An NIH study compares four commonly used medications for type 2 diabetes

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 than glimepiride or sitagliptin, according to results of a study funded by the National Institutes of Health (NIH).

Multicenter, randomized, controlled approaches to glycemic control in diabetes: a comparative efficacy study (GRADE) ( Identifier: NCT01794143) to compare the effectiveness of 4 glucose-lowering drugs approved by the Food and Drug Administration (FDA) at the time GRADE was started. The study included 5,047 patients with type 2 diabetes who were already taking metformin Glycated hemoglobin (HbA1c) levels were from 6.8% to 8.5%.

Patients were randomly assigned to receive 1 of 4 treatments with metformin: sitagliptindipeptidyl peptidase 4 inhibitor, liraglutideglucagon-like peptide-1 receptor agonist, glimepiridesulfonylureas, or Insulin glargine U-100. The primary end point was the initial failure time defined as HbA1c greater than or equal to 7.0%.

After a median follow-up of 5 years, the results showed that a 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) than with glimepiride (30.4 per 100 participant-years). – years) and sitagliptin (38.1 per 100 participants – years); The difference between the four treatment arms was found to be significant (s < .001 for a global test for differences across all formats).

No different treatment effects were found based on age, gender, race or ethnicity, although there was greater benefit with insulin glargine, liraglutide and glimepiride in patients with a higher baseline HbA1c, compared with sitagliptin. At the launch of the GRADE study, the sodium-glucose transporter 2 (SGLT2) inhibitors were not approved by the Food and Drug Administration and therefore were not included in the analysis.

“GRADE effectively shows which drugs have worked best in achieving and maintaining blood glucose goals over time, but we need to devise more effective strategies to maintain acceptable glucose levels in the long term,” said Dr. David M. Nathan, GRADE study leader. From 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 manage their glucose long-term.”

Regarding safety, the incidence of hypoglycemia was rare but significantly greater with glimepiride (2.2% of patients) than with insulin glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Gastrointestinal side effects were more common in the liraglutide arm than in the other treatment arms. Weight loss was observed to be greater in the liraglutide and sitagliptin arms (average 7 lbs and 4 lbs, respectively) than in the insulin glargine and glimepiride (<2 lbs) arms. Patients in the liraglutide arm had a lower risk of developing cardiovascular disease.

“This study is designed to provide healthcare providers with important information on how to guide the long-term management of type 2 diabetes,” Dr. Henry Burch, NIDDK project scientist told GRADE. “This is an essential step toward precision medicine for diabetes care, as these findings can now be used in individual patient decision-making given glucose control levels, drug tolerance, and other health considerations.”


  1. Two common diabetes medications outperformed others in large clinical trials. New release. National Institutes of Health. Accessed September 22, 2022.
  2. Nathan DM, Lachin JM, Balasupramaniam A, et al. Low blood sugar in type 2 diabetes – blood sugar results. N Eng J Med. Published online September 22, 2022. doi: 10.1056 / NEJMoa2200433