Metformin does not reduce insulin resistance in adults with Type 1 diabetes

Metformin does not appear to reduce insulin resistance in adult patients with type 1 diabetes (T1D), according to a new study.

The findings, which were reported in Nature Communications, are important because insulin resistance is a major cardiovascular risk factor in patients with T1D.

Corresponding author Jennifer R. Snaith, M.B.B.S., Ph.D., of the University of New South Wales Sydney, and colleagues, explained that it is not clear exactly why insulin resistance seems to elevate the risk of cardiovascular disease, nor is it known whether the link is associated with muscle or liver insulin resistance.

“This differentiation is important, since targeted intervention with adjunctive therapies that ameliorate insulin resistance may provide cardioprotection in type 1 diabetes,” Snaith and colleagues wrote.

Metformin is considered a first-line therapy in Type 2 diabetes, where it has been shown to reduce cardiovascular risk and mortality. Previous research has suggested that giving metformin to patients with T1D can allow patients to reduce their daily insulin dose. Such findings may suggest an improvement in insulin resistance, Snaith and colleagues said, though no studies have yet examined the question in adult patients using the hyperinsulinemic-euglycemic clamp technique, which the investigators said is the gold-standard method of directly measuring insulin resistance.

Snaith and colleagues recruited 40 adults with T1D along with 20 adults without diabetes and assessed their insulin resistance using the two-step hyperinsulinemic-guglycemic clamp. They found that patients with T1D had higher hepatic, muscle, and adipose insulin resistance, measured by endogenous glucose production (EGP; 64% higher in patients with T1D), glucose infusion rate (GIR; 29% lower in the T1D), and higher nonesterified fatty acids (NEFA), respectively.

At the same time, they designed a randomized placebo-controlled trial in which 20 adults with T1D were given extended-release doses of metformin and 20 patients with T1D were given a placebo for 26 weeks. The patients in the metformin cohort were given titrated doses, starting with 500 milligrams (mg) for seven days, then 1,000 mg for the next week, followed by 1,500 mg doses for the rest of the 26-week trial period. Both the metformin group and the placebo group had similar adherence rates, of 89% and 88%, respectively. One patient in the metformin group and two patients in the placebo group discontinued and did not complete the trial.

After 26 weeks, the investigators found no significant difference in EGP between the metformin group and the placebo group nor were there differences in hypoglycemia and ketoacidosis rates.

“These results do not support the use of metformin to reduce insulin resistance in adults with type 1 diabetes,” Snaith and colleagues said. “This finding contrasts with studies of metformin in adolescents with Type 1 diabetes that reported improved peripheral insulin sensitivity and no change in hepatic glucose production (a measure of liver insulin resistance).”

Snaith and colleagues said patients in the metformin group were able to reduce their daily insulin dose by 0.1 units/kg/day. Yet, they noted that while a reduction in insulin dose is often interpreted as a sign of a reduction in insulin resistance, that is not necessarily the case.

“Our findings suggest that in adults with Type 1 diabetes, metformin may have metabolic impacts that translate to sparing of insulin requirements via effects independent of insulin resistance,” they wrote.

One possibility, they said, is that growth differentiation factor 15 (GDF15, which was elevated at baseline in patients with T15, may promote metformin-induced glucose transport into enterocytes, which they said could help reduce the need for insulin. They said further studies would be needed to understand the connection, if any.