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Metformin For T1D Benefits – REMOVAL Study

The results of the REMOVAL study were presented at the 2017 European Association for the Study of Diabetes (EASD) in Lisbon

While the main data was presented at the American Diabetes Association Scientific Sessions back in June of this year, new information was presented at EASD, consisting of new data, particularly renal [function] data, biomarker data, and subgroup analysis results that are relevant to the updated guidelines about metformin in type 1 diabetes.

Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. The researchers 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.

REMOVAL was a double-blind, placebo-controlled trial 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 and at least three of ten specific cardiovascular risk factors were randomly assigned to oral metformin 1000 mg twice daily or placebo. Participants and site staff were masked to treatment allocation. The primary outcome was averaged mean far-wall cIMT, quantified annually for 3 years, analyzed in a modified intention-to-treat population. Secondary outcomes were HbA1c, LDL cholesterol, estimated glomerular filtration rate (eGFR), incident microalbuminuria (not reported), incident retinopathy, bodyweight, insulin dose, and endothelial function, also analyzed in all participants with post-randomization data available for the outcome of interest at any given timepoint.

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 timepoint 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. Discontinuation of treatment in 59 (27%) participants on metformin versus 26 (12%) on placebo was mainly due to an excess of gastrointestinal adverse effects, and there was no increase in hypoglycemia with metformin. Five deaths occurred among patients allocated to metformin and two occurred among those allocated to placebo; none were judged by site principal investigators to be related to study medication.

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.

Peter Rossing presented a report on the renal data from REMOVAL:

We looked at the biomarkers. We found a reduction in tissue plasminogen activator of about 20%, a reduction in C-reactive protein of about 16%, LDL reduction, apolipoprotein B reduction, and that high-sensitivity troponin-T was unaffected.  We have looked in more detail at B12 deficiency, which is in the guidelines for metformin and type 1 diabetes in that B12 does go down in long-term treatment. In REMOVAL, the effects of hemoglobin were very minimal and probably not mediated by B12 deficiency because mean corpuscular volume was unaffected.

From the results it was concluded that this 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 suggests that it might have a wider role in cardiovascular risk management.

Finally, Helen Colhoun talked about the subgroup analysis:

We found no evidence for a threshold at which metformin is more or less effective above or below a body mass index (BMI) of 30, as claimed by the guidelines. The small effects in cholesterol, renal [function], and weight are really quite consistent across the board. If anything, people with a higher BMI have a lower A1c by 0.2% because they are on more insulin rather than less insulin.

Practice Pearls:

  • 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