You are leaving Medscape Education
Cancel Continue
Log in to save activities Your saved activities will show here so that you can easily access them whenever you're ready. Log in here CME & Education Log in to keep track of your credits.


Metformin Top Oral Antidiabetic for CV-Risk Reduction, Says Meta-Analysis

  • Authors: News Author: Steve Stiles
    CME Author: Désirée Lie, MD, MSEd
  • CME/CE Released: 10/28/2008
  • Valid for credit through: 10/28/2009, 11:59 PM EST
Start Activity

Target Audience and Goal Statement

This article is intended for primary care clinicians, endocrinologists, cardiologists, nephrologists, and other specialists who care for patients with type 2 diabetes.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Describe the effect of oral antidiabetic agents on cardiovascular outcomes in patients with type 2 diabetes.
  2. Compare the effect of 1 oral antidiabetic agent against another for cardiovascular outcomes in patients with type 2 diabetes.


As an organization accredited by the ACCME, Medscape, LLC requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


  • Steve Stiles

    Steve Stiles is a journalist for, part of the WebMD Professional Network. He has been reporting on cardiovascular medicine since 1984 and for the past 4 years has been a journalist for Steve is a graduate of Kenyon College and has an MS from the journalism department at Boston University. He can be contacted at [email protected].


    Disclosure: Steve Stiles has disclosed no relevant financial relationships.


  • Brande Nicole Martin

    Brande Nicole Martin is the News CME editor for Medscape Medical News.


    Disclosure: Brande Nicole Martin has disclosed no relevant financial information.


  • Laurie E. Scudder, MS, NP-C

    Nurse Planner, Medscape; Adjunct Assistant Professor, School of Health Sciences, George Washington University, Washington, DC;  Curriculum Coordinator, Nurse Practitioner Alternatives, Inc., Ellicott City; Nurse Practitioner,  Baltimore City School-Based Health Centers, Baltimore, Maryland


    Disclosure: Laurie Scudder, MS, NP-C, has disclosed no relevant financial information.

CME Author(s)

  • Désirée Lie, MD, MSEd

    Clinical Professor, Family Medicine, University of California, Orange; Director, Division of Faculty Development, UCI Medical Center, Orange, California


    Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.

Accreditation Statements

    For Physicians

  • Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

    Medscape, LLC designates this educational activity for a maximum of 0.25 AMA PRA Category 1 Credit(s)™ . Physicians should only claim credit commensurate with the extent of their participation in the activity. Medscape Medical News has been reviewed and is acceptable for up to 350 Prescribed credits by the American Academy of Family Physicians. AAFP accreditation begins 09/01/08. Term of approval is for 1 year from this date. This activity is approved for 0.25 Prescribed credits. Credit may be claimed for 1 year from the date of this activity.

    Note: Total credit is subject to change based on topic selection and article length.

    AAFP Accreditation Questions

    Contact This Provider

    For Nurses

  • Medscape is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.

    Awarded 0.25 contact hour(s) of continuing nursing education for RNs and APNs; 0.25 contact hours are in the area of pharmacology.

    Contact This Provider

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]

Instructions for Participation and Credit

There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page.

Follow these steps to earn CME/CE credit*:

  1. Read the target audience, learning objectives, and author disclosures.
  2. Study the educational content online or printed out.
  3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. Medscape encourages you to complete the Activity Evaluation to provide feedback for future programming.
You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 5 years; at any point within this time period you can print out the tally as well as the certificates by accessing "Edit Your Profile" at the top of your Medscape homepage.

*The credit that you receive is based on your user profile.


Metformin Top Oral Antidiabetic for CV-Risk Reduction, Says Meta-Analysis

Authors: News Author: Steve Stiles CME Author: Désirée Lie, MD, MSEdFaculty and Disclosures

CME/CE Released: 10/28/2008

Valid for credit through: 10/28/2009, 11:59 PM EST


From Heartwire — a professional news service of WebMD

October 28, 2008 — The widely prescribed metformin was alone among oral antidiabetic agents to show a significant effect on cardiovascular (CV) risk in a meta-analysis of 40 select controlled trials reported in the October 27, 2008 issue of the Archives of Internal Medicine [1]. It reduced CV mortality by 26% relative to any other antidiabetic agent or placebo, but there was no effect on all-cause mortality.

Rosiglitazone was the only such drug to show a possible risk increase, and it did so for all evaluated end points, none significantly, however.

"Our meta-analysis suggested that . . . metformin appeared moderately protective against cardiovascular effects and that rosiglitazone was possibly harmful, but a lack of power prohibited firmer conclusions," write the authors, led by Dr Elizabeth Selvin (Johns Hopkins Bloomberg School of Public Health, Baltimore, MD).

The group is up-front about the limitations of available data on the subject; in particular, the trials generally had glycemia-based end points and were too short to sufficiently evaluate CV risks. Few were longer than six months.

"I think that the study was well done and that they did the best they could with the available data. Meta-analyses can't be better than the data that underlie them," Dr David M Nathan (Massachusetts General Hospital, Boston) told heartwire . The author of an accompanying editorial [2], Nathan observed that until the potential CV risks of thiazolidinediones were known, diabetic trials didn't focus much on CV end points. "Sometimes they were collected haphazardly or without uniform definitions. So the data are what they are. They're okay, but they aren't definitive or conclusive in any way."

The included studies had been culled from 142 published randomized, controlled trials of oral drug therapy in type 2 diabetes. They were limited to those looking at second-generation sulfonylureas, biguanides, thiazolidinediones, and meglitinides that reported CV outcomes. Only two of the studies, however, included CV outcomes as prospectively defined end points.

Odds ratios (95% CI) for the effect of metformin vs any oral-antidiabetic comparator regimen or placebo in meta-analysis

End point OR (95% CI) Studies, n Total participants, n
CV morbidity* 0.85 (0.69 - 1.05) 7 11,986
CV mortality 0.74 (0.62 - 0.89) 6 11,385
All-cause mortality 0.81 (0.60 - 1.08) 9 13,046

*Fatal and nonfatal myocardial infarction (MI) or stroke.

The meta-analysis had excluded heart-failure (HF) outcomes except when they couldn't be distinguished from other events in combined end points. That was done, Selvin explained to heartwire , "to isolate the possible risk related to fatal and nonfatal myocardial infarction or stroke," events that defined the third main end point of the meta-analysis, "cardiovascular morbidity."

Without consideration of HF end points, the analysis could not show whether the oral drugs might promote heart failure. However, Nathan observed, the thiazolidinedione effect on fluid retention and possible heart failure and the lack of such an effect with the other antidiabetic agents are well defined.

Given the limitations of the current meta-analysis and others that have recently looked at the CV safety of antidiabetic agents, according to Nathan's editorial, "the conclusions drawn will be disappointing for healthcare practitioners who want a clear answer to the question 'Is it safe?' "

The meta-analysis was supported by the Agency for Healthcare Research and Quality and the National Institute of Diabetes and Digestive and Kidney Diseases; neither its coauthors nor Dr. Nathan has disclosed any relevant financial relationships.


  • Selvin E, Bolen S, Hsin-Chieh Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes medications: A systematic review. Arch Intern Med. 2008;168:2070-2080.
  • Nathan DM. Glycemic management of type 2 diabetes: How tight is right and how to get there. Arch Intern Med. 2008;168:2064-2066.

The complete contents of Heartwire , a professional news service of WebMD, can be found at, a Web site for cardiovascular healthcare professionals.

Clinical Context

The effect of oral antidiabetic agents, especially newer classes such as the thiazolidinediones, on CV outcomes of type 2 diabetes remains unclear, and hard clinical outcomes of CV morbidity and mortality rates are needed.

This is a systematic review of studies comparing oral antidiabetic agents vs placebo or other agents to determine and compare their effect on CV outcomes.

Study Highlights

  • The investigators identified articles by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (1966-2005).
  • Included were single-therapy or combination-therapy (2 agents) studies with original data in adults with CV outcomes reported.
  • Oral agents covered included metformin, second-generation sulfonylureas, biguanides, meglitinides, and thiazolidinediones.
  • Excluded were studies with 3 or more agents in combination and the alpha-glucosidase inhibitors and studies that did not include CV outcomes.
  • First-generation sulfonylureas were excluded.
  • 2 reviewers independently extracted data, and the trials were summarized both qualitatively and quantitatively.
  • 434 trials were relevant to the study questions.
  • Only 40 trials from the United States and the United Kingdom included CV data and were included.
  • Mean age of participants was 52 to 69 years, mean hemoglobin A1c level at baseline was 6.2% to 10.2%, and two thirds of studies were less than 1 year in duration.
  • More than half of studies reported support from the pharmaceutical industry.
  • Qualitative analysis
    • In most studies, CV outcomes were reported as adverse events and not primary outcomes.
    • In many studies, a history of CV events was an exclusion factor.
    • The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study and the United Kingdom Prospective Diabetes Study (UKPDS) were the largest studies.
    • The UKPDS provided the largest database, with more than 4000 participants and a mean of 10.7 years of follow-up.
    • A borderline 22% reduction in MI was seen with glyburide vs conventional treatment (P = .06) in the UKPDS 33 study.
    • The PROactive study had 5000 participants who were observed for 34.5 months.
    • It showed a nonsignificant 10% CV composite outcome reduction, and a significant 16% reduction in stroke, all-cause mortality, and nonfatal MI (P = .03) for oral antidiabetic agents.
  • Quantitative analysis
    • The mean Jadad quality score was 3 of 5.
    • 8 of 40 trials that included CV events were reported as a primary or secondary outcome in 8 trials.
    • Results from these trials were pooled quantitatively with the Mantel-Haenszel method.
    • Comparisons of metformin vs other medications were the most robust, with 7 trials that included 11,986 patients vs other agents, diet, or placebo.
    • The pooled relative risk (RR) for metformin was 0.74 for CV mortality and 0.85 for CV morbidity.
    • For metformin, 9 trials contributed to all-cause mortality, and the pooled RR estimate was 0.81.
    • No other significant associations of oral antidiabetic agents with fatal or nonfatal CV events or all-cause mortality were found overall.
    • Rosiglitazone was the only oral agent associated with increased CV risk for mortality and morbidity and increased all-cause mortality with RRs of more than 1.0.
    • However, these estimates were not statistically significant.
    • The authors concluded that better reporting of CV outcomes in short-term studies were needed and that more robust research was also needed to compare long-term CV outcomes of oral antidiabetic agents.

Pearls for Practice

  • Among the oral antidiabetic agents, reduction in CV morbidity and mortality rates has not been clearly demonstrated except for metformin.
  • Use of rosiglitazone for type 2 diabetes may be associated with increased CV mortality and morbidity rates.


  • Print