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October 4, 2022
Diabetes affects more than 37 million Americans. Up to about 95% of them have type 2 diabetes, in which their body doesn’t make or use insulin well. This can impair the ability to keep levels of blood sugar (also called blood glucose) in a safe range. When blood glucose gets too high, it can cause complications such as nerve, kidney, eye, and heart-related conditions.
A drug called metformin has long been the considered the first-line medication for type 2 diabetes. Health care professionals generally recommend metformin combined with diet and exercise as the best early approach to diabetes care. If blood glucose becomes difficult to control over time, a second medication is often added. But there had been no consensus regarding which medications might best be added to metformin to keep blood glucose levels in check. And it had been unclear which drugs might best protect against common side effects, such as cardiovascular disease.
To find answers, NIH supported a large clinical trial to directly compare four drugs often used in combination with metformin to treat type 2 diabetes. The trial was conducted at 36 study centers nationwide. Findings were described in a pair of papers that appeared in the New England Journal of Medicine on September 22, 2022.
The trial enrolled more than 5,000 people with type 2 diabetes who were already taking metformin. They were from diverse racial and ethnic backgrounds. Participants were randomly placed into one of four treatment groups. Three groups took metformin plus a medicine that increased insulin levels: sitagliptin, liraglutide, or glimepiride. The fourth group took metformin and insulin glargine U-100, a long-acting insulin.
After about five years of follow-up, the researchers found that all four drugs improved blood glucose levels when added to metformin. But those taking metformin plus liraglutide or the long-acting insulin achieved and maintained their target blood levels for the longest time. They had about six months more time with blood glucose levels in the target range compared with those taking sitagliptin, the least effective in maintaining target levels. The effects of treatment did not differ with age, sex, race, or ethnicity.
However, none of the combinations overwhelmingly outperformed the others. Although average blood sugar levels decreased during the study, nearly three of four participants were unable to maintain the blood glucose target over the study period. This underscores the difficulty for many patients with type 2 diabetes to maintain recommended targets.
The study also looked at the drugs’ effects on developing diabetes-related cardiovascular disease and other conditions. Although the differences were small, participants in the liraglutide group were least likely to experience any cardiovascular disease. However, gastrointestinal symptoms were more common with liraglutide than with the other groups. Severe hypoglycemia, or low blood glucose, was generally uncommon, but affected more participants assigned to glimepiride.
“This study was designed to provide health care providers with important information on how to guide the long-term management of type 2 diabetes,” says the study’s project scientist, Dr. Henry Burch of NIH’s National Institute of Diabetes and Digestive and Kidney Diseases. “This is an integral step toward precision medicine for diabetes care, as these results can now be used in the decision-making process for each individual patient in light of their levels of glucose control, how well the medications are tolerated, and the person’s other health considerations.”
References: Glycemia Reduction in Type 2 Diabetes – Glycemic Outcomes. GRADE Study Research Group, Nathan DM, Lachin JM, Balasubramanyam A, Burch HB, Buse JB, Butera NM, Cohen RM, Crandall JP, Kahn SE, Krause-Steinrauf H, Larkin ME, Rasouli N, Tiktin M, Wexler DJ, Younes N; The GRADE Study Research Group. N Engl J Med. 2022 Sep 22;387(12):1063-1074. doi: 10.1056/NEJMoa2200433. PMID: 36129996.

Glycemia Reduction in Type 2 Diabetes – Microvascular and Cardiovascular Outcomes. GRADE Study Research Group, Nathan DM, Lachin JM, Bebu I, Burch HB, Buse JB, Cherrington AL, Fortmann SP, Green JB, Kahn SE, Kirkman MS, Krause-Steinrauf H, Larkin ME, Phillips LS, Pop-Busui R, Steffes M, Tiktin M, Tripputi M, Wexler DJ, Younes N; The GRADE Study Research Group. N Engl J Med. 2022 Sep 22;387(12):1075-1088. doi: 10.1056/NEJMoa2200436. PMID: 36129997.
Funding: NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Heart, Lung, and Blood Institute (NHLBI), National Institute of General Medical Sciences (NIGMS), and National Center for Advancing Translational Sciences (NCATS); Centers for Disease Control and Prevention; American Diabetes Association; Department of Veterans Affairs; Becton, Dickinson and Company; Bristol-Myers Squibb; Merck & Co., Inc.; Novo Nordisk; Roche Diagnostics; Sanofi.
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