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The national GRADE study, with leadership and participation from UNC School of Medicine’s John Buse, MD, PhD, and Sue Kirkman, MD, found that two of four common type 2 diabetes treatments — glargine and liraglutide — worked better than the other drugs, sitagliptin and glimepiride, to maintain blood glucose levels.

People with well-controlled diabetes generally have a high quality of life and have a much lower risk of disability and early death, and they generally respond well to changes in diet and exercise, though most people need medications to manage their blood glucose levels and avoid complications.

“There is general agreement among doctors that metformin, the most common first-line medication for treating type 2 diabetes, combined with diet and exercise is the best early approach in diabetes care,” said John Buse, MD, PhD, the Verne S. Caviness Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism in the UNC Department of Medicine. “However, most people with diabetes will require more than one medicine to control their condition over time.”

The nation-wide GRADE study, with leadership and participation from UNC School of Medicine researchers, compared four different second-line therapies on the background of metformin and their ability to maintain blood glucose levels in a healthy range over time. The trial found that two of the treatments, glargine and liraglutide, worked better than the other drugs, sitagliptin and glimepiride, to maintain blood glucose levels.

Sue Kirkman, MD
Sue Kirkman, MD

Their results were published in a pair of papers in the New England Journal of Medicine. Sue Kirkman, MD, a professor of medicine in the division of endocrinology and metabolism, was a principal investigator on the study and co-chair of the outcomes adjudication committee.

Launched in 2013, the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study, funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH), was designed to compare four major medication classes approved by the FDA to treat diabetes in combination with metformin.

“The hope is that this data will inform people with diabetes and their providers regarding what the right choice is for them if they need a second medication after metformin to help control their disease with an aim to reducing the risk of complications and promoting a long and healthy life,” said Buse, director of the UNC Diabetes Center and co-director of the North Carolina Translational and Clinical Sciences Institute (NC TraCS).

The study enrolled 5,047 people with type 2 diabetes from diverse racial and ethnic groups who were already taking metformin. Participants were then randomly placed into one of four treatment groups. Three groups took metformin and one of three medications that can increase the body’s own production of insulin: sitagliptin, liraglutide, or glimepiride. The fourth group took metformin and insulin glargine U-100, a long-acting insulin.

After an average of four years of follow-up, the study found that participants taking metformin and liraglutide or insulin glargine achieved and maintained their target blood glucose levels for the longest time compared to sitagliptin or glimepiride. This translated into approximately 6 months more time with blood glucose in the target range compared with sitagliptin, which was the least effective in maintaining target levels. Treatment effects did not differ based on age, sex, race, or ethnicity.

However, none of the combinations yielded perfect results. Nearly three-quarters of all participants were unable to maintain the lowest blood glucose target over four years, underscoring the difficulty in maintaining recommended targets in many patients with type 2 diabetes.

The study also looked at treatments’ effects on developing diabetes-related complications. Researchers found that participants in the liraglutide group were least likely to experience any cardiovascular disease.

Additionally, the study examined the side effects of the drugs. Serious adverse events were similar overall in the four groups. Severe low blood sugar reaction affected more participants who had taken glimepiride, and gastrointestinal symptoms were more common with liraglutide than with the other three treatment groups.

On average, participants in all treatment groups lost weight. Over four years, people in the liraglutide and sitagliptin groups lost significantly more weight (an average of seven and four pounds, respectively) than the glargine and glimepiride groups (less than two pounds).