Diabetes affects more than 37 million Americans, and 90–95% of them have type 2 diabetes. Complications of diabetes, such as nerve, kidney, and eye disorders, are significantly less common in people with diabetes who maintain blood glucose levels in the near-normal range.

In order to maintain stable blood sugar levels over time, the majority of people who have type 2 diabetes need to take more than one medication.

The best early strategy for treating diabetes is metformin paired with diet and exercise, however, there is disagreement among medical specialists as to what to do next to best control high blood glucose levels.

The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study began in 2013 and involved 36 research facilities in the United States. It was developed to compare four FDA-approved drugs when GRADE began using them to treat diabetes in conjunction with metformin.

“This study was designed to provide health care providers with important information on how to guide the long-term management of type 2 diabetes,” explains Dr. Henry Burch, NIDDK’s project scientist for GRADE. “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.”

About 5,047 patients with type 2 diabetes from various racial and cultural backgrounds who were previously taking metformin participated in the trial. Participants were assigned to one of four treatment groups at random. Three groups each received metformin together with sitagliptin, liraglutide, or glimepiride, a drug that raised insulin levels. The fourth group was given metformin along with the long-acting insulin glargine U-100.

After following up with people for an average of four years, the study found that those who took metformin plus liraglutide or insulin glargine reached and kept their target blood levels for the longest time compared to those who took sitagliptin or glimepiride. This meant that blood sugar levels stayed in the target range for about six months longer than with sitagliptin, which was the least effective at keeping levels in the target range. The outcomes of treatment were consistent across age groups, sexes, and ethnicities.

However, none of the combos performed significantly better than the others. Even though the average blood sugar level went down during the study, nearly three-quarters of all participants were unable to keep the blood sugar target over four years. This shows how hard it is for many people with type 2 diabetes to keep the recommended targets.

“GRADE effectively shows which drugs worked best at achieving and maintaining blood glucose targets over time,” adds GRADE Study Chair Dr. David M. Nathan, director of the Massachusetts General Hospital Diabetes Center, Boston, “but we need to establish even more effective strategies for the long-term maintenance of acceptable glucose levels. 

“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 how the medications affected the onset of cardiovascular disease in people with diabetes. Comparing individuals in the liraglutide group to those in the other groups, researchers discovered that they had the lowest overall risk of cardiovascular disease.

The study also looked at the medications’ negative effects and discovered:

• The incidence of severe hypoglycemia, often known as a low blood glucose reaction, was higher among those using glimepiride (2.2%).
• Compared to the other three therapy groups, liraglutide was linked to a higher incidence of gastrointestinal symptoms.
• Participants in all therapy groups also lost weight on average. Over the course of four years, participants in the liraglutide and sitagliptin arms lost more weight (on average, 7 and 4 pounds less) than those in the glargine and glimepiride arms (less than 2 pounds).

“With many treatment options available for type 2 diabetes, health care providers and patients can find it difficult to know which drug is best for which person,” adds NIDDK Director Dr. Griffin P. Rodgers. “NIDDK stands uniquely poised to support comparative effectiveness trials like GRADE to help providers make evidence-based recommendations that lead to better health for their patients, and for all people living with type 2 diabetes.”

At the start of the GRADE study, the FDA had not approved SGLT2 inhibitors, a type of diabetes drug that is now available, so it was not part of the study.

The study findings were reported in two separate articles published in The New England Journal of Medicine.

The trial received funding from the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Source: NCT01794143

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