In the largest head-to-head comparison of type 2 diabetes medications to date, researchers have found that insulin glargine and liraglutide demonstrated superior performance when added to metformin therapy. The findings from the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness) study, published in The New England Journal of Medicine, provide crucial evidence for clinicians treating the 37 million Americans with diabetes.
Study Design and Participants
The GRADE study enrolled 5,047 people with type 2 diabetes who were already taking metformin, representing the first large-scale trial to directly compare four commonly prescribed diabetes medications. Participants were randomly assigned to receive one of four treatments alongside metformin: insulin glargine, liraglutide, glimepiride, or sitagliptin.
The study population was notably diverse, with almost two-thirds of participants being white, one-fifth Black, and almost one-fifth identifying as Hispanic or Latinx. "This multicultural patient base helps bring a better understanding of how different groups in our communities can be served," said Dr. Ilan Shapiro, chief health correspondent and medical affairs officer at AltaMed Health Services in Los Angeles.
Primary Efficacy Results
Over an average follow-up period of five years, participants taking liraglutide or insulin glargine achieved and maintained their target blood glucose levels for the longest duration. Insulin glargine emerged as the most effective treatment for maintaining target blood glucose levels, while sitagliptin proved least effective.
The superior performance of these two medications translated into approximately six months more time with blood glucose levels in the target range compared to sitagliptin. "The GRADE study is the first to compare the efficacy of four drugs commonly used to treat type 2 diabetes when added to metformin in people with short-duration diabetes," said Dr. Elizabeth Seaquist, Department of Medicine Chair at the University of Minnesota Medical School.
Importantly, treatment effects did not differ based on age, sex, race, or ethnicity. However, people who started the study with higher blood glucose levels experienced "progressively worse metabolic outcomes" with sitagliptin compared to other treatments.
Cardiovascular and Safety Outcomes
Beyond glucose control, the study revealed additional benefits for liraglutide users, who demonstrated a lower risk of developing diabetes-related cardiovascular disease compared to those taking other medications.
The safety profile varied among treatments. Severe hypoglycemia was uncommon overall but occurred more frequently in people taking glimepiride. Gastrointestinal side effects were more common with liraglutide compared to other medications. Weight loss patterns also differed, with liraglutide users losing an average of 7.7 pounds and sitagliptin users losing 4.4 pounds, while those taking glargine or glimepiride lost less than 2 pounds.
Clinical Challenges Remain
Despite the comparative effectiveness demonstrated by all four medications, the study highlighted persistent challenges in diabetes management. Nearly three-quarters of participants were unable to maintain their blood glucose levels within the recommended range over the five-year follow-up period.
"The overall results of the current trial highlight the difficulty in achieving and maintaining recommended [blood glucose] levels in participants with type 2 diabetes," the researchers noted, "even in a clinical trial in which all care [including medications] is provided free of charge."
Implications for Clinical Practice
The GRADE study results provide evidence-based guidance for the approximately 90% to 95% of Americans with diabetes who have type 2 diabetes. "For a long time we had the 'gold standard' of metformin and insulin," said Shapiro. "Now we are moving forward with a better understanding of how to help our patients with the current medications."
The research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, with additional backing from multiple NIH institutes and the American Diabetes Association. The study's comprehensive design and diverse participant population make it a landmark contribution to diabetes treatment optimization.
