Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus

Ann Intern Med. 2007 Sep 18;147(6):386-99. doi: 10.7326/0003-4819-147-6-200709180-00178. Epub 2007 Jul 16.


Background: As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy.

Purpose: To summarize the English-language literature on the benefits and harms of oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and alpha-glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus.

Data sources: The MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception through January 2006 for original articles and through November 2005 for systematic reviews. Unpublished U.S. Food and Drug Administration and industry data were also searched.

Study selection: 216 controlled trials and cohort studies and 2 systematic reviews that addressed benefits and harms of oral diabetes drug classes available in the United States.

Data extraction: Using standardized protocols, 2 reviewers serially abstracted data for each article.

Data synthesis: Evidence from clinical trials was inconclusive on major clinical end points, such as cardiovascular mortality. Therefore, the review was limited mainly to studies of intermediate end points. Most oral agents (thiazolidinediones, metformin, and repaglinide) improved glycemic control to the same degree as sulfonylureas (absolute decrease in hemoglobin A1c level of about 1 percentage point). Nateglinide and alpha-glucosidase inhibitors may have slightly weaker effects, on the basis of indirect comparisons of placebo-controlled trials. Thiazolidinediones were the only class that had a beneficial effect on high-density lipoprotein cholesterol levels (mean relative increase, 0.08 to 0.13 mmol/L [3 to 5 mg/dL]) but a harmful effect on low-density lipoprotein (LDL) cholesterol levels (mean relative increase, 0.26 mmol/L [10 mg/dL]) compared with other oral agents. Metformin decreased LDL cholesterol levels by about 0.26 mmol/L (10 mg/dL), whereas other oral agents had no obvious effects on LDL cholesterol levels. Most agents other than metformin increased body weight by 1 to 5 kg. Sulfonylureas and repaglinide were associated with greater risk for hypoglycemia, thiazolidinediones with greater risk for heart failure, and metformin with greater risk for gastrointestinal problems compared with other oral agents. Lactic acidosis was no more common in metformin recipients without comorbid conditions than in recipients of other oral diabetes agents.

Limitations: Data on major clinical end points were limited. Studies inconsistently reported adverse events other than hypoglycemia, and definitions of adverse events varied across studies. Some harms not assessed in trials or observational studies may have been overlooked.

Conclusions: Compared with newer, more expensive agents (thiazolidinediones, alpha-glucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.
  • Review
  • Systematic Review

MeSH terms

  • Administration, Oral
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetic Angiopathies / prevention & control
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / therapeutic use*
  • Risk Factors


  • Hypoglycemic Agents