Older agents for type 2 diabetes equal or superior to newer agents for glycemic control, lipid levels, body weight

Key Points

An extensive systematic review published in the Annals of Internal Medicine demonstrated that older oral drugs for type 2 diabetes are just as, if not more, effective than newer agents for gylcemic control, lipid control, and other intermediate end points.

However, the authors stated that the results are inconclusive in terms of major clinical end points including all-cause mortality, cardiovascular mortality or morbidity, peripheral arterial disease, neuropathy, retinopathy, and nephropathy; they suggested that large long-term comparative studies are needed. They noted that since this review was completed, both A Diabetes Outcome Progression Trial (ADOPT) (N Engl J Med. 2006;355:2427–2443) and an interim analysis of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial (N Engl J Med. 2007;357:28-38) have demonstrated an increased risk of cardiovascular events with rosiglitazone use.

This analysis included 216 controlled trials and cohort studies and 2 systematic reviews addressing the benefits and harms of oral diabetes drugs (all data that were available in the United States as of January 2006). Studies using common combinations of 2, but not 3, oral agents were included in the review.

The analysis demonstrated that the use of thiazolidinediones (TZDs), metformin, repaglinide, and second-generation sulfonylureas as monotherapy provided similar glycemic control, reducing HbA_1c levels approximately 1%. Combination therapy with these agents was associated with an additional ~1% reduction in HbA_1c levels compared with monotherapy. An indirect comparison using placebo-controlled trials indicated that nateglinide and alpha-glucosidase inhibitors had slightly weaker effects, reducing HbA_1c levels by 0.5% compared with TZDs and metformin.

The use of metformin was associated with a mean 10-mg/dL decrease in LDL cholesterol levels compared with a mean 10-mg/dL increase with TZD use. Use of other oral agents was not associated with a significant effect on LDL cholesterol levels.

Use of TZDs was associated with a mean 3- to 5-mg/dL increase in HDL cholesterol levels compared with metformin or second-generation sulfonylureas, which did not greatly affect HDL cholesterol levels.

Triglyceride levels were reduced with the use of pioglitazone (mean, –26 mg/dL), metformin (mean, –10 mg/dL), repaglinide (mean, –10 to –30 mg/dL), and acarbose (mean, –10 to –30 mg/dL). Increases in triglyceride levels were demonstrated with the use of rosiglitazone (mean, 10 mg/dL).

The use of metformin was not associated with weight gain compared with other oral agents and placebo; acarbose produced no weight gain compared with placebo. Treatment with TZDs and treatment with repaglinide was associated with weight gain of 1 to 5 kg compared with sulfonylureas.

Treatment with second-generation sulfonylureas and with repaglinide was associated with the greatest risk of major or minor hypoglycemic episodes compared with other treatments. The risk of heart failure was greatest with TZD use (monotherapy or combination therapy) compared with nonTZDs (TZDs, range 0.8%–3.6% vs nonTZDs, range, 0–2.6%). Metformin use was associated with the greatest risk of gastrointestinal adverse events compared with other treatments.

The authors stated that in terms of intermediate outcomes and adverse events, metformin was equal or superior to other oral agents currently available for the treatment of type 2 diabetes. Second-generation sulfonylureas compared favorably with other treatments, although the sulfonylureas were associated with a greater risk of hypoglycemia. The authors stated that "Compared with newer agents, metformin and second-generation sulfonylureas share 3 additional advantages: lower cost, longer use in practice, and more intensive scrutiny in long-term trials with clinically relevant end points."

SOURCE

Bolen S, Feldman L, Vassy J, et al. Systematic review: Comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007;147:386–399.