Metformin Doesn't Improve HbA1c in Kids with Type 1 Diabetes

Veronica Hackethal, MD

December 04, 2015

Giving metformin to obese and overweight adolescents with type 1 diabetes, in addition to their insulin therapy, did not improve glycemic control but did result in reduced insulin doses and weight, according to results of a 6-month study, published in the December 1 issue of the Journal of the American Medical Association.

The trial is the largest to date to look at the effect of adjunctive metformin in overweight and obese adolescents with type 1 diabetes.

"The reduction in body weight, or improved adiposity, as well as the significant reduction in insulin dose, are significant end points that will benefit patients in the long run," commented Sanjoy Dutta, PhD, Juvenile Diabetes Research Foundation (JDRF) assistant vice president for translational development and international partnerships. Dr Dutta was not directly involved in the study, but JDRF sponsored the research.

Obese and overweight adolescents with type 1 diabetes represent a population in which glucose management is probably at its worst, Dr Dutta pointed out.

Such kids require higher doses of insulin, which may contribute to further weight gain, and puberty also represents a challenging time for glycemic control.

Almost a Quarter of Adolescents With Type 1 Diabetes Are Overweight

Even though people with type 1 diabetes are often thought of as normal or underweight, studies suggest that rates of obesity and overweight are increasing in this population.

Up to 24% of children and adolescents with type 1 diabetes may be overweight, while 15% may be obese, according to background information in the article.

Metformin is approved for use in children 10 years and older for the treatment of type 2 diabetes, but studies of its use in adolescents have been small or of short duration or have used nonstandard doses of metformin, according to first author of this new study, Ingrid Libman, MD, PhD, associate professor at Children's Hospital of Pittsburgh, Pennsylvania.

A recent meta-analysis of metformin use in adults with type 1 diabetes showed that it significantly reduced insulin dose but had no effect on HbA1c levels (Diabetologia. 2010;53:809-820).

The current study, a double-blind, placebo-controlled randomized trial, took place at 26 sites in the US T1D Exchange Clinical Network from October 2013 to February 2014.

It included 140 adolescents with type 1 diabetes (mean age, 15.3 years; 66% female; 74% white; mean duration of diabetes, 7.0 years; mean body mass index [BMI], 94th percentile; mean total daily insulin, 1.1 U/kg; and mean HbA1c, 8.8%).

Participants were randomized to metformin, titrated up to a dose of 2000 mg/day (n = 71) or to placebo (n = 69), both added to basal-bolus insulin  for 26 weeks.

Results at 3 months showed an initial improvement in HbA1c with metformin, but it was not maintained. At 26 weeks, both groups had the same mean change in HbA1c of 0.2% (P = .92).

Insulin dosing was left to the discretion of clinicians, so this may have made it more difficult to tease out the effects of metformin on glycemic control, according to the authors.

At 26 weeks, the metformin group had lower mean total daily insulin dose (−0.1 U/kg per day), compared with placebo (0.0 U/kg per day; mean difference, −0.1; P < .001). And a larger proportion of patients in the metformin group experienced a decrease in total daily insulin dose over the course of the study (P = .003).

Twenty-four percent (n = 17) of the metformin group and 7% (n = 5) of the placebo group showed a reduction in BMI of 10% or more from baseline (mean difference, 17%; P = .01).

Compared with placebo, the metformin group also experienced significantly less weight gain (0 kg vs 2 kg, respectively; mean difference, −2; P = .003) and a significantly greater reduction in total body fat measured on dual-energy X-ray absorptiometry (DXA) scans (mean difference, −2 kg; P < .001).

Insulin Sensitivity Improved?

"Favorable changes in body weight, body composition, and insulin requirements could reflect improved insulin sensitivity, which would be considered a beneficial effect" of metformin therapy, Dr Libman said.

The researchers are now exploring this issue with a mechanistic study evaluating the effect of metformin on insulin resistance using clamps, the gold standard to assess insulin resistance.

However, the two groups did not show any significant differences in lipid levels, blood pressure, inflammatory markers, or C-reactive protein (CRP) over the 6 months of the study.

But 6 months may not have been long enough to show beneficial effects on these surrogate cardiovascular disease markers, so longer trials to investigate the drug's effects on these outcomes will be needed, according to Dr Libman.

Regarding side effects, more people in the metformin group reported gastrointestinal adverse effects than in the control group (mean difference, 36%; P < .001).

And five participants (7%) in the metformin group compared with none in the placebo group experienced severe hypoglycemia (P = .06). In four of five patients on metformin, the severe hypoglycemia occurred during insulin-dose adjustment in the first 6 weeks of the trial.

These results suggest that tighter titration of insulin dose may be needed to minimize the risk of hypoglycemia, Dr Dutta said.

Adjunctive Metabolic Therapy for Type 1 Diabetes a High Priority

Aside from insulin, the only other approved therapy for type 1 diabetes is pramlintide acetate (Symlin, AstraZeneca), but its adoption has been very weak owing to potential nausea/vomiting and a challenging titration schedule, Dr Dutta explained.

But research into adjunctive metabolic therapy for type 1 diabetes is a very high priority for JDRF, he stressed.

Overall, metformin is one of the safest approved therapies for type 2 diabetes and is very inexpensive, Dr Dutta added. The main risks involve gastrointestinal side effects, which are manageable and often transient.

JDRF, the National Institutes of Health, and many pharmaceutical companies are looking at other adjunctive treatments for insulin, some of which are new and some of which are repurposed, such as other, newer, drug classes already approved for use in type 2 diabetes. These include the injectable glucagonlike peptide-1 (GLP-1) agonists and oral sodium glucose cotransporter 2 (SGLT2) inhibitors (although there have been reports of a serious side effect of diabetic ketoacidosis when the latter are used in type 1 diabetes, and experts are divided on their use).

"The next 12 to 24 months will be very critical as we find more results coming out from ongoing studies," Dr. Dutta said.

Given the current dearth of treatment options for type 1 diabetics, however, Dr Libman stressed that checking blood glucose, getting the proper dose of insulin, and incorporating healthy habits such as portion control, good food choices, and physical activity, is vital.

"Knowing that we were not able to show that metformin really had an effect on glycemic control, I would say that emphasizing compliance with diabetes management overall is imperative," she emphasized.

The study was funded by the JDRF. Dr Libman reports receipt of a grant from the JDRF and of grants to the institution from Novo Nordisk. Disclosures for the coauthors are listed in the article.

JAMA. 2015;314:2241-2250. Abstract

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