Shari Bolen, MD, MPH; Leonard Feldman, MD; Jason Vassy, MD, MPH; Lisa Wilson, BS, ScM; Hsin-Chieh Yeh, PhD; Spyridon Marinopoulos, MD, MBA; Crystal Wiley, MD, MPH; Elizabeth Selvin, PhD; Renee Wilson, MS; Eric B. Bass, MD, MPH; Frederick L. Brancati, MD, MHS
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or of the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank Steven Fox for his help as the Task Order Officer.
Grant Support: This article is based on research conducted by the Johns Hopkins Evidence-based Practice Center under contract number 290-02-0018 with the Agency for Healthcare Research and Quality. Dr. Brancati was supported by a mid-career investigator award for patient-oriented research in diabetes from the National Institute of Diabetes and Digestive and Kidney Diseases (5 K24 DK062222-05).
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Shari Bolen, MD, MPH, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, 2024 East Monument Street, Suite 2-600, Room 2-615, Baltimore, MD 21205; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Bolen, Yeh, Selvin, and Brancati: Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, 2024 East Monument Street, Suite 2-600, Baltimore, MD 21205.
Dr. Feldman: Johns Hopkins University, Jefferson Building, 600 North Wolfe Street, Room 242, Baltimore, MD 21287.
Dr. Vassy: University of Pennsylvania Health System, 3400 Spruce Street, Philadelphia, PA 19104.
Ms. L. Wilson, Ms. R. Wilson, and Drs. Wiley and Bass: Johns Hopkins University, 1830 East Monument Street, Eighth Floor, Baltimore, MD 21287.
Dr. Marinopoulos: University Health Services, Johns Hopkins University, 401 North Caroline Street, Baltimore, MD 21231.
As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy.
To summarize the English-language literature on the benefits and harms of oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and α-glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus.
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.
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.
Using standardized protocols, 2 reviewers serially abstracted data for each article.
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 α-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.
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.
Compared with newer, more expensive agents (thiazolidinediones, α-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.
Study flow diagram.
Table 1. Evidence of the Comparative Effectiveness of Oral Diabetes Medications on Mortality, Microvascular and Macrovascular Outcomes, and Intermediate End Points
Weighted mean difference in blood pressure, laboratory values, and body weight with use of oral medications for type 2 diabetes mellitus.
Appendix Table 1. Summary Measures: Weighted Mean Absolute Difference in Hemoglobin A1c Level between Groups for Randomized, Controlled Trials Comparing Oral Diabetes Medications with Placebo or Diet
Appendix Table 2. Summary Measures: Weighted Mean Absolute Difference in Body Weight between Groups for Randomized, Controlled Trials Comparing Oral Diabetes Medications with Placebo or Diet
Pooled hypoglycemia results for randomized trials, by drug comparison.
Table 2. Adverse Effects Related to Oral Diabetes Medications in Head-to-Head Comparisons
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Bolen S, Feldman L, Vassy J, Wilson L, Yeh H, Marinopoulos S, et al. Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus. Ann Intern Med. 2007;147:386–399. doi: 10.7326/0003-4819-147-6-200709180-00178
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Published: Ann Intern Med. 2007;147(6):386-399.
Cardiology, Coronary Risk Factors, Diabetes, Endocrine and Metabolism.
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