Two common diabetes medications outperform two others in a direct comparison

The GRADE national study, led and co-led by UNC School of Medicine John Buse, MD, and Sue Kirkman, MD, found that two of four common treatments for type 2 diabetes — glargine and liraglutide — work better than the other medications, sitagliptin. Glimepiride to maintain blood sugar levels.


People with well-controlled diabetes generally have a high quality of life, have a much lower risk of disability and early death, and generally respond well to changes in diet and exercise, although most people require medication to control glucose levels in blood and avoid complications.

“There is general agreement among clinicians that metformin, the most common first-line drug for treating type 2 diabetes, along with diet and exercise is the best early approach in diabetes care,” said John Buss, MD, Verne S. Cavins, Distinguished Professor of Medicine at Department of Endocrinology and Metabolic Diseases In the UNC . Department of Medicine. “However, most people with diabetes will need more than one medication to control their condition over time.”

The nationwide GRADE study, led and co-led by UNU School of Medicine researchers, compared four different second-line therapies against metformin and their ability to maintain blood sugar levels in a healthy range over time. The trial found that two treatments, glargine and liraglutide, work better than the other drugs, sitagliptin and glimepiride, to maintain blood glucose levels.

Sue Kirkman, MD
Sue Kirkman, MD

Their results have been published in two research papers in New England Journal of Medicine. Sue Kirkman, MD, professor of medicine in the Division of Endocrinology and Metabolism, was the study’s principal investigator and co-chair of the findings’ panel.

Launched in 2013, The Glycemic Lowering Approach to Diabetes: The Comparative Efficacy Study (GRADE), funded by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)part of National Institutes of Health (NIH)to compare four major drug classes approved by the Food and Drug Administration for the treatment of diabetes in combination with metformin.

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

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

After an average of four years of follow-up, the study found that participants who took metformin, liraglutide or insulin glargine achieved and maintained target blood sugar levels for longer than either sitagliptin or glimepiride. This translated into approximately 6 more months with blood glucose in the target range compared to sitagliptin, which was less effective in maintaining target levels. Treatment effects did not differ based on age, gender, 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 goal over a four-year period, underscoring the difficulty of maintaining recommended goals in many people with type 2 diabetes.

The study also looked at the effects of treatments on the development of diabetes-related complications. The researchers found that participants in the liraglutide group were less likely to develop cardiovascular disease.

Additionally, the study examined the side effects of the medications. Serious adverse events were generally similar in the four groups. Severely low blood sugar affected more participants who took 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 the course of four years, subjects 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).

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