Authors’ Reply to “Comment on Generalizability of GLP-1 RA CVOTs in US T2D Population”

April 8, 2019
Eric T. Wittbrodt, PharmD, MPH

James M. Eudicone, MS, MBA

Kelly F. Bell, PharmD, MSPhr

Devin M. Enhoffer, PharmD

Keith Latham, PharmD

Jennifer B. Green, MD

Volume 25, Issue 4

The authors of the manuscript “Generalizability of Glucagon-Like Peptide-1 Receptor Agonist Cardiovascular Outcome Trials Enrollment Criteria to the US Type 2 Diabetes Population” respond to a letter to the editor.

Am J Manag Care. 2019;25(4):171-172We acknowledge the letter to the editor1 regarding our published analysis of the enrollment criteria for the 7 glucagon-like peptide-1 receptor agonist (GLP-1 RA) cardiovascular outcomes trials (CVOTs) and their generalizability to a well-established, representative, real-world subsample of US individuals (National Health and Nutrition Examination Survey [NHANES]) with type 2 diabetes (T2D).2 The author specifically addresses our analysis of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial criteria and correctly states that the study protocol was amended partway through the trial to enroll approximately 70% of patients with a prior cardiovascular (CV) event at baseline. CV events were defined as a “history of major clinical manifestation of coronary artery disease, ischemic cerebrovascular disease, or atherosclerotic peripheral arterial disease.”3 Coronary artery disease was defined as a prior myocardial infarction, coronary revascularization, or angiographic evidence of 50% or greater stenosis of a major coronary vessel. Ischemic cerebrovascular disease required either history of ischemic stroke or evidence of carotid artery stenosis. Baseline characteristics from EXSCEL reveal that 73% of participants had a prior CV event at randomization. Ultimately, until the 70% threshold with established cardiovascular disease (CVD) was reached, the protocol states that “patients with any level of CV risk and meeting all other inclusion criteria may be enrolled” into EXSCEL. The broad CV risk eligibility criteria for EXSCEL were reported in a recent meta-analysis of GLP-1 RA CVOTs,4 and EXSCEL also enrolled the smallest proportion of patients with chronic kidney disease (CKD) at baseline.5 Of note, EXSCEL enrolled adults 18 years and older and 60% were younger than 65 years, whereas the other CVOTs had a minimum age of 30 (ELIXA), 40 (FREEDOM, HARMONY), or 50 (LEADER, REWIND, SUSTAIN-6) years and all with either established CVD or CKD, or at least 1 or 2 CV risk factors depending on age. The mean age of 63 years in EXSCEL was the lowest of all CVOTs reported to date, and the mean glycated hemoglobin at enrollment was 8.0%, lower than in all CVOTs other than REWIND. The pragmatic design of EXSCEL was more reflective of real-world practice compared with the other CVOTs.6 These important differences, when evaluated in totality, served to illustrate the broad clinical profile of the EXSCEL trial population extending beyond those of the other CVOTs. For the individual patients enrolled in each trial, the prespecified eligibility criteria for all CVOTs were used for the NHANES analysis and remain an accurate reflection of the intended population. We did not have access to the study population baseline characteristics for all CVOTs at the time of the analysis and, therefore, did not have the option of pursuing that more robust approach. Also, confining the analysis to the eligible trial populations allowed the results to be interpreted in terms of what the study objectives set out to achieve—namely, to identify the intended population most suited to benefit from the intervention. We acknowledge that assessment of the trial population baseline characteristics is an important step in evaluating CVOTs. However, combining analyses of eligibility criteria and trial population characteristics, as the letter author has done, only serves to confuse the reader and cloud the interpretation of the results in terms of their applicability to the general T2D population.Author Affiliations: AstraZeneca (ETW, JME, KFB, KL), Wilmington, DE; Rutgers University (DME), Piscataway, NJ; Division of Endocrinology, Duke University Medical Center (JBG), Durham, NC.

Source of Funding: None; the original study was funded by AstraZeneca.

Author Disclosures: Drs Wittbrodt, Eudicone, and Latham report employment with AstraZeneca, which has products in the class of drugs studied in the manuscript. Dr Bell reports employment with GlaxoSmithKline (GSK). Dr Latham reports stock ownership in Amgen and AstraZeneca. Dr Green reports consultancies or paid advisory boards for AstraZeneca, Boehringer Ingelheim (BI), Novo Nordisk, Regeneron, and Sanofi; grants pending from BI and Lilly; and grants received from BI, GSK, and Sanofi. The remaining author reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (ETW, JME, KFB, DME, KL, JBG); acquisition of data (JME, DME); analysis and interpretation of data (ETW, JME, KFB, DME, JBG); drafting of the manuscript (ETW, DME, KL, JBG); critical revision of the manuscript for important intellectual content (ETW, JME, KFE, DME, JBG); statistical analysis (JME); administrative, technical, or logistic support (KL); and supervision (ETW).

Address Correspondence to: Eric T. Wittbrodt, PharmD, MPH, AstraZeneca, 1800 Concord Pike, Wilmington, DE 19803. Email:

1. Lage MJ. Comment on generalizability of GLP-1 RA CVOTs in US T2D population. Am J Manag Care. 2019;25(4):170-171.

2. Wittbrodt ET, Eudicone JM, Bell KF, Enhoffer DM, Latham K, Green JB. Generalizability of glucagon-like peptide-1 receptor agonist cardiovascular outcome trials enrollment criteria to the US type 2 diabetes population. Am J Manag Care. 2018;24(suppl 8):S146-S155.

3. Holman RR, Bethel MA, Mentz RJ, et al; EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228-1239. doi: 10.1056/NEJMoa1612917.

4. Bethel MA, Patel RA, Merrill P, et al; EXSCEL Study Group. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6(2):105-113. doi: 10.1016/S2213-8587(17)30412-6.

5. Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose co-transporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus: a systematic review and meta-analysis of cardiovascular outcomes trials [published online February 21, 2019]. Circulation. doi: 10.1161/CIRCULATIONAHA.118.038868.

6. Al Yami MS, Alfayez OM, Alsheikh R. Update in cardiovascular safety of glucagon like peptide-1 receptor agonists in patients with type 2 diabetes: a mixed treatment comparison meta-analysis of randomised controlled trials. Heart Lung Circ. 2018;27(11):1301-1309. doi: 10.1016/j.hlc.2018.03.018.