Researchers conducting a meta-analysis of studies related to the diabetes medication metformin have found that the drug may be linked to a lower risk of death from cardiovascular disease. The study, which appears in the October 27 issue of Archives of Internal Medicine, did not find any other associations between diabetes medications and positive or negative cardiovascular effects – but frequently because the necessary data were unavailable.
“A wide variety of oral diabetes medications are currently available for the treatment of type 2 diabetes mellitus,” write Elizabeth Selvin, Ph.D., M.P.H. (Johns Hopkins Bloomberg School of Public Health, Baltimore) and colleagues. “With the addition of newer oral therapies to the market in the late 1990s (e.g., thiazolidinediones and meglitinides), it is critical to evaluate how these agents compare with older medications. This is particularly important in light of the expense of many of the newer therapies.” There is still no clear evidence oh how these medications affect cardiovascular health, and there has been considerable debate concerning cardiac risks associated with a newer drug called rosiglitazone.
To clarify the extant evidence that links diabetes drugs to cardiovascular outcomes, Selvin and colleagues analyzed data from 40 clinical trials published on or before Jan. 19, 2006. The selected trials focused on assessments of oral diabetes medications that have been approved for use in the United States, and the authors also examined commonly prescribed combination therapies. Each study also included additional information about heart attack, stroke or other cardiovascular events among trial participants. Participants in the trials ranged in age from 52 to 69 years, and 68% (27) of studies lasted less than one year.
The researchers found that, “Treatment with metformin hydrochloride was associated with a decreased risk of cardiovascular morality [death] compared with any other oral diabetes agent or placebo; the results for cardiovascular morbidity [illness] and all-cause mortality were similar but not statistically significant.” They add: “No other significant associations of oral diabetes agents with fatal or non-fatal cardiovascular disease or all-cause mortality were observed. When compared with any other agent or placebo, rosiglitazone was the only diabetes agent associated with an increased risk of cardiovascular morbidity and mortality, but this result was not statistically significant.”
Selvin and colleagues found it difficult to draw strong conclusions due to a lack of long-term studies and cardiovascular data that was inconsistent and of poor quality. “Our study demonstrates that there have been few trials of oral diabetes therapies that have lasted longer than six months and that reporting of adverse events for cardiovascular disease is poor,” explain the researchers.
“There is a critical need for studies of oral diabetes medications with long-term outcomes,” conclude the authors. “The relatively modest differences in blood pressure, cholesterol levels and weight observed after treatment with oral diabetes medications in short-term trials may not translate to changes in long-term cardiovascular risk. Only long-term trials can provide definitive conclusions regarding the comparative efficacy of oral diabetes medications and long-term risks.”
In an accompanying editorial, David M. Nathan, M.D. (Massachusetts General Hospital, Boston) writes that, “Selvin et al noted that, when it comes to choosing the safest oral agents, the quality of the data are problematic.”
“The current approach to assessing the relatively rare but clinically important adverse effects of diabetes management is unsatisfactory,” adds Nathan. “The vagaries of meta-analyses make them unreliable. On the other hand, increasing the size and duration of controlled clinical trials to provide adequate statistical power to detect relatively infrequent events would potentially bankrupt the pharmaceutical industry that supports most of the trials and delay the development of new drugs.”
Dr. Nathan calls for new approaches to ensure the safety of drugs without impeding their development. “For example, the phased introduction of new medications with uniform, standardized collection of adverse outcome data might identify relatively rare complications before the drugs are used by millions. Similarly, the use of clinical databases may provide an early alert regarding adverse outcomes.”
“In the meantime, there are well-established and safe treatments that, if used aggressively, can improve the long-term health of patients with type 2 diabetes,” concludes Dr. Nathan.
Cardiovascular Outcomes in Trials of Oral Diabetes Medications
Elizabeth Selvin, PhD, MPH; Shari Bolen, MD, MPH; Hsin-Chieh Yeh, PhD; Crystal Wiley, MD, MPH; Lisa M. Wilson, ScM; Spyridon S. Marinopoulos, MD, MBA; Leonard Feldman, MD; Jason Vassy, MD, MPH; Renee Wilson, MS; Eric B. Bass, MD, MPH; Frederick L. Brancati, MD, MHS
Archives of Internal Medicine (2008); 168[19]: pp. 2070-2080.
Written by: Peter M Crosta