medwireNews: The REMOVAL findings show an uncertain effect of metformin on atherosclerosis in overweight patients with type 1 diabetes, and only a transient effect on glycemic outcomes.
REMOVAL (REducing with MetfOrmin Vascular Adverse Lesions) missed its primary endpoint of reduced progression of common carotid artery intima-media thickness (cIMT). It did show a significant effect on progression of maximal cIMT, although this was a tertiary endpoint, and improved weight and lipid endpoints.
“Our results provide a more rational basis for prescribing metformin, an inexpensive oral therapy, in patients with type 1 diabetes,” write John Petrie (University of Glasgow, UK) and co-investigators in The Lancet Diabetes & Endocrinology.
“Type 1 diabetes guidelines should therefore be revised to reflect the absence of a sustained effect of adjunctive metformin on glycaemia and to remove the suggestion of particular efficacy in patients with a BMI [body mass index] greater than 25 kg/m2.”
The study participants were aged an average of 55.5 years, and had an average BMI of 28.5 kg/m2 and glycated hemoglobin (HbA1c) level of 8.05%. During 3 years of taking metformin 1000 mg twice daily, the 193 patients randomly assigned to this treatment had an average annual mean cIMT increase of 0.006 mm per year, compared with 0.010 mm per year among the 194 patients who took placebo. The between-group difference of 0.005 mm per year was not statistically significant.
The difference for maximal cIMT, however, was 0.013 mm per year, and was significant. In an accompanying commentary, Eberhard Standl (Helmholtz Center, Neuherberg, Germany) notes that this measure includes atherosclerotic plaque (ie, measures more advanced disease than mean cIMT) and says that “based on this finding, the hope that metformin might delay the development of atherosclerotic lesions in type 1 diabetes is still alive.”
He says that a large cardiovascular outcomes trial would be necessary to test this, however.
Patients taking metformin had a 0.24% reduction in HbA1c at the 3-month study visit, relative to the placebo group, but this was not sustained with longer follow-up. They did, however, have a significant reduction in low-density lipoprotein (LDL) cholesterol levels versus the placebo group, by 0.13 mmol/L, and in bodyweight, by 1.17 kg.
“Rather than a role in glycaemic control, our findings suggest that long-term use of metformin in type 1 diabetes might reduce the long-term risk of cardiovascular disease via small but sustained reductions in bodyweight and LDL cholesterol,” say the researchers.
They note: “Since larger and longer trials to investigate the effect of metformin on clinical cardiovascular outcomes in type 1 diabetes are unlikely to be done in the medium term, treatment decisions will have to be based on interpretation of the existing evidence.”
The research was also presented at the American Diabetes Association scientific sessions in San Diego, California, USA.
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