September 14, 2017 — A global team of researchers reported in the New England Journal of Medicine that the study did not meet its primary efficacy endpoint, but yielded important results for all-cause mortality.
Diabetes is a widespread and increasing problem currently affecting 30.3 million Americans, 4.5 million people living in the United Kingdom, and 422 million people worldwide. In 2015, an estimated 1.6 million deaths worldwide were directly caused by diabetes. There is a clear need to improve health outcomes, particularly for cardiovascular events, which represent the greatest burden in terms of morbidity and mortality.
The EXSCEL trial (EXenatide Study of Cardiovascular Event Lowering) was among the largest ever carried out in type 2 diabetes, setting out to evaluate the safety and efficacy of a once-weekly extended-release formulation of exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist. The drug works by mimicking a hormone in that reduces blood sugar levels after meals but its impact on heart disease is unknown.
Launched in 2009 and completed in April 2017, the EXSCEL trial was a Phase IIIB/IV, double-blind, placebo-controlled, global cardiovascular outcomes trial involving 14,752 patients with type 2 diabetes in 35 countries. Participants – who were eligible with or without additional cardiovascular risk factors or prior cardiovascular events – all received usual type 2 diabetes care and were randomized to receive subcutaneous injections of 2mg exenatide once-weekly, or a matching placebo. The trial compared the risk of major adverse cardiac events (MACE) – a composite endpoint of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke – in the two groups of patients. The median length of follow-up was 3.2 years.
The trial met its primary safety objective of non-inferiority for MACE. The efficacy objective of a superior reduction in MACE did not reach statistical significance, although a prespecified analysis suggested all-cause mortality was lower with exenatide than placebo.
The results were presented today at the European Association for the Study of Diabetes (EASD) annual meeting in Lisbon, Portugal. They were also published simultaneously in the New England Journal of Medicine.
EXSCEL was run jointly by the DCRI and the University of Oxford Diabetes Trials Unit (DTU).
“The study results show that exenatide had no adverse effects on cardiovascular health, meaning that the drug can be used safely in people with type 2 diabetes who may have a wide range of existing cardiovascular conditions,” said the DTU’s Rury R. Holman, who co-led the study. “There did not seem to be any increase in the risk of hypoglycemia, acute pancreatitis, pancreatic cancer, or medullary thyroid carcinoma.”
“It’s encouraging for the field of diabetes to see these results in patients similar to what we see in clinical practice can have a potentially lower risk of death from all causes with the convenience of once-weekly dosing,” said the DCRI’s Adrian F. Hernandez, MD, MHS, Holman’s co-leader on the trial.
“This confirms the importance of carrying out large studies to evaluate impacts on cardiovascular outcomes. EXSCEL largely mirrored what we’ve learned from other studies of this class of medications – that they are safe and may have outcomes benefits.”
In addition to Holman and Hernandez, co-authors on the EXCSEL paper were Angelyn Bethel,MD, from the DTU, and Robert Mentz, MD; Vivian Thompson, MPH; Yuliya Lokhnygina, PhD; and Neha Pagidipati, MD, MPH, from Duke and DCRI.