For Type 2 Diabetes, Older Drugs Seem Tried and True

BALTIMORE, July 16 -- Older and cheaper oral drugs for type 2 diabetes may be just as effective at controlling glycemia and improving lipid profiles as newer agents, suggested a systematic literature review.

Poring over data from more than 200 controlled clinical trials and cohort studies, Shari Bolen, M.D., M.P.H., and colleagues, of John Hopkins, found that second-generation sulfonylureas and metformin (Glucophage) controlled blood glucose and other cardiovascular risk factors well.

Metformin, discovered in 1929 and on the U.S. market since the 1950s, appears to have the most favorable risk-benefit profile, the investigators wrote in the July 17 issue of the Annals of Internal Medicine.

"Each oral diabetes agent is associated with adverse events that counterbalance its benefits," the authors wrote. "Overall, metformin seemed to have the best profile of benefit to risk. Large, long-term comparative studies on major clinical end points, such as myocardial infarction, chronic kidney disease, and cardiovascular mortality, are needed to determine definitively the comparative effects of the oral diabetes agents, especially in light of recent controversy regarding rosiglitazone [Avandia]."

The authors did not look at the newest class of anti-diabetes agents, the incretin mimetics, such as exenatide (Byetta) and sitagliptin (Januvia).

That controversy was sparked by the publication of a meta-analysis of data from 42 clinical trials, which found a 43% increase in relative risk of myocardial infarction among type 2 diabetics treated with rosiglitazone.

The odds ratio for MI was 1.43 (95% confidence interval 1.03-1.98, P=0.03), said Steven E. Nissen, M.D., of the Cleveland Clinic, lead author of the meta-analysis, which was released online in May and in the June 14 print issue of the New England Journal of Medicine.

To help clinicians and patients get a better sense of the benefits and risks of various type 2 diabetes drugs, the Hopkins authors reviewed medical databases for original articles, systematic reviews, and unpublished FDA and industry data.

They identified 216 controlled trials and cohort studies, and two systematic reviews looking at pros and cons of oral agents for type 2 diabetes marketed in the U.S.

The strength of evidence was moderate to high that most oral agents (thiazolidinediones, metformin, and repaglinide [Prandin]) improved glycemic control to the same degree as sulfonylureas," the authors wrote.

Each drug category was associated with a decrease in glycosylated hemoglobin A1c (HbA1c) levels of about one absolute percentage point, they found.

They also found that nateglinide (Starlix) and ?-glucosidase inhibitors (e.g, acarbose) may have slightly less potent effects on HbA1c levels, but this finding was based on indirect comparisons of placebo-controlled trials.

"The strength of evidence was moderate that compared with most other oral agents, thiazolidinediones had a beneficial effect on HDL cholesterol levels (relative mean increase, 0.08 to 0.13 mmol/L [3 to 5 mg/dL] but a harmful effect on LDL cholesterol levels (relative mean increase, 0.26 mmol/L [10 mg/dL])," they wrote.

Metformin, in contrast, was associated with a decrease in LDL levels of by about 0.26 mmol/L. Other oral agents had no apparent effects on LDL levels.

There was also moderately good evidence that thiazolidinediones, second-generation sulfonylureas, and metformin had similar, minimally positive effects on systolic blood pressure.

But when it came to weight gain, only metformin was neutral, compared with all other agents, which were associated with an increase in body weight ranging from 1 kg to 5 kg (2.2 lbs to 11 lbs).

"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," the reviewers wrote. "Lactic acidosis was no more common in metformin recipients without comorbid conditions than in recipients of other oral diabetes agents."

The Hopkins findings essentially echo those of consensus recommendations issued jointly by the American Diabetes Association and European Association for the Study of Diabetes in 2006, commented David M. Nathan, M.D., of Harvard and Massachusetts General Hospital.

In a commentary published in the New England Journal of Medicine last February, Dr. Nathan wrote, "In theory, newer classes of antidiabetes medications might be welcome additions to the existing armamentarium; however, those that have been developed recently are generally no more potent, and often less effective in lowering glycemia, than the three oldest classes (insulin, the sulfonylureas, and the biguanides), all of which are more than 50 years old."

Cindy Halstenson, R.D., L.D., C.D.E., of the United Health Group in Minneapolis, a dietitian and certified diabetes educator who was not involved in the Hopkins study, said that the newer agents still play an important role in glycemic control for some patients.

"I think there are some advantages [of the newer agents]," she said in an interview. "One of the greatest advantages is probably just the fact that if other medications are contraindicated, it gives physicians yet another chance to find an effective method for lowering blood sugar, without putting them on insulin."