Results from the REMOVAL trial revealed reduction in the risk of cardiovascular disease among other benefits with metformin in type 1 diabetes patients.
Atherosclerosis leads to macrovascular complications in diabetes. These complications contribute to the majority of deaths in patients with diabetes. The use of metformin in previous studies have established a reduction in risk of cardiovascular disease in patients with type 2 diabetes. This is one of the reasons why metformin is currently recommended as first line therapy for these patients. However, it is only recommended for off label use in overweight or obese patients with type 1 diabetes to assist in weight loss and to decrease insulin dose requirements. Researchers wanted to investigate the potential use of metformin in patients with type 1 diabetes, to evaluate if these patients could also benefit from the reduction in risk of cardiovascular disease.
An international, double-blind study called the REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) study enrolled 493 participants over the age of 40 with a minimum of five year duration of type 1 diabetes and at least three cardiovascular risk factors. The ten defined risk factors in the study include known CVD, strong family history of CVD, diabetes duration > 20 years, a BMI ≥ 28 kg/m2, HbA1c > 8.0%, current smoker, microalbuminuria, eGFR < 90 mL/min/1.732, hypertension and dyslipidemia. After a 3 month run in period, 428 participants were randomized to receive either placebo or 1000 mg of metformin twice a day. All baseline characteristics were similar between the two study groups. Researchers used a marker, average mean far wall cIMT, to measure the progression of atherosclerosis in the primary outcome. This marker is typically used to predict cardiovascular events. Secondary outcomes included HbA1c, LDL-C, eGFR, incident retinopathy, body weight, insulin dose and endothelial function. Progression of average maximal far wall cIMT, frequency of hypoglycemia, treatment satisfaction and vitamin B12 status were the tertiary outcomes of interest. All data was gathered at baseline, 12, 24 and 36 months. The study utilized several statistical analyses, such as repeated-measures random regression mode, ANCOVA, cox proportional hazard, negative binomial regression model and logistic regression analysis.
Although the results did not show a statistical significance in the primary outcome (-0.005 mm per year; 95% CI -0.012 to 0.002; p = 0.167), the study did show a reduction in the progression of atherosclerosis in the tertiary outcome of average maximal far wall cIMT (-0.013 mm per year; 95% CI -0.024 to -0.003; p = 0.0093). HbA1c was found to be reduced around 3 months but the reduction was not maintained throughout the study. In addition, the results indicated a small reduction in insulin dose requirement after 6 months, which was maintained with the use of metformin. Body weight (-1.17 kg; 95% CI -1.66 to -0.69; p < 0.0001) and LDL-C (-0.13 mmol/L ; 95% CI -0.24 to -0.03; p = 0.0117) were also reduced in the metformin study group. The results also indicated a significant increase in eGFR with the metformin study group (4.0 mL/min/1.732; 95% CI 2.19 to 5.81; p < 0.0001). There were no evidence of statistical significance between the two study groups on endothelial function, retinopathy, hypoglycemia and treatment satisfaction. A significant number of patients did discontinue therapy in the metformin study group, mainly due to gastrointestinal adverse effects (p = 0.0002). Lastly, vitamin B12 deficiency was also statistically significant in the metformin study group (p = 0.0094).
This study suggests using metformin in adults with type 1 diabetes can reduce the risk of cardiovascular disease. It can be presumed that metformin’s mechanism of cardiovascular benefit is independent of glycemic control because a reduction in HbA1c was not maintained in the study. Reduction in body weight and LDL-C could also contributed to the benefit seen with metformin use. These results are important because it can expand the population parameters of off label recommendation of metformin in type 1 diabetes with the added benefit of reducing the risk of cardiovascular disease. The study also brought to light the need for monitoring vitamin B12 levels due to the significant deficiency in the metformin study group. Future studies on the benefits of metformin on cardiovascular outcomes should be conducted using clinical measures.
- The use of metformin in adult patients with type 1 diabetes has many benefits such as reduction in weight, LDL-C, insulin dose requirement and a potential decrease in the risk of cardiovascular disease.
- Although significant number of patients discontinued the use of metformin due to gastrointestinal adverse effects, the risk of these side effects can be minimized by the use of extended release formulations.
- This study suggests the need for monitoring vitamin B12 levels in patients on long term therapy with metformin.
Petrie J, Chaturvedi I, Brouwers M, et al. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. The Lancet: Diabetes & Endocrinology. 2017. Epub 2017/06/11. doi: 10.1016/S2213-8587(17)30194-8
American Diabetes Association. Long-Term Metformin Treatment Found to Reduce Risk of Heart Disease in Adults with Type 1 Diabetes. Press Release. Available at: http://www.diabetes.org/newsroom/press-releases/2017/petrie-scientific-sessions-2017.html. Accessed June 15, 2017.
Joanna Martinez-Mendez, PharmD Candidate 2018, Lake Erie College of Osteopathic Medicine School of Pharmacy: FL Campus