Metformin not beneficial in Type 1 Diabetes – REMOVAL Study updates

New data of the REMOVAL study pertaining to the updated guidelines about metformin in type 1 diabetes has been presented at the 2017 European Association for the Study of Diabetes (EASD) in Lisbon. This new data regarding renal function, biomarker and subgroup analysis results does not support use of metformin to improve glycemic control in adults with long-standing type 1 diabetes as suggested by current guidelines.

Metformin is currently recommended by the ADA and other bodies in type 1 diabetes for obese people in order to try to control A1c and reduce insulin requirement. The findings of REMOVAL originally cast doubt upon that recommendation but did show some effects on body weight, LDL cholesterol, and on atherosclerosis progression by a tertiary endpoint.

The newer data is showing that metformin actually reduces the attenuation of estimated glomerular filtration rate (eGFR) that you normally see in type 1 diabetes, with an effect size of about 1 mL/min/year of eGFR measured by cystatin C, not just by creatinine. This is a robust finding. It also showed a strong trend in the reduction of microalbuminuria as a categorical variable.

Petrie JR et al. aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by progression of common carotid artery intima-media thickness (cIMT), in adults with type 1 diabetes at increased risk for cardiovascular disease.

In a double-blind, placebo-controlled trial (REMOVAL) undertaken at 23 hospital diabetes clinics in five countries.,adults aged 40 years and older with type 1 diabetes of at least 5 years’ duration were enrolled.They had at least three of ten specific cardiovascular risk factors and were randomly assigned to oral metformin 1000 mg twice daily or placebo.

1. Out of 428 randomly assigned patients, 219 were allocated to metformin and 209 to placebo. HbA1c (mean 8·1% for metformin and 8·0% for placebo at baseline) was reduced on average over 3 years by metformin but this was accounted for by a reduction at the 3-month time point that was not sustained thereafter. Bodyweight and LDL cholesterol were reduced with metformin over 3 years of treatment, and eGFR was increased. Insulin requirement was not reduced on average over 3 years, but there was a significant visit-by-treatment interaction. There was no effect on endothelial function, or on retinopathy. More participants on metformin discontinued treatment as compared to those on placebo mainly due to an excess of gastrointestinal adverse effects, and there was no increase in hypoglycemia with metformin. The major conclusions drawn were that

• Data does not support use of metformin to improve glycemic control in adults with long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a wider role in cardiovascular risk management.


• A reduction in tissue plasminogen activator of about 20%, a reduction in C-reactive protein of about 16%, and LDL reduction, apolipoprotein B reduction.


• Metformin actually reduces the attenuation of estimated glomerular filtration rate (eGFR).

Reference:

Lancet Diabetes Endocrinol. 2017; 5(8):597-609 (ISSN: 2213-8595); Petrie JR, Chaturvedi N, Ford I, et al. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5:597-609. Abstract