Skip to main content

Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes.

Publication ,  Journal Article
Bethel, MA; Stevens, SR; Buse, JB; Choi, J; Gustavson, SM; Iqbal, N; Lokhnygina, Y; Mentz, RJ; Patel, RA; Öhman, P; Schernthaner, G; Lecube, A ...
Published in: Circulation
April 28, 2020

BACKGROUND: EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. METHODS: Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. RESULTS: Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 (P=0.061) to 0.85 (P=0.008) and the ACM HR from 0.86 (P=0.016) to 0.81 (P=0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection. CONCLUSIONS: EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01144338.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

April 28, 2020

Volume

141

Issue

17

Start / End Page

1360 / 1370

Location

United States

Related Subject Headings

  • Stroke
  • Risk Factors
  • Risk Assessment
  • Myocardial Infarction
  • Middle Aged
  • Male
  • Hypoglycemic Agents
  • Humans
  • Follow-Up Studies
  • Female
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Bethel, M. A., Stevens, S. R., Buse, J. B., Choi, J., Gustavson, S. M., Iqbal, N., … Holman, R. R. (2020). Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes. Circulation, 141(17), 1360–1370. https://doi.org/10.1161/CIRCULATIONAHA.119.043353
Bethel, M Angelyn, Susanna R. Stevens, John B. Buse, Jasmine Choi, Stephanie M. Gustavson, Nayyar Iqbal, Yuliya Lokhnygina, et al. “Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes.Circulation 141, no. 17 (April 28, 2020): 1360–70. https://doi.org/10.1161/CIRCULATIONAHA.119.043353.
Bethel MA, Stevens SR, Buse JB, Choi J, Gustavson SM, Iqbal N, et al. Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes. Circulation. 2020 Apr 28;141(17):1360–70.
Bethel, M. Angelyn, et al. “Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes.Circulation, vol. 141, no. 17, Apr. 2020, pp. 1360–70. Pubmed, doi:10.1161/CIRCULATIONAHA.119.043353.
Bethel MA, Stevens SR, Buse JB, Choi J, Gustavson SM, Iqbal N, Lokhnygina Y, Mentz RJ, Patel RA, Öhman P, Schernthaner G, Lecube A, Hernandez AF, Holman RR. Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes. Circulation. 2020 Apr 28;141(17):1360–1370.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

April 28, 2020

Volume

141

Issue

17

Start / End Page

1360 / 1370

Location

United States

Related Subject Headings

  • Stroke
  • Risk Factors
  • Risk Assessment
  • Myocardial Infarction
  • Middle Aged
  • Male
  • Hypoglycemic Agents
  • Humans
  • Follow-Up Studies
  • Female