Early combination therapy for the treatment of type 2 diabetes mellitus: systematic review and meta-analysis

Diabetes Obes Metab. 2014 May;16(5):410-7. doi: 10.1111/dom.12233. Epub 2013 Dec 16.


Aims: Guidelines for type 2 diabetes recommend add-on agents when metformin alone fails to provide adequate glycaemic control. However, early combination therapy may benefit health outcomes. We conducted a systematic review and meta-analysis to investigate this question.

Methods: We searched MEDLINE and Cochrane CENTRAL (up to July 2012) without language restrictions. We sought randomized controlled trials (RCTs) evaluating initial combination therapy with metformin versus metformin monotherapy in patients with untreated type 2 diabetes. Weighted mean differences (WMDs) for changes from baseline and relative risks (RRs) [with 95% confidence intervals (CIs)] were calculated using random-effects model.

Results: In 15 RCTs (N = 6693), the mean age range was 48.4-62.7 years; mean baseline glycosylated haemoglobin (A1c) was 7.2-9.9% and mean diabetes duration was 1.6-4.1 years, with median follow-up of 6 months and with 13 comparisons for A1c change, 14 comparisons for A1c goal attainment of <7% and 13 comparisons for change in fasting plasma glucose (FPG). Drugs combined with metformin included thiazolidinediones (TZDs), insulin secretagogues, dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium glucose transporterase (SGLT-2) inhibitors. Compared to metformin alone, combination therapy with metformin provided statistically significant reductions in A1c (WMD -0.43%, 95% CI -0.56, -0.30), increases in attainment of A1c goal of less than 7% (RR 1.40, 95% CI 1.33-1.48) and reductions in FPG (WMD -14.30 mg/dl, 95% CI -16.09, -12.51).

Conclusions: These results suggest a potential benefit of initial combination therapy on glycaemic outcomes in diabetes compared to metformin monotherapy across a wide range of baseline A1c levels. Further research should explore if early combination treatment may also affect longer term health outcomes in diabetes.

Keywords: antidiabetic drug; diabetes mellitus; medicines management; meta-analysis; type 2 diabetes.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Blood Glucose / drug effects
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Drug Therapy, Combination
  • Female
  • Glycated Hemoglobin / drug effects
  • Glycated Hemoglobin / metabolism*
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Male
  • Metformin / therapeutic use*
  • Middle Aged
  • Sulfonylurea Compounds / therapeutic use*
  • Treatment Outcome


  • Blood Glucose
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Sulfonylurea Compounds
  • hemoglobin A1c protein, human
  • Metformin