Metformin has long been considered the first-line medication for type 2 diabetes mellitus (T2DM). Combined with diet and exercise, the 3-part treatment regimen has been considered the best early approach to diabetes care. But when blood glucose becomes difficult to control and a second medication is needed, 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, the National Institutes of Health supported a large clinical trial to directly compare 4 drugs often used in combination with metformin to treat T2DM. The trial was conducted at 36 study centers nationwide. Findings were published in a pair of papers in the New England Journal of Medicine. The trial enrolled more than 5,000 people with T2DM who were already taking metformin. They were from diverse racial and ethnic backgrounds. Participants were randomly placed into 1 of 4 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 5 years of follow-up, the researchers found that all 4 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 6 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 glucose levels decreased during the study, nearly 3 of 4 participants were unable to maintain the blood glucose target over the study period. This underscores the difficulty for many patients with T2DM 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.”
Sources: Nathan DM, Lachin JM, Balasubramanyam A, et al for the GRADE Study Research Group. Glycemia reduction in type 2 diabetes – glycemic outcomes. N Engl J Med. 2022;387(12):1063-1074. doi: 10.1056/NEJMoa2200433. Nathan DM, Lachin JM, Bebu I, et al for the GRADE Study Research Group. Glycemia Reduction in Type 2 Diabetes – Microvascular and Cardiovascular Outcomes. N Engl J Med. 2022;387(12):1075-1088. doi: 10.1056/NEJMoa2200436.
