When added to metformin, liraglutide and insulin glargine were found to be more effective at achieving and maintaining blood glucose levels in the recommended range compared with glimepiride or sitagliptin, according to findings from a National Institutes of Health (NIH)-funded study.

The multicenter, randomized, controlled Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study (ClinicalTrials.gov Identifier: NCT01794143) was designed to compare the effectiveness of 4 glucose-lowering medications approved by the Food and Drug Administration (FDA) at the time GRADE started. The study included 5047 patients with type 2 diabetes who were already taking metformin and had glycated hemoglobin levels (HbA1c) of 6.8% to 8.5%.

Patients were randomly assigned to receive 1 of 4 treatments in combination with metformin: sitagliptin, a dipeptidyl peptidase 4 inhibitor, liraglutide, a glucagon-like peptide-1 receptor agonist, glimepiride, a sulfonylurea, or insulin glargine U-100. The primary endpoint was the time to primary failure defined as an HbA1c greater than or equal to 7.0%.

After a mean follow-up of 5 years, results showed that the cumulative incidence of HbA1c of 7.0% or higher was lower with insulin glargine (26.5 per 100 participant-years) and liraglutide (26.1 per 100 participant-years) compared with glimepiride (30.4 per 100 participant-years) and sitagliptin (38.1 per 100 participant-years); the difference among the 4 treatment arms was found to be significant (P <.001 for a global test of differences across all arms).

Treatment effects were not found to be different based on age, sex, race, or ethnicity, though a greater benefit was observed with insulin glargine, liraglutide, and glimepiride in patients with higher baseline HbA1c, compared with sitagliptin. At the launch of the GRADE study, sodium-glucose cotransporter 2 (SGLT2) inhibitors had not yet been approved by the FDA and were therefore not included in the analysis.

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

As for safety, the incidence of severe hypoglycemia was rare but was significantly greater with glimepiride (2.2% of patients) compared with insulin glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Gastrointestinal side effects were more frequent in the liraglutide arm compared with the other treatment arms. Weight loss was observed to be greater in the liraglutide and sitagliptin arms (an average of 7lbs and 4lbs, respectively) compared with the insulin glargine and glimepiride arms (<2lbs). Patients in the liraglutide arm were also least likely to experience any cardiovascular disease.

“This study was designed to provide health care providers with important information on how to guide the long-term management of type 2 diabetes,” said Dr Henry Burch, the National Institute of Diabetes and Digestive and Kidney Diseases 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.”


  1. Two popular diabetes drugs outperformed others in large clinical trial. News release. National Institutes of Health. Accessed September 22, 2022. https://www.nih.gov/news-events/news-releases/two-popular-diabetes-drugs-outperformed-others-large-clinical-trial
  2. Nathan DM, Lachin JM, Balasubramanyam A, et al. Glycemia reduction in type 2 diabetes — glycemic outcomes. N Eng J Med. Published online September 22, 2022. doi:10.1056/NEJMoa2200433