EXSCEL Contributes to New Discoveries via Secondary Manuscripts

January 15, 2020 – The EXSCEL trial, which explored the impact of exenatide on major cardiovascular events in patients with Type 2 diabetes, has also published nearly a dozen secondary manuscripts on a range of topics.

The study team on the EXSCEL trial, which was co-led by the DCRI and Oxford University’s Diabetes Trial Unit (DTU), continues to draw insights and share knowledge through impactful secondary manuscripts nearly three years after the conclusion of the trial.

EXSCEL logoEXSCEL, which was sponsored by Amylin Pharmaceuticals, a subsidiary of AstraZeneca, was a global trial run over the course of eight years. The study assessed whether patients with Type 2 diabetes who were given once-weekly exenatide experienced fewer major adverse cardiovascular events than those on placebo. Although the results from the exenatide group did not meet statistical significance for superiority in reducing cardiovascular events as compared to placebo, a prespecified analysis suggested that all-cause mortality was lower for patients taking exenatide. Primary results from the trial were published in 2017 in the New England Journal of Medicine.

Since then, data from EXSCEL have been leveraged to publish 11 secondary manuscripts. In the fall and winter of 2019 alone, members of the DCRI contributed to six EXSCEL publications in topics ranging from heart failure to medical costs.

“Initial results from EXSCEL answered an important question about the safety and efficacy of treating patients with Type 2 diabetes with once-weekly exenatide,” said the DCRI’s Adrian Hernandez, MD, MHS, who served as a co-principal investigator of EXSCEL. “We are also pleased to see how many additional questions this dataset has been able to answer via a robust set of secondary manuscripts. Because of the work of these investigators, EXSCEL has had an even broader impact on patient care.”

Read below to see a sampling of recently published studies that used EXSCEL data to answer research questions.

How Are Patients with Heart Failure Affected by Exenatide?

A DCRI-led group of researchers examined EXSCEL data to determine the associations of once-weekly exenatide with secondary endpoints in patients with and without heart failure. The researchers were also interested in determining associations with recurrent hospitalization for heart failure.

Although exenatide was safe for both patients with and without baseline heart failure, there was evidence that those who did have heart failure saw less benefit from the treatment. Patients without heart failure were more likely to see a decrease in rates of all-cause death and hospitalization for heart failure as compared to those with baseline heart failure.

Adrian Hernandez, MD, MHSThe results were published online in Circulation in September 2019. Former DCRI fellow Marat Fudim, MD, served as the lead author, with the DCRI’s Robert Mentz, MD, as the senior investigator. Additional DCRI faculty contributors included Neha Pagidipati, MD, MPH; Renato Lopes, MD, PhD; Yuliya Lokhnygina, PhD; and Hernandez. Jennifer White, MS provided staff statistical support for this publication.

How Do Different Classes of Diabetes Medications Interact and Affect Cardiovascular Outcomes?

Hernandez (pictured left) and Mentz worked with researchers from other institutions and with representatives of the study’s sponsor to study the 8.7 percent of participants who also received an SGLT2 inhibitor either with or shortly after their assigned treatment of exenatide or placebo. A post-hoc analysis suggested that combining SGLT2 inhibitor therapy with exenatide may benefit cardiovascular outcomes and mortality.

The findings were published in October 2019 in Cardiovascular Diabetology.

How Does Exenatide Affect Patients with Peripheral Artery Disease?

Researchers also analyzed EXSCEL data to take a closer look at peripheral artery disease (PAD). The investigators were interested in determining the association between baseline PAD at the trial’s outset with rates of subsequent major adverse cardiovascular events and lower extremity amputation. They also assessed the effects of exenatide in patients both with and without PAD.

The results showed that trial participants with PAD had higher rates of all-cause mortality and amputation than participants without PAD. However, patients treated with exenatide or placebo had similar rates of major adverse cardiovascular events and lower extremity amputation, regardless of whether they had PAD.

Duke’s Anish Badjatiya, MD, served as lead author on this paper, which was published in Circulation: Cardiovascular Interventions in November 2019. The DCRI’s Schuyler Jones, MD, was senior investigator. Other DCRI contributors to this paper included Pagidipati; Manesh Patel, MD; Hernandez; and Mentz.

How Does Exenatide Affect Outcomes In Patients of Differing Renal Function?

Investigators on this study evaluated the microvascular and cardiovascular outcomes of trial participants after separating them into groups based on their baseline renal function. Results showed that exenatide had no impact on unadjusted retinopathy or renal outcomes.

Angelyn Bethel, MD, previously at the DTU and now at Eli Lilly and Company, served as the lead author for this paper, which was published in Diabetes Care in November 2019. DCRI faculty contributors included Mentz, Lopes, Hernandez, and Lokhnygina. Peter Merrill, PhD, provided staff statistical support for this publication.

Does Exenatide Help Alleviate Health Care Costs?

A study led by the DCRI’s Shelby Reed, PhD, followed patients enrolled in the EXSCEL trial for an average of 3.3 years to analyze medical resource use and costs for each arm of the trial.

Overall medical costs, including diabetes medications other than the study drug, exenatide, were lower in the group receiving exenatide. However, when the cost of branded exenatide was factored in, the total costs were lower in the placebo arm.

Other DCRI contributors to this study included Mentz, Pagidipati, and Hernandez. The paper was published in Diabetes Care in December 2019.

Is There A Relationship Between Severe Hypoglycemic Events and Cardiovascular Events?

A study sought to determine whether there was a bidirectional association between severe hypoglycemic events and cardiovascular events, and to characterize individuals who are at risk for both.Robert Mentz, MD

Although severe hypoglycemic events were uncommon in the EXSCEL trial, fully adjusted models showed that these events were associated with an increased risk of all-cause mortality, cardiovascular death, and hospitalization for heart failure. Certain cardiovascular events, such as heart attack, stroke, and hospitalization for acute coronary syndrome or heart failure, were also associated with an increased risk of subsequent severe hypoglycemic events. These results confirm the bidirectional nature of the two adverse outcomes in patients with high comorbidity scores.

Eberhard Standl, PhD, of the Munich Diabetes Research Group e.V. at Helmholtz Centre, served as the lead author for the paper, which was published in Diabetes Care in December 2019. The DCRI’s Mentz and Hernandez also contributed to the study.

“EXSCEL has been a fascinating project to work on over the years as we continued to learn new insights and worked with colleagues around the world on new secondary manuscripts,” Mentz (pictured right) said. “Not only is this a great example of the ways in which DCRI shares knowledge, but the study has also provided exciting breakthroughs in the cardio-metabolic space as we care for patients with an increasingly wide spectrum of comorbidities.”