Perspectives on Diabetes Care

High-Dose Weekly GLP-1 RAs: An Exciting Option for Diabetes and Obesity Management

May 24, 2021, 13:37 PM

By John Bucheit, PharmD, BCACP, CDCES  

Over 34 million people in the United States are estimated to have diabetes and approximately 88 million more have prediabetes. An alarming 89% of those with diabetes also exhibit a BMI ≥ 25 kg/m² .Obesity is a major risk factor for cardiovascular disease, but comorbid diabetes and obesity further amplifies the risk for atherosclerotic cardiovascular disease.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are effective diabetes agents because they reduce cardiovascular events, improve glycemic management and promote weight loss. Fortunately, two agents in the GLP-1 RA class (dulaglutide and semaglutide) have new data evaluating higher dose options than originally approved by the Food and Drug Administration (FDA). While high-dose liraglutide is already approved for weight loss, dulaglutide and semaglutide offer potentially new dosing strategies to further help individuals lose weight.

The originally approved doses for dulaglutide are 0.75 mg and 1.5 mg. The 1.5 mg dose of dulaglutide is also indicated for cardiovascular disease reduction in people with diabetes based on the REWIND Trial. The AWARD-11 trial later compared HbA1c lowering and weight loss effects of dulaglutide 1.5 mg, 3 mg and 4.5 mg. Treatment differences in weight and HbA1c for the 1.5 mg and 4.5 mg treatment arms were -3.52 lb. and -0.24%, respectively in favor of the high-dose arm at 36 weeks. Gastrointestinal adverse effects were approximately 15% across treatment arms, but overall discontinuation rates were < 10% in all the treatment arms. High-dose dulaglutide is now FDA approved and it appears most beneficial at providing additional weight loss with smaller changes to HbA1c.

STEP Trials Show Positive Results

Recently published data from the STEP trials highlights a potentially exciting option for patients with diabetes AND prediabetes. In these studies, semaglutide was titrated to a dose of 2.4 mg in patients with a BMI ≥ 27 kg/ m² and compared to a lifestyle intervention. Interestingly, diabetes was not a required inclusion criteria in all of the STEP trials. In fact, no one in the STEP 1 trial had diabetes, but approximately 44% reported prediabetes at baseline. At the end of 68 weeks, the estimated treatment difference in weight loss between semaglutide and placebo was 12.7 kg for entire study population. That’s about 28 pounds! Additionally, 84% of the participants with prediabetes normalized their HbA1c!

The STEP 2 trial evaluated semaglutide 2.4 mg in those with type 2 diabetes. The weight loss noted was less, but the estimated treatment difference between semaglutide 2.4 mg and placebo (lifestyle changes) was 6.21 kg or 13.7 lb. Similar to dulaglutide, an additional 0.2% reduction in HbA1c was noted with semaglutide 2.4 mg compared to the currently approved dose of 1.0 mg in STEP 2. Not all patients were able to tolerate the highest doses of semaglutide, but discontinuation rates were below 7% illustrating an excellent safety profile.

Diabetes care and education specialists should consider maximum tolerated doses of GLP-1 RAs to improve the cardiometabolic health of the people they care for with diabetes. Once approved by the FDA, semaglutide should also be considered for treatment of obesity in those with or without diabetes. Because of the dramatic weight loss and the favorable safety profile, once weekly high-dose GLP-1 RAs (dulaglutide and semaglutide) present a new and exciting option for diabetes and weight management. For more on GLP-1 RAs, visit DiabetesEducator.org/GLP1. For more on obseity and weight management, visit DiabetesEducator.org/Obesity.