REMOVAL Trial Results Presented at ADA 77th Scientific Sessions

In a busy day at the American Diabetes Association’s 77th Scientific Sessions in San Diego, data from the Results of the JDRF Reducing with Metformin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL) study were released to the estimated 16,000 attendees at the meeting.

According to the study findings, metformin may reduce the risk of heart disease in adults with type 1 diabetes (T1D). The inexpensive medication is considered as a first-line therapy for glucose control to improve the cardiovascular risk in adults with type 2 diabetes (T2D), and it may also be prescribed for people with T1D who are also overweight to help control blood sugar and weight, thereby allowing these patients to titrate to a lower daily insulin dose.

The REMOVAL study examined whether similar benefits could be seen in patients with T1D. Researchers investigated whether 3 years of treatment with metformin would reduce heart disease in middle-aged patients with T1D who are also at increased risk for cardiovascular disease (CVD).

To do this, the multicenter, international clinical trial enrolled 428 middle-aged patients with longstanding (average >33 years) T1D at 23 centers in the United Kingdom, Australia, Canada, Denmark, and the Netherlands. The study participants had >3 risk factors for CVD, such as body mass index (BMI) >27; hemoglobin A1C >8.0; known CVD/peripheral vascular disease; current smoking status; high blood pressure, cholesterol, or triglycerides; and a strong family history of CVD.

The participants were assigned to 2 groups of interventions, both 3 years in duration: either oral metformin, 2 glucophage 500-mg tablets up to twice daily, or matching placebos. Ultrasound was used to measure atherosclerosis, the leading cause of heart attacks, strokes and peripheral vascular disease, in the carotid arteries as a surrogate marker of heart disease.

The progression of atherosclerosis, as measured by the Diabetes Control and Complications Trial ultrasound protocol, was significantly reduced over the 3-year trial with metformin treatment; it also trended in the same direction as measured by the protocol recommended for people without diabetes. Because there was only a short-term reduction in A1C, glucose control could not account for this effect.

Metformin directly combats atherosclerosis by inhibiting white blood cell function, improving aspects of endothelial function, and slowing the production of advanced glycation end-products.

The patients who received metformin lost weight, and their insulin doses were reduced during the study. However, the reduction in A1C levels only occurred during the first 3 months of metformin treatment. Cholesterol was also reduced, although it should be noted that more than 80% of the study participants were already taking statins.

“A decrease in weight and insulin dose was more or less expected; however, we were surprised to discover a reduction in LDL-cholesterol and atherosclerosis progression with metformin treatment,” chief investigator John Petrie, MD, PhD, professor of diabetic medicine at the University of Glasgow in Scotland, explained. “The results of REMOVAL support wider prescribing of metformin to help reduce heart disease risk factors over a lifetime of type 1 diabetes, mirroring its current use in adults with type 2 diabetes.”

With 3 years of follow up, the REMOVAL trial is already one of the longest studies to be conducted to date on metformin use for people with T1D, and the investigators emphasize that evidence on the long-term effects of metformin on cardiovascular events rather than intermediate markers of cardiovascular health is required.

“Since our study confirmed that metformin only improved blood sugar control in the very short term, guidelines in the US and United Kingdom should be updated to reflect the lack of a sustained effect of metformin on blood glucose levels in adults with type 1 diabetes,” Petrie concluded. “So after REMOVAL there may actually be less prescribing in type 1 diabetes for blood glucose control.”

The complete study is being published simultaneously in Lancet Diabetes and Endocrinology.