CVD Risk Management in Type 1 Diabetes Improved With Metformin

Metformin does not improve glycemic control in patients with long-term type 1 diabetes (T1D), but the treatment does have a role in managing cardiovascular (CV) risk in these patients, according to data from a recent international trial published in Lancet Diabetes and Endocrinology.

Researchers enrolled 493 participants with type 1 diabetes across 23 centers in Australia, Canada, Denmark, The Netherlands, and the United Kingdom between December 2011 and June 2014 in the double-blind placebo-controlled trial, Reducing With Metformin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL; ClinicalTrials.gov identifier: NCT01483560) to determine the role of metformin in decreasing atherosclerosis risk through reduced common carotid artery intima-media thickness (cIMT).

The participants were a minimum of 40 years old and had a minimum disease duration of 5 years. Participants also had 3 of 10 different CV disease (CVD) risk factors, which included established CVD; smoking; microalbuminuria; body mass index ≥27 kg/m²; hemoglobin A1c (HbA1c) >8.0%, hypertension; dyslipidemia; >20 years’ T1D duration; estimated glomerular filtration rate (eGFR) <90 mL/min per 1.73 m²; and a family history of CVD from a parent, biological aunt or uncle, or sibling who had a CV event such as a myocardial infarction, coronary artery bypass graft after aged 60 years, or stroke.

The researchers randomly assigned participants to receive either oral metformin (1000 mg) twice daily or placebo for 3 years. Mean cIMT was not significantly reduced in the metformin group (−0.005 mm/year; 95% CI, −0.012 to 0.002; P =.1664).

However, the researchers did find maximal cIMT was significantly reduced each year (−0.013 mm/year; 95% CI, −0.024 to -0.003; P =.0093) and HbA1c was reduced on average during the 3-year follow-up (−0.13%; 95% CI, −0.22 to −0.037; P =.0060) with a significant reduction at 3 months (−0.24%; 95% CI, −0.34 to −0.13; P <.0001).

Participants also saw reductions in body weight (−1.17 kg; 95% CI, −1.66 to −0.69; P <.0001) and low-density lipoprotein cholesterol (−0.13 mmol/L; 95% CI, −0.24 to −0.03; P =.0117), as well as increases in eGFR (4.0 mL/min per 1.73 m²; 95% CI, 2.19-5.82; P <.0001).

There was no average reduction of insulin during the follow-up period (−0.005 units/kg; 95% CI, −0.022 to 0.012; P =.545), as well as no significant effect on endothelial function or retinopathy. Treatment was discontinued in 27% of participants in the metformin group (n=59) and 12% of participants in the placebo group (n=26), primarily associated with gastrointestinal-related adverse effects. A total of 5 deaths occurred in the metformin group and 2 deaths occurred in the placebo group, both unrelated to treatment.

“The results of REMOVAL do not support the assertion by current guidelines that metformin can improve glycemic control in patients with type 1 diabetes, nor do they provide a rationale for restricting its use to those who are overweight or obese,” the researchers concluded. “However, they do suggest that wider off-label use of metformin might be warranted to improve CVD risk management in [T1D], and possibly also reduce insulin dose requirement.”

Reference

Petrie JR, Chaturvedi N, Ford I, et al; for the REMOVAL Study Group. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial.[published online June 11, 2017]. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(17)30194-8