8 Recent Clinical Trials on Diabetes Medication

The understood link between diabetes and cardiovascular disease (CVD) has played a key role in shaping clinical trials on diabetes medications, according to a presentation at the American Society of Health System Pharmacists Midyear Clinical Meeting and Exhibition.

One of the session’s 2 presenters, University of Connecticut School of Pharmacy associate professor William L. Baker, PharmD, began by discussing the association between type 2 diabetes (T2D) and CVD, pointing out that patients with diabetes were 2-4 times more likely to develop CVD than nondiabetic patients. He also pointed to data indicating that 25%-40% of patients with T2D experience heart failure (HF) and that about two-thirds of diabetes-related deaths are attributed to myocardial infraction (MI).

Dr. Baker explained that, in trials investigating diabetes therapies prior to December 2008, HbA1c as a measure of glycemic control was used as a primary efficacy endpoint and CVD was often an exclusion criterion. In 2008, however, after anti-diabetic drugs such as muraglitazar and rosiglitazone were linked to increased risks of CVD or CVD-related death, the FDA updated its Diabetes Guideline Recommendations to require that clinical trials include patients at increased risk for CVD and demonstrate that a drug will not result in an “unacceptable increase” in CVD risk.

Co-presenter Daniel Riche, PharmD, an associate professor at the University of Mississippi School of Pharmacy, then proceeded to highlight several trials on diabetes medications that were conducted in light of these guidelines, including:

1. EXAMINE

The EXAMINE trial looked at alogliptin, a DPP4 inhibitor, in 5380 patients with T2D and acute coronary syndrome (ACS). After a median follow-up period of 18 months, the hazard ratio (HR) of CVD-related death was found to be 0.79 among participants treated with alogliptin and the HR of nonfatal MI in these patients was found to be 1.08.

2. SAVOR-TIMI

The SAVOR-TIMI trial examined saxagliptin, a DPP4 inhibitor, in 16,492 patients with T2D and CVD or CVD risk. After a median follow-up period of 2.1 years, the HR of CVD-related death was found to be 1.03 among participants treated with saxagliptin.

3. TECOS

The TECOS trial investigated sitagliptin, a DPP4 inhibitor, in 14,671 patients with T2D and CVD. After a median follow-up period of 3 years, the HR of CVD-related death was found to be 1.03 among participants treated with sitagliptin, the HR of fatal or nonfatal MI in these patients was found to be 0.95, and the HR of hospitalization for HF in these patients was 1.09.

4. ELIXA

The ELIXA trial investigated lixisenatide, a GLP-1 agonist, in 6068 patients with T2D and high CVD risk. After a median follow-up period of 25 months, the HR of CVD-related death was found to be 0.98 among participants treated with lixisenatide, the HR of fatal or nonfatal MI in these patients was found to be 1.03, and the HR of hospitalization for HF in these patients was 0.96.

5. EXSCEL

The EXSCEL trial investigated exenatide, a GLP-1 agonist, in 14,752 patients with T2D. After a median follow-up period of 25 months, the HR of CVD-related death was found to be 0.88 among participants treated with exenatide, the HR of fatal or nonfatal MI in these patients was found to be 0.97, and the HR of hospitalization for HF in these patients was 0.94.

6. SUSTAIN-6

The SUSTAIN-6 trial investigated semaglutide, a GLP-1 agonist, in 3297 patients with T2D and high CVD risk. After a median follow-up period of 2.1 years, the HR of CVD-related death was found to be 0.98 among participants treated with semaglutide and the HR of nonfatal MI in these patients was found to be 0.74.

7. LEADER

The LEADER trial investigated liraglutide, a GLP-1 agonist, in 9340 patients with T2D and high CVD risk. After a median follow-up period of 3.5 years, the HR of CVD-related death was found to be 0.78 among participants treated with liraglutide and the HR of fatal or nonfatal MI in these patients was found to be 0.86.

Dr. Riche noted that, due in part to the results of the LEADER study, the FDA expanded the indication of liraglutide in August 2017, approving the drug for the reduction of MI, stroke, and CVD-related death risk in adults with T2D and established CVD.

8. EMPA-REG

The EMPA-REG trial investigated empagliflozin, an SGLT antagonist, in 7020 patients with T2D and CVD. After a median follow-up period of 3.1 years, the HR of CVD-related death was found to be 0.62 among participants treated with empagliflozin, the HR of fatal or nonfatal MI in these patients was found to be 0.87, and the HR of hospitalization for HF in these patients was 0.65.

The FDA expanded the indication of empagliflozin in December 2016, Dr. Riche stated, approving the drug for the reduction of CVD-related death risk in adults with T2D. Additionally, guidelines from the American Diabetes Association recommend adding empagliflozin or liraglutide to metformin in patients with uncontrolled T2D and established atherosclerotic CVD.

Reference

Baker W and Riche D. Getting to the Heart of Antidiabetic Safety and Efficacy. Presented at: American Society of Health System Pharmacists Midyear Clinical Meeting and Exhibition. December 4, 2017. Orlando, Florida.