Effect of Adjunct Metformin Treatment in Patients with Type-1 Diabetes and Persistent Inadequate Glycaemic Control. A Randomized Study

Abstract

BackgroundDespite intensive insulin treatment, many patients with type-1 diabetes (T1DM) have longstanding inadequate glycaemic control. Metformin is an oral hypoglycaemic agent that improves insulin action in patients with type-2 diabetes. We investigated the effect of a one-year treatment with metformin versus placebo in patients with T1DM and persistent poor glycaemic control.Methodology/Principal FindingsOne hundred patients with T1DM, preserved hypoglycaemic awareness and HaemoglobinA1c (HbA1c) ≥8.5% during the year before enrolment entered a one-month run-in on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1 g twice daily) or placebo for 12 months (double-masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. The primary outcome measure was change in HbA1c after one year of treatment. At enrolment, mean (standard deviation) HbA1c was 9.48% (0.99) for the metformin group (n = 49) and 9.60% (0.86) for the placebo group (n = 51). Mean (95% confidence interval) baseline-adjusted differences after 12 months with metformin (n = 48) versus placebo (n = 50) were: HbA1c, 0.13% (−0.19; 0.44), p = 0.422; Total daily insulin dose, −5.7 U/day (−8.6; −2.9), p<0.001; body weight, −1.74 kg (−3.32; −0.17), p = 0.030. Minor and overall major hypoglycaemia was not significantly different between treatments. Treatments were well tolerated.Conclusions/SignificanceIn patients with poorly controlled T1DM, adjunct metformin therapy did not provide any improvement of glycaemic control after one year. Nevertheless, adjunct metformin treatment was associated with sustained reductions of insulin dose and body weight. Further investigations into the potential cardiovascular-protective effects of metformin therapy in patients with T1DM are warranted.Trial RegistrationClinicalTrials.gov NCT00118937

The use of metformin in type 1 diabetes: a systematic review of efficacy

“…Of the remaining 12 publications, one concerned insulin-requiring type 2 diabetes rather than type 1 diabetes (noted after translation) [61], and one covered a treatment period of fewer than 7 days [62]. Only ten studies were therefore identified [16,17,20,21,23,25,26,[63][64][65]. One of these, which was conducted on participants living in a children's home and did not mention informed consent, was excluded from further analysis [64].…”

“…The final nine studies [16,17,20,21,23,25,26,63,65] covered a total of 192.8 patient years, and the number of completed participants ranged from ten to 92 (median 26) (two studies did not report number completed [17,26]) ( Table 1). The total maximum daily metformin dose varied from 1,000 to 2,550 mg; duration of therapy ranged from 7 days to 12 months (median 4 months).…”

“…A recent review [15] did not include the two largest trials to date [16,17] but did include data from a non-randomised controlled study [18]. A recent Cochrane review [19] only included the two trials [20,21] conducted in adolescents.…”

Could there be a role for metformin in type 1 and type 2 diabetic pregnancies?

“…The long-term effects on offspring of maternal metformin use during pregnancy are unknown. Moreover, there have been concerns regarding an increased propensity to hypoglycaemia in type 1 diabetic patients treated with metformin [2]. Nevertheless, we suggest that there may be a role for metformin in selected obese women with type 1 diabetes in pregnancy.…”

“…Given the current epidemic of obesity, this is highly relevant because insulin sparing in the treatment of type 1 diabetes may also attenuate weight gain, as shown in several small studies not included in the formal meta-analysis [2].…”