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Adriaan Kooy, MD, PhD; Jolien de Jager, MD; Philippe Lehert, PhD; Daniël Bets, MSc; Michiel G. Wulffelé, MD, PhD; Ab J. M. Donker, MD, PhD; Coen D. A. Stehouwer, MD, PhD

Arch Intern Med. 2009;169(6):616-625.

Background  We investigated whether metformin hydrochloride has sustained beneficial metabolic and (cardio) vascular effects in patients with type 2 diabetes mellitus (DM2).

Methods  We studied 390 patients treated with insulin in the outpatient clinics of 3 hospitals in a randomized, placebo-controlled trial with a follow-up period of 4.3 years. Either metformin hydrochloride, 850 mg, or placebo (1-3 times daily) was added to insulin therapy. The primary end point was an aggregate of microvascular and macrovascular morbidity and mortality. The secondary end points were microvascular and macrovascular morbidity and mortality, as separate aggregate scores. In addition, effects on hemoglobin A_1c (HbA_1c), insulin requirement, lipid levels, blood pressure, body weight, and body mass index were analyzed.

Results  Metformin treatment prevented weight gain (mean weight gain, –3.07 kg [range, –3.85 to –2.28 kg]; P < .001), improved glycemic control (mean reduction in HbA_1c level, 0.4% percentage point [95% CI, 0.55-0.25]; P < .001) (where CI indicates confidence interval), despite the aim of similar glycemic control in both groups, and reduced insulin requirements (mean reduction, 19.63 IU/d [95% CI, 24.91-14.36 IU/d]; P < .001). Metformin was not associated with an improvement in the primary end point. It was, however, 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. The number needed to treat to prevent 1 macrovascular end point was 16.1 (95% CI, 9.2-66.6).

Conclusions  Metformin, added to insulin in patients with DM2, improved body weight, glycemic control, and insulin requirements but did not improve the primary end point. Metformin did, however, reduce the risk of macrovascular disease after a follow-up period of 4.3 years. These sustained beneficial effects support the policy to continue metformin treatment after the introduction of insulin in any patient with DM2, unless contraindicated.

Trial Registration  ClinicalTrials.gov Identifier: NCT00375388

Author Affiliations: Department of Internal Medicine and Bethesda Diabetes Research Center, Bethesda Hospital, Hoogeveen, the Netherlands (Drs Kooy, de Jager, and Wulffelé); Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands (Dr de Jager); Department of Statistics, Faculty of Economics, Mons, Belgium (Dr Lehert); Clinical Research and Development, Amsterdam (Mr Bets); Department of Internal Medicine, Free University Medical Center, Amsterdam (Dr Donker); and Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands (Dr Stehouwer).

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