Metformin May Have Long-Term Benefits in Patients With Type 2 Diabetes

Laurie Barclay, MD

April 10, 2009

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April 10, 2009 — Metformin may have long-term benefits in patients with type 2 diabetes mellitus (DM2), according to the results of a randomized, placebo-controlled trial reported in the March 23 issue of the Archives of Internal Medicine.

"Several short-term studies in insulin-treated patients with DM2 have shown that metformin can improve glycemic control and reduce insulin requirements and weight gain," write Adriaan Kooy, MD, PhD, from the Academic Medical Center in Amsterdam, the Netherlands, and colleagues. "To our knowledge, the long-term beneficial effects of metformin in such patients have not been studied. We hypothesized that, in patients with DM2 treated with insulin, metformin, compared with placebo, will have sustained beneficial metabolic effects, even at the same level of glycemic control, and thus decrease (cardio) vascular disease."

In the outpatient clinics of 3 hospitals, 390 patients treated with insulin were randomly assigned to receive metformin hydrochloride, 850 mg, or placebo (1 – 3 times daily), added to insulin therapy. The main study outcome was an aggregate of microvascular and macrovascular morbidity and mortality during a follow-up period of 4.3 years. Secondary outcome measures were separate aggregate scores for microvascular and macrovascular morbidity and mortality, as well as effects on glycated hemoglobin, insulin requirement, lipid levels, blood pressure, body weight, and body mass index.

Compared with the placebo group, the metformin group had prevention of weight gain (mean weight gain, −3.07 kg; range, −3.85 to −2.28 kg; P < .001), better glycemic control (mean reduction in glycated hemoglobin level, 0.4%; 95% confidence interval [CI], 0.55 – 0.25; P < .001), and lower insulin requirements (mean reduction, 19.63 U/day; 95% CI, 24.91 – 14.36 U/day; P < .001).

Although metformin was not associated with an improvement in the main outcome, it was associated with an improvement in the secondary, macrovascular end point (hazard ratio, 0.61; 95% CI, 0.40 – 0.94; P = .02), which was partly explained by the difference in weight between groups. To prevent 1 macrovascular end point, the number needed to treat was 16.1 (95% CI, 9.2 – 66.6).

"Add-on metformin improved glycemic control and reduced body weight and insulin requirements," Nikolaos Papanas, MD, DSc, an assistant professor in internal medicine at Democritus University of Thrace in Greece, told Medscape Diabetes & Endocrinology when asked for independent comment. "Metformin did not improve the primary endpoint. However, the drug was associated with an almost 40% improvement in the secondary macrovascular endpoint."

Dr. Papanas notes that this significant effect on macrovascular disease agrees with recent data from the United Kingdom Prospective Diabetes Study at 20-year follow-up, which showed a 33% reduction in myocardial infarction (N Engl J Med 2008;359:1577–1589).

"The strengths of the study [are that] it is the first randomized controlled trial on the effects of metformin specifically in insulin-treated patients," Dr. Papanas said. "A further strength is the relatively long follow-up period (4.3 years). Moreover, the authors achieved a sustained participation of patients in the trial."

Limitations of this study include its relatively small sample size, and consequently limited power; the combination of separate microvascular and macrovascular clinical events; an imbalance between the 2 treatment groups after randomization; a possible lack of generalizability to patients receiving less intensive care; and the performance of multiple analyses, suggesting that the positive finding on the secondary end point might possibly be a result of chance.

"A further limitation is the absence of a clearly documented mechanism by which the observed effects could be explained," Dr. Papanas said. "Indeed, long-term use of metformin contributes to the reduction of weight gain and to the improvement in metabolic control, while it may also have a very modest beneficial effect on blood pressure and serum lipids."

Because of contraindications to metformin use, metformin should be avoided in high-risk patients to avoid the danger of lactic acidosis (Acta Clin Belg. 2009;64:42–48). The authors of the present study conclude that their findings support the policy to continue metformin treatment after insulin is introduced in any patient with DM2, unless contraindicated.

"Future research is needed into the long-term effect of metformin on cardiovascular morbidity in insulin-treated type 2 diabetic patients," Dr. Papanas concludes. "We also need to clarify the mechanisms of the beneficial action of metformin and identify to what extent this action is attributable to the reduction of body weight and insulin requirements, to the amelioration of insulin resistance and, possibly, to additional pleiotropic actions."

Altana; Lifescan; E. Merck/Santé; Merck, Sharpe, & Dohme; and Novo Nordisk supported this study. The study authors and Dr. Papanas have disclosed no relevant financial relationships.

Arch Intern Med. 2009;169:616–625.

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