The first outcomes trial comparing four of the most commonly used type 2 diabetes agents will be presented at the 81st Scientific Sessions. Results of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study compares the clinical outcomes of glimepiride, sitagliptin, insulin Lantus, and liraglutide in 5,047 type 2 diabetes patients who are also taking metformin.
“We hope to give clinicians a comprehensive, comparative view of which drugs do what and in which people,” said GRADE Principal Investigator David Nathan, MD. “It’s about time that we started to find out how these different drugs act in different populations. Clinicians need to be able to make more informed choices based on glucose-lowering effects, side effects, and effects on complications for that patient who is sitting right there.”
GRADE results will be presented at 4:30 p.m. ET Monday, June 28.
“There is a very small group of statisticians and the data safety monitoring board who have seen the data, but no one else has seen the results,” said Dr. Nathan, Director of the Massachusetts General Hospital Diabetes Center and Clinical Research Center, and Professor of Medicine at Harvard Medical School. “It may turn out that there is no difference between these drugs, or one could be clearly superior. They could have different effects in different populations. We don’t know—yet.”
Dr. Nathan proposed the study in 2008 and recruitment began in 2013 with sponsorship from the National Institute of Diabetes and Digestive and Kidney Diseases. The average follow-up is five years with some patients followed for seven years. A total of 45 U.S. centers participated in the study. Longer-term follow-up has not been funded, Dr. Nathan said.
Patients in the trial had a baseline A1C between 6.8 and 8.5, had been diagnosed within the past five years, were in their mid-50s, and were taking metformin. The study is more representative of the broad U.S. population than many diabetes trials, Dr. Nathan said, with 35% non-Hispanic white representation. Men make up about 65% of the study population.
The primary endpoint of the study is change in A1C level and overall glycemic control. Secondary endpoints include changes in weight, as well as cardiovascular, kidney, gastrointestinal, and other complications, and costs across different age, sex, and racial/ethnic categories.
The four drugs tested were donated by their manufacturers, but industry had no input into study design, conduct, analysis, or evaluation, Dr. Nathan said.
The trial includes sulfonylureas, dipeptidyl peptidase-4 inhibitors, basal insulin, and glucagon-like peptide-1 receptor agonists. It does not include a fifth widely used class of type 2 diabetes agents, sodium-glucose cotransporter-2 (SGLT2) inhibitors.
SGLT2s were not yet approved when the study protocol was developed, Dr. Nathan said. Canagliflozin, the first SGLT2 inhibitor, became available as recruitment was beginning in 2013. Adding a fifth agent would have required a new protocol, a larger study population of about 7,000 patients, a larger budget, and would have delayed study recruitment.
The primary purpose of the study is examining the metabolic effects of the four drugs, Dr. Nathan said, but long-term considerations like side effects, tolerability, weight changes, cholesterol levels, and blood pressure also must be evaluated.
“We want to know, for example, if drug X gives you more diarrhea and drug Y more hypoglycemia, and if you are African American maybe drug Z is better,” he said. “We tend to treat type 2 diabetes as if it’s all the same, and it’s not. It’s about time we started finding out how these different drugs work in different people.”