Comparative Efficacy and Safety of Antidiabetic Drug Regimens Added to Metformin Monotherapy in Patients with Type 2 Diabetes: A Network Meta-Analysis

Abstract

IntroductionWhen first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone.Materials and MethodsA search of MEDLINE and CENTRAL, clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3–12 months duration, evaluating Food and Drug Administration or European Union approved agents (noninsulin and long acting, once daily basal insulins) in patients experiencing inadequate glycemic control with metformin monotherapy (≥1500 mg daily or maximally tolerated dose for ≥4 weeks). Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI).ResultsSixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent (range, 0.43% for miglitol to 1.29% for glibenclamide). Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo (range, 4.00–11.67). Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW (range, 1.15–2.26kg) whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain (range, 1.19–2.44kg). SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP (range, 1.88–5.43mmHg). No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI (range, 2.16–8.03).ConclusionsAdding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI which should impact clinician choice when selecting adjunctive therapy.

Comparative effectiveness and safety of empagliflozin on cardiovascular mortality and morbidity in adults with type 2 diabetes

“…Although the RR reduction is larger with empagliflozin, well-designed direct RCTs are needed to conclude the comparative effectiveness of the 2 drugs. Previously published network meta-analyses of intermediate outcomes also suggest that empagliflozin has a favorable benefits-toharms profile, because it decreases HbA1c without increased risk of hypoglycemia or weight gain (9,15,85).…”

“…statistical interaction were not significant, ethnic and gender differences in drug benefits need further investigation. Previously published network meta-analyses also suggest that empagliflozin has a favorable benefits-to-harm profile, because it decreases HbA1c and arterial blood pressure without increased risk of hypoglycemia or weight gain (9,85). The evidence regarding the effects of empagliflozin on quality of life and the long-term safety of empagliflozin is insufficient.…”

“…Older meta-analyses focused on intermediate outcomes of empagliflozin when compared with placebo; e.g., HbA1c, blood pressure, and body weight (7)(8)(9)(10)(11)(12)(13)(14)(15). The most recent high-quality meta-analyses included 13 (6) and 16 (5) randomized controlled trials (RCTs) that reported mortality and morbidity in adults with type 2 diabetes treated with empagliflozin but did not examine the comparative effectiveness of empagliflozin and other specific antidiabetic drugs (5,6).…”

This house believes that sulphonylureas should not be used routinely as second-line treatments for patients with type 2 diabetes

“…Well-designed randomised trials in type 2 diabetic populations have shown that GLP-1 agonists or SGLT2 inhibitors induce weight loss, while SUs lead to increased weight. 10 Moreover, the greater the patient's initial weight, the more they are likely to lose during treatment with a GLP-1 agonist. 11 DPP4 inhibitors are a weight-neutral alternative.…”

“…10 Hypoglycaemia All of the newer classes of antidiabetic agents mentioned above have a lower risk of hypoglycaemia than SUs; indeed, incretin-based agents only induce a clinically significant incidence of hypoglycaemia when co-prescribed with SU or insulin (see Figure 2). 10,12 It is particularly important to avoid hypoglycaemia for the many frail, elderly diabetes patients who are at risk of lifelimiting trauma from falls. Emergency admissions for SU-related hypoglycaemia are a frequent and an unnecessary burden on healthcare systems.…”