Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes.
BACKGROUND
Metformin is the recommended initial drug therapy for patients with type 2 diabetes mellitus (DM). However, the optimal second-line drug when metformin monotherapy fails is unclear.


OBJECTIVE
To determine the comparative efficacy, risk of weight gain, and hypoglycemia associated with noninsulin antidiabetic drugs in patients with type 2 DM not controlled by metformin alone.


METHODS
A literature search via MEDLINE (beginning in January 1950) and Cochrane CENTRAL through January 2010 and a manual search of references for additional relevant studies.


METHODS
Randomized controlled trials (RCTs) with at least 3 months' duration, evaluating noninsulin antidiabetic drugs added to metformin in patients experiencing an inadequate response to maximized and stable (> or = 4 weeks at > or = 1500 mg or maximally tolerated dose) metformin therapy.


METHODS
Inclusion/exclusion criteria; duration of patient follow-up; drug, dose, and schedule used; use of concurrent lifestyle modification; and baseline characteristics (age, sex, anthropometrics, glycated hemoglobin A(1c) [HbA(1c)], duration of DM, and metformin dose). End points collected included mean change in HbA(1c), proportion of patients achieving HbA(1c) goal of less than 7%, change in weight, and incidence of hypoglycemia. Mixed-treatment comparison meta-analysis was used to calculate the weighted mean difference for changes from baseline in HbA(1c) and body weight and relative risk (RR) of HbA(1c) goal attainment and hypoglycemia, with associated 95% credible intervals.


RESULTS
Overall, 27 RCTs (n = 11 198) were included. Mean (range) trial duration was 32 (12-52) weeks. The different classes of drugs were associated with similar HbA(1c) reductions (range, 0.64%-0.97%) compared with placebo. Although use of thiazolidinediones, sulfonylureas, and glinides were associated with weight gain (range, 1.77-2.08 kg), glucagon-like peptide-1 analogs, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change. Sulfonylureas and glinides were associated with higher rates of hypoglycemia than with placebo (RR range, 4.57-7.50).


CONCLUSIONS
When added to maximal metformin therapy, all noninsulin antidiabetic drugs were associated with similar HbA(1c) reductions but differed in their associations with weight gain and risk of hypoglycemia.
Phung
Olivia J
OJ
University of Connecticut School of Pharmacy, Storrs, and Drug Information Center, Hartford Hospital, Hartford, Connecticut 06102-5037, USA.
Scholle
Jennifer M
JM
Talwar
Mehak
M
Coleman
Craig I
CI
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D015430:Weight Gain
D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; C517652:hemoglobin A1c protein, human