Long-Term Metformin Treatment Found to Reduce Risk of Heart Disease in Adults with Type 1 Diabetes


Michelle Kirkwood

San Diego, California
June 11, 2017

According to results of international REMOVAL trial of more than 400 adults with type 1 diabetes 

Metformin may be an effective long-term strategy worthy of adding to an individual’s diabetes care plan in order to reduce the risk of heart disease in adults with type 1 diabetes, according to the findings of the study titled, “Results of the JDRF Reducing with Metformin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL),” presented today at the American Diabetes Association’s 77th Scientific Sessions® at the San Diego Convention Center.

Metformin is an inexpensive medication considered first-line therapy for treatment of glucose control in individuals with type 2 diabetes. It is also widely used to improve cardiovascular risk in adults with type 2 diabetes. This study examined if similar benefits could be expected for people with type 1 diabetes. Metformin may be prescribed for people with type 1 diabetes who are also overweight, to help control blood sugar and weight, allowing a lower daily insulin dose. This multi-center, international clinical trial enrolled patients at 23 centers across the United Kingdom, Australia, Canada, Denmark and the Netherlands. Researchers investigated if three years of treatment with metformin reduces heart disease in middle-aged adults with type 1 diabetes who are at increased risk for cardiovascular disease (CVD). Ultrasound was used to measure thickening (atherosclerosis) in the carotid arteries—large blood vessels in the neck— as a surrogate marker of heart disease. Atherosclerosis is a form of hardening of the arteries that is the leading cause of heart attacks, strokes and peripheral vascular disease. 

REMOVAL studied 428 middle-aged adults with longstanding type 1 diabetes--on average for 33 years. The patients had three or more risk factors for cardiovascular disease, including BMI over 27; A1C greater than 8.0; known CVD/peripheral vascular disease; current smoker; high blood pressure; high cholesterol or triglycerides; strong family history of CVD; or duration of diabetes more than 20 years.

Trial participants were assigned interventions of three years duration of either oral metformin treatment (two glucophage 500mg tablets, titrated up to twice daily); or matching placebos. Progression of atherosclerosis, measured using the Diabetes Control and Complications Trial ultrasound protocol, was significantly reduced over three years by metformin and also trended in the same direction when measured by the protocol recommended for people without diabetes. As there was only a short-term reduction in A1C, glucose control could not account for this effect. Metformin has direct effects to combat atherosclerosis, including inhibiting the function of white blood cells, improving aspects of endothelial function, and slowing production of advanced glycation end-products (AGEs).

Patients who received metformin lost weight, and their insulin doses were able to be reduced during the study. However, A1C levels showed reduction only during the first three months of metformin treatment. Cholesterol was also reduced, even though more than 80 percent of trial participants were already taking statins. Weight reduction and lowering of cholesterol may therefore have played a role in reducing atherosclerosis. Estimated Glomerular Filtration Rate (eGFR) by the Modification of Diet in Renal Disease (MDRD) equation was sharply increased on starting metformin, however, the investigators believe this needs to be studied further to determine if there is any clinical significance. Some people stopped taking metformin because of nausea or abdominal pain, and there was no increase in the risk of hypoglycemia. 

“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,” said chief investigator John Petrie, MD, PhD, professor of diabetic medicine at the University of Glasgow in Scotland. “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.” 

“Since our study confirmed that metformin only improved blood sugar control in the very short term, guidelines in the U.S. 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 explained. “So after REMOVAL there may actually be less prescribing in type 1 diabetes for blood glucose control.”

The REMOVAL trial, with three years of follow up, is already one of the longest studies to have been conducted to-date of metformin use for people with type 1 diabetes, and evidence on the long-term effects of metformin on cardiovascular events rather than intermediate markers of cardiovascular health is required. 

The complete study will also be published simultaneously today in Lancet Diabetes and Endocrinology. To speak with Dr. Petrie, please contact the Association’s media relations team on-site at the San Diego Convention Center on June 9 - 13, by phone at 619-525-6250 or by email at press@diabetes.org.

The American Diabetes Association’s 77th Scientific Sessions, to be held June 9-13, 2017, at the San Diego Convention Center, is the world’s largest scientific meeting focused on diabetes research, prevention and care. During the five-day meeting, health care professionals have exclusive access to more than 2,500 original research presentations, participate in provocative and engaging exchanges with leading diabetes experts, and can earn Continuing Medical Education (CME) or Continuing Education (CE) credits for educational sessions. The program is grouped into eight interest areas: Acute and Chronic Complications; Behavioral Medicine, Clinical Nutrition, Education and Exercise; Clinical Diabetes/Therapeutics; Epidemiology/Genetics; Immunology/Transplantation; Insulin Action/Molecular Metabolism; Integrated Physiology/Obesity; and Islet Biology/Insulin Secretion. Brenda Montgomery, RN, MSHS, CDE¹, President of Health Care and Education , will deliver her address on Saturday, June 10, and Alvin C. Powers, MD, President of Medicine and Science, will present his address on Sunday, June 11. Eight abstracts were selected by the Scientific Sessions Meeting Planning Committee to be presented on Tuesday, June 13, in the President’s Oral Session. These abstracts represent important research being conducted in the field of diabetes today. In total, the 2017 Scientific Sessions includes 378 abstracts in 49 oral sessions; 2,152 poster presentations including 50 moderated poster discussions; and 360 published-only abstracts.

About the American Diabetes Association

More than 29 million Americans have diabetes, and every 23 seconds another person is diagnosed with diabetes. The American Diabetes Association (Association) is the global authority on diabetes and since 1940 has been committed to its mission to prevent and cure diabetes and to improve the lives of all people affected by diabetes. To tackle this global public health crisis, the Association drives discovery in research to treat, manage and prevent all types of diabetes, as well as to search for cures; raises voice to the urgency of the diabetes epidemic; and provides support and advocacy for people living with diabetes, those at risk of developing diabetes and the health care professionals who serve them. For more information, please call the American Diabetes Association at 1-800-DIABETESS (1-800-342-2383) or visit diabetes.org. Information from both of these sources is available in English and Spanish. Find us on Facebook (American Diabetes Association), Twitter (@AmDiabetesAssn) and Instagram (@AmDiabetesAssn)

1 Disclosures for Brenda Montgomery. Employer: AstraZeneca Pharmaceuticals. Montgomery's role as President, Health Care & Education of the American Diabetes Association (Association) is a voluntary position to which she was elected by the members of the Association in 2015. She continues to recuse herself from any and all discussions, decisions or votes that have or could be perceived as having a conflict of interest with her employer.