The EXSCEL study may not have shown that once-weekly exenatide had cardiovascular benefits for patients with diabetes, but did show a benefit in some significant areas.
A post-hoc analysis of the EXSCEL study, presented at the 2020 Virtual Meeting of the European Association for the Study of Diabetes (EASD), found that once-weekly exenatide reduced urine albumin-to-creatinine ratio (UACR) and improved estimated glomerular filtration rate (eGFR) slope in patients with diabetes, specifically in those patients with elevated baseline UACR. The estimated glomerular filtration rate is used to screen for and detect early kidney damage, help diagnose chronic kidney disease, and monitor kidney status. Urine albumin to creatine ratio is used to diagnose and monitor kidney damage in patients with type 1 and type 2 diabetes. The EXSCEL study initially found that exenatide was non-inferior to placebo at preventing adverse cardiac events; however, later studies helped use this study’s information to determine that once-weekly exenatide wasn’t beneficial to the cardiovascular system. Still, it did benefit the estimated glomerular filtration rate slopes in patients with high albuminuria levels.
The EXSCEL trial, an interventional clinical trial, had 14,752 total patients with diabetes and high cardiovascular risk. They were randomly placed into groups receiving 2mg subcutaneous injection once weekly of exenatide or a placebo. The study had a median follow up time of 3.3 years, in which the once-weekly exenatide showed significant improvement in the estimated glomerular filtration rate slope in patients with a baseline urine albumin to creatine ratio greater than 100 milligrams per gram (+0.79 mL/min/1.73/year) and urine albumin to creatine ratio greater than 200 milligrams per gram (+1.32mL/min/year). However, unfortunately, patients who had lower urine albumin to creatine ratio thresholds did not show any improvements in their estimated glomerular filtration rate slope. On the other hand, patients with albuminuria measurements at baseline had a follow-up at 8.9 months, reflecting significant reductions across the urine albumin to creatine subgroups on once-weekly exenatide patients. The analysis assessed 3,503 patients from the study with a baseline urine albumin to creatine ratio and greater than one post-baseline eGFR. 21.2 % of patients with a baseline urine albumin to creatine ratio less than 30 milligrams per gram showed a significant reduction, and 28.2% of patients with a baseline urine albumin to creatine ratio greater than 30 milligrams per gram also showed substantial reduction compared to the placebo groups.
The outcome of exenatide once weekly on the estimated glomerular filtration rate slope, considering other renal risk markers, showed consistency across the baseline estimated glomerular filtration rate, history of cardiovascular disease, use of the renin-angiotensin-aldosterone system inhibitors, and systolic blood pressure. An overall significant benefit was explicitly noticed with non-obese patients. According to Annemarie B. van der Aart, PharmD, University of Groningen, “Exenatide treatment slowed the progression of eGFR decline in participants with higher levels of albuminuria, but not among the participants with lower levels of albuminuria.”
- Exenatide once weekly showed a slow progression of estimated glomerular filtration rate decline in patients with higher levels of albuminuria.
- Exenatide weekly did not benefit patients with a lower level of albuminuria than the placebo group.
- A small but still significant benefit has been noticed in once-weekly exenatide for non-obese patients.
- Exenatide does not improve the risks of major adverse cardiovascular events such as myocardial infarction, stroke, heart failure, or hospitalization for the acute coronary syndrome.
Berrie, Chris. “Effect of Once-Weekly Exenatide on EGFR Slope Depends on Baseline Renal Risk.“ NTK Institute, September 28, 2020, ntk-institute.org/node/167978/?overlay=2.
Holman, Rury R., et al. “Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes: NEJM.“ New England Journal of Medicine, December 21. 2017, www.nejm.org/doi/full/10.1056/NEJMoa1612917.
“Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL): A Trial To Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly In Patients With Type 2 Diabetes Mellitus – Full–Text View.“ Full Text View – ClinicalTrials.gov, 2010, www.clinicaltrials.gov/ct2/show/NCT01144338.
A‘Kira Shavers, PharmD Candidate, South College School of Pharmacy