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Comparison of Oral Antidiabetic Drugs as Add-On Treatments in Patients with Type 2 Diabetes Uncontrolled on Metformin: A Network Meta-Analysis.

ABSTRACT: We assessed the efficacy and safety of oral antidiabetic drugs (OADs) as an add-on treatment in patients with type 2 diabetes uncontrolled on metformin. PubMed, the Cochrane Library, and Embase were searched from inception to October 20, 2017. Pairwise and network meta-analyses were conducted using Stata 14.1 software. Odds ratios (ORs) and weighted mean differences (WMDs) were used to evaluate outcomes. Sixty-eight trials including 36,746 patients were analyzed. No significant differences in the risk of major adverse cardiovascular events (MACEs) and all-cause mortality were observed among any class of OADs when combined with metformin. All classes of OADs as add-ons to metformin improved glucose control, while sodium-glucose co-transporter-2 (SGLT-2) inhibitors showed greater fasting plasma glucose (FPG) reductions {WMD, - 1.49 [95% confidence interval (CI) - 1.69 to - 1.28] mmol/l} and 2 h postprandial glucose (2 h PPG) reductions [WMD, - 3.07 (95% CI - 4.12 to - 2.03) mmol/l]. Thiazolidinediones and sulfonylureas were associated with weight gain [WMD, 2.53 (95% CI 1.95-3.10) kg and 2.00 (95% CI 1.63-2.36) kg, respectively] when added to metformin. Sulfonylureas [WMD, 6.52 (95% CI 4.07-10.45)] were associated with the highest ORs of hypoglycemia. Our results suggest that the seven classes of OADs were not associated with any increased risk of MACEs or all-cause mortality when combined with metformin. Most OADs were associated with similarly large reductions in HbA1c levels when added to metformin, while SGLT-2 inhibitors might be the best option for reducing body weight, FPG, and 2-h PPG.

SUBMITTER: Qian D

PROVIDER: S-EPMC6167280 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionAlthough metformin is recommended as a first-line treatment for patients with type 2 diabetes (T2D) in Western countries, no specific treatment is recommended in Japan, and various agents are used. Metformin has long been used at low doses in Japan, and information regarding its effect at the maximum maintenance dose is lacking. Here, we compared the efficacy and safety of metformin at 1500 mg/day with those of the other oral anti-diabetic drugs (OADs) approved in Japan.MethodsRandomized controlled trials comparing a change in hemoglobin A1c (HbA1c) from baseline at 12 weeks or later (ΔHbA1c) among OADs (including placebo) as a first-line treatment in adult patients with T2D were selected by systematic review with comprehensive searching of CENTRAL, MEDLINE, Ichushi Web, and EMBASE and manual searching of clinical trial registries. The ΔHbA1c and incidence of hypoglycemia were compared among OAD treatments using Bayesian network meta-analysis (NMA). The relative risk (RR) of the incidence of hypoglycemia was determined relative to that of placebo.ResultsForty-six randomized controlled trials were identified in the systematic review, and 37 studies, comprising 38 different types of treatments, including placebos, were selected for the NMA of ΔHbA1c. Compared with metformin 1500 mg/day, 20 OAD treatments were significantly less effective in reducing HbA1c from baseline (differences from metformin 1500 mg/day: 0.40-0.96%). Two treatments (glimepiride 2 mg/day and pioglitazone 45 mg/day) showed greater mean reductions in HbA1c from baseline than metformin 1500 mg/day (- 0.38% and - 0.03%), although these differences were not significant. Regarding the incidence of hypoglycemia, only pioglitazone 30 mg/day among 31 treatments showed a lower RR (< - 0.01), whereas 23 treatments showed a significantly higher RR (1.02-66.71) than metformin 1500 mg/day.ConclusionThe NMA suggested a preferable efficacy and safety profile of metformin 1500 mg/day compared with the other OADs approved in Japan.

Project description:IntroductionCurrent guidelines recommend adding an oral antihyperglycemic agent (AHA) to metformin in patients with type 2 diabetes mellitus (T2DM) uncontrolled on metformin. Recent randomized clinical trials (RCTs) have demonstrated that adding dual AHAs instead of a single AHA provided more effective glycemic control. However, the comparative efficacy of approved single and dual initiation strategies is unknown. Therefore, we conducted a Bayesian network meta-analysis to compare the efficacy of dual and single add-on oral AHAs in patients uncontrolled on metformin.MethodsA systematic literature review of RCTs was conducted following Cochrane and ISPOR guidelines. MEDLINE, Embase, and CENTRAL were searched from inception to November 19, 2019. Approved oral doses of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists in single or dual initiation therapies were indirectly compared. Outcomes focused on efficacy and included mean change from baseline in hemoglobin A1c (HbA1c), weight, systolic blood pressure (SBP), diastolic blood pressure, and achieving HbA1c target?<?7% at 24-26 weeks. Fixed and random effects models with Markov chain Monte Carlo simulations were used.ResultsOf 1955 unique records screened, 25 RCTs (14,264 participants) were included. In patients uncontrolled on metformin, dual AHA added to metformin had statistically significant or a trend of greater reduction in HbA1c compared to single AHAs, with ertugliflozin?+?sitagliptin showing the greatest improvement. Statistically significant reductions in weight and SBP were observed with ertugliflozin?+?sitagliptin, ertugliflozin, or canagliflozin compared to single initiation DPP-4 inhibitors.ConclusionFor reduction of HbA1c, weight, and SBP in patients uncontrolled on metformin, add-on dual AHAs showed greater improvement compared to single AHAs. These findings can further inform the treatment of T2DM patients uncontrolled on metformin.

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Comparison of Oral Antidiabetic Drugs as Add-On Treatments in Patients with Type 2 Diabetes Uncontrolled on Metformin: A Network Meta-Analysis.

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