Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes
Abstract
CONTEXT: 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. DATA SOURCES: 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. STUDY SELECTION: 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. DATA EXTRACTION: 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. DATA SYNTHESIS: 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). CONCLUSION: 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.
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Sulfonylureas and glinides were associated with higher rates of hypoglycemia than placebo.
“Sulfonylureas and glinides were associated with higher rates of hypoglycemia than with placebo.”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [22]
All noninsulin antidiabetic drugs added to maximal metformin therapy are associated with similar HbA1c reduction but varying degrees of weight gain and hypoglycemia risk.
“All noninsulin antidiabetic drugs when added to maximal metformin therapy are associated with similar HbA1c reduction but with varying degrees of weight gain and hypoglycemia risk.”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [22]
A meta-analysis of 27 randomized trials showed that thiazolidinediones, sulfonylureas, and glinides were associated with weight gain, while glucagon-like peptide-1 analogs, glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change.
“A meta-analysis of 27 randomized trials showed that thiazolidinediones, sulfonylureas, and glinides were associated with weight gain; glucagon-like peptide-1 analogs, glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change.”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [22]
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- Authors
- Phung, O. J.
- Affiliations
- Hartford Hospital (US)
- Corresponding author
- Phung, Olivia J.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2010-04-14
- Volume
- 303
- Issue
- 14
- Pages
- 1410
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2098289172
- Cited by
- 520
- References
- 45
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 19 · 2023: 20 · 2022: 21 · 2021: 21 · 2020: 28 · 2019: 28 · 2018: 43 · 2017: 31 · 2016: 40 · 2015: 46 · 2014: 50 · 2013: 58 · 2012: 50
- FWCI
- 38.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type 2 diabetes, metformin, second-line therapy, glycemic control, HbA1c, weight gain, hypoglycemia, thiazolidinediones, sulfonylureas, glinides, glucagon-like peptide-1 analogues, alpha-glucosidase inhibitors, DPP-4 inhibitors, incretin-based therapy
- MeSH terms
- Diabetes Mellitus, Type 2, Drug Therapy, Combination, Glycated Hemoglobin, Humans, Hypoglycemia, Hypoglycemic Agents, Metformin, Weight Gain, Randomized Controlled Trials as Topic
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