors. 3,[8][9][10] These include urinary and genital infection, diabetic ketoacidosis, bone fracture, cancers, and foot and toe amputation.…”

“…The SGLT2 inhibitor mechanism of action is also associated with a risk of urinary tract infections and genital mycotic infections as a consequence of glycosuria 7 . For empagliflozin, current data indicate that urinary tract, but not genital, infections are more frequent compared with placebo, although these events are generally mild to moderate in severity and do not usually lead to treatment discontinuation 2–5 …”