Two popular diabetes drugs outperformed others in large clinical trial

NIH-funded researchers have completed the first study comparing commonly used drugs to treat type 2 diabetes.

In a large clinical trial directly comparing four drugs commonly used to treat type 2 diabetes, researchers found that insulin glargine and liraglutide performed best among four FDA-approved drugs to keep blood glucose levels in the recommended range. Controlling blood glucose levels is a key component of maintaining the health of people with type 2 diabetes. All four of the evaluated drugs were added to treatment with metformin, which is the first-line treatment for type 2 diabetes. The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health.

More than 37 million Americans have diabetes, and about 90-95% of them have type 2 diabetes. People with diabetes who keep their blood glucose levels within normal limits usually have a much lower risk of developing diabetes complications such as nerve, kidney, and eye disease. Most people with type 2 diabetes need several medications to control their blood sugar levels for a long time.

Despite general agreement among health professionals that metformin combined with diet and exercise is the best approach to treating early-stage diabetes, there is no consensus on what to do next to keep high blood glucose levels under control.

The Approaches to Glycemic Reduction in Diabetes: A Comparative Effectiveness (GRADE) Study, which began in 2013, was conducted in 36 U.S. research centers. Its aim was to compare the four main drugs approved by the FDA at the start of the GRADE study for the treatment of diabetes in combination with metformin. The main results were published in a pair of articles in The New England Journal of Medicine.

"This study was designed to provide health care providers with important information about how to guide long-term treatment of type 2 diabetes," said Dr. Henry Burch, a GRADE project researcher at NIDDK. "This is an important step toward precision medicine in diabetes management because these results can now be used in the decision-making process for each individual patient based on glucose control levels, medication tolerance and other aspects of health."

The study included 5,047 people with type 2 diabetes from different racial and ethnic groups who were already taking metformin. Participants were randomly assigned to one of four groups. Three groups were taking metformin plus an insulin-boosting drug, 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 showed that participants taking metformin plus liraglutide or insulin glargine achieved and maintained target blood glucose levels the longest compared to sitagliptin or glimepiride. This means about six months more time that blood glucose levels were in the target range compared with sitagliptin, which was the least effective at maintaining target levels. Treatment effect did not differ by age, sex, race, or ethnicity.

However, none of the combinations outperformed the others. Although average blood sugar levels fell during the study, nearly three-quarters of all participants failed to maintain target blood glucose levels for four years, highlighting the difficulty of maintaining recommended levels in many patients with type 2 diabetes.

"GRADE effectively shows which drugs work best to achieve and maintain blood glucose targets, but we need to develop even more effective strategies for long-term maintenance of acceptable glucose levels," said GRADE study chairman Dr. David M. Nathan, director of the Diabetes Center at Massachusetts General Hospital, Boston. "We still have more work to do, such as evaluating other interventions and treatment combinations, to help people with type 2 diabetes achieve long-term glucose control."

The study also examined the effect of treatment on the development of diabetes-related cardiovascular disease. The researchers found that participants in the liraglutide group were least likely to develop cardiovascular disease compared with the other groups.

The study also examined the side effects of the drugs:

• Severe hypoglycemia, often referred to as a response to low blood glucose levels, was rare overall, but affected more participants who received glimepiride (2.2%).
• Gastrointestinal symptoms were more common with liraglutide than with the other three treatment groups.

In addition, on average, participants in all treatment groups lost weight. Over four years, people in the liraglutide and sitagliptin groups lost more weight (an average of 7 and 4 pounds, respectively) than those in the glirgin and glimepiride groups (less than 2 pounds).

"With so many treatment options for type 2 diabetes, it can be difficult for providers and patients to know which drug is best for a particular individual," said NIDDK Director Dr. Griffin P. Rogers. "NIDDK is uniquely positioned to support comparative effectiveness trials, such as GRADE, to help providers make evidence-based recommendations that will lead to better health outcomes for their patients and all people living with type 2 diabetes."

The type of diabetes drug now available called SGLT2 inhibitors was not approved by the FDA when GRADE enrollment began and was not included in the study.

The GRADE study was supported by an NIDDK grant (U01DK098246). Additional support was provided by the National Heart, Lung, and Blood Institute; the National Institute of General Medical Sciences; the National Center for Translational Science Development; the Centers for Disease Control and Prevention; and the American Diabetes Association. The Department of Veterans Affairs provided resources and facilities. Material support in the form of donated drugs and supplies was provided by Becton, Dickinson and Company, Bristol-Myers Squibb, Merck & Co., Inc., Novo Nordisk, Roche Diagnostics and Sanofi. ClinicalTrials.gov number: NCT01794143.

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