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Relation of Insulin Treatment for Type 2 Diabetes to the Risk of Major Schwartz et al. Cardiovasc Diabetol (2021) 20:125 https://doi.org/10.1186/s12933-021-01311-9 Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Relation of insulin treatment for type 2 diabetes to the risk of major adverse cardiovascular events after acute coronary syndrome: an analysis of the BETonMACE randomized clinical trial Gregory G. Schwartz1* , Stephen J. Nicholls2, Peter P. Toth3,4, Michael Sweeney5, Christopher Halliday5, Jan O. Johansson5, Norman C. W. Wong5, Ewelina Kulikowski5, Kamyar Kalantar‑Zadeh6, Henry N. Ginsberg7 and Kausik K. Ray8 Abstract Background: In stable patients with type 2 diabetes (T2D), insulin treatment is associated with elevated risk for major adverse cardiovascular events (MACE). Patients with acute coronary syndrome (ACS) and T2D are at particularly high risk for recurrent MACE despite evidence‑based therapies. It is uncertain to what extent this risk is further magni‑ fed in patients with recent ACS who are treated with insulin. We examined the relationship of insulin use to risk of MACE and modifcation of that risk by apabetalone, a bromodomain and extra‑terminal (BET) protein inhibitor. Methods: The analysis utilized data from the BETonMACE phase 3 trial that compared apabetalone to placebo in patients with T2D, low HDL cholesterol, andACS. The primary MACE outcome (cardiovascular death, myocardial infarc‑ tion, or stroke) was examined according to insulin treatment and assigned study treatment. Multivariable Cox regres‑ sion was used to determine whether insulin use was independently associated with the risk of MACE. Results: Among 2418 patients followed for median 26.5 months, 829 (34.2%) were treated with insulin. Despite high utilization of evidence‑based treatments including coronary revascularization, intensive statin treatment, and dual antiplatelet therapy, the 3‑year incidence of MACE in the placebo group was elevated among insulin‑treated patients (20.4%) compared to those not‑treated with insulin (12.8%, P 0.0001). Insulin treatment remained strongly associ‑ ated with the risk of MACE (HR 2.10, 95% CI 1.42–3.10, P 0.0002)= after adjustment for demographic, clinical, and treatment variables. Apabetalone had a consistent, favorable= efect on MACE in insulin‑treated and not insulin‑treated patients. Conclusion: Insulin‑treated patients with T2D, low HDL cholesterol, and ACS are at high risk for recurrent MACE despite the use of evidence‑based, contemporary therapies. A strong association of insulin treatment with risk of MACE persists after adjustment for other characteristics associated with MACE. There is unmet need for additional treatments to mitigate this risk. *Correspondence: [email protected] 1 Division of Cardiology, University of Colorado School of Medicine, 1700 N. Wheeling St. (Cardiology 111B), Aurora, CO 80045, USA Full list of author information is available at the end of the article © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Schwartz et al. Cardiovasc Diabetol (2021) 20:125 Page 2 of 8 Trial registration ClinicalTrials.gov NCT02586155, registered October 26, 2015 Keywords: Acute coronary syndrome, Diabetes, Epigenetics, BET proteins Introduction the responsible institutional review board at each par- Patients with acute coronary syndrome (ACS) are at high ticipating site, and each patient gave written, informed risk for additional major adverse cardiovascular events consent. In brief, inclusion criteria were age at least (MACE). Patients with type 2 diabetes comprise approxi- 18 years, ACS within the preceding 7–90 days, low high- mately 30% of those with ACS and experience up to twice density lipoprotein cholesterol (HDL-C) levels, and a the risk of recurrent MACE as those without type 2 dia- diagnosis of type 2 diabetes. Concomitant high-intensity betes [1–3]. statin therapy with atorvastatin 40–80 mg or rosuvas- Chronic insulin treatment is required in approximately tatin 20–40 mg daily was required unless a lower dose 25% of patients with type 2 diabetes to control hyper- was medically indicated. Other concomitant treatments, glycemia [4]. Among patients with type 2 diabetes and including therapies for type 2 diabetes, were assessed at ACS, approximately 35% receive chronic insulin treat- the randomization and subsequent visits. Patients with a ment [5–7]. In patients with type 2 diabetes who have prescription for any insulin product were considered to not had prior MACE or who have stable coronary heart be insulin-treated. Eligible patients were randomized to disease, insulin use is associated with elevated risk of treatment with apabetalone 100 mg twice daily or match- incident or recurrent MACE and death despite use of ing placebo. Te trial continued until a blinded clinical evidence-based cardiovascular therapies [8–11]. How- events committee determined that at least 250 patients ever, the extent to which insulin treatment is associated had experienced the primary MACE outcome (cardiovas- with elevated cardiovascular risk after ACS is uncertain. cular death, non-fatal myocardial infarction or non-fatal Moreover, no diabetes medication has been shown to stroke). Secondary endpoints included hospitalization reduce MACE after ACS. Medications that have shown for heart failure. Adverse and serious adverse events, favorable cardiovascular efects in stable patients have including hypoglycemia, were reported by investigators not been studied after ACS [metformin, sodium–glu- and categorized according to the Medical Dictionary for cose loop transporter-2 (SGLT2) inhibitors] and drugs in Regulatory Activities (MedDRA). other classes that have been studied after ACS failed to show beneft [glucagon-like peptide-1 (GLP-1) receptor Statistical analysis agonists, dipeptidyl peptidase-4 inhibitors] [6, 12]. Tis was a post hoc analysis. Baseline characteristics Bromodomain and extra-terminal (BET) proteins are were summarized as percentages for dichotomous data epigenetic regulators of gene transcription. Apabetalone is and means (SDs) for approximately normal or medians a selective BET protein inhibitor with potentially salutary (IQRs) for non-normal continuous data. Characteristics efects on pathways implicated in infammation, endothelial were compared between patients with diabetes who were dysfunction, thrombosis, and vascular calcifcation [13–15]. or were not treated with insulin during the trial using Tese injurious processes are prognostically important in t-tests or Wilcoxson tests for continuous variables and patients with ACS [16]. Phase 2 clinical data suggested that chi-square tests for categorical variables. apabetalone might have favorable efects on MACE, par- Te cumulative incidence of the primary MACE end- ticularly among those with type 2 diabetes [17]. Accordingly, point was described in each treatment group and insulin the phase 3 BETonMACE trial [7] was designed to com- use subgroup with Kaplan–Meier survival analysis. Cox pare apabetalone with placebo in patients with type 2 dia- proportional hazards models were used to determine betes and recent ACS. Te present analysis used data from treatment hazard ratios (HR) with 95% confdence inter- BETonMACE to determine the association of insulin use val (CI) and interaction of study treatment and insulin with risk of MACE after ACS in a contemporary cohort of treatment on MACE. patients receiving evidence-based background cardiovascu- Cox regression models were used to determine whether lar treatments. In addition, we evaluated the interaction of insulin treatment was an independent predictor of insulin use and apabetalone on that risk. MACE and hospitalization for heart failure in the placebo group. Model 1 was stratifed for country and baseline Methods statin allocation. Model 2 was adjusted for demographic Study design variables (age, sex, race) and other characteristics that Te design and principal results of the BETonMACE trial difered between insulin-treated and not insulin-treated have been described [7, 18]. Te study was approved by patients including duration of diabetes; history of heart Schwartz et al. Cardiovasc Diabetol (2021) 20:125 Page 3 of 8 failure, myocardial infarction, or coronary revasculariza- Computing). P-values less than 0.05 were considered sta- tion procedure prior to the qualifying ACS; statin treat- tistically signifcant. ment intensity, and hemoglobin A1c. Model 3 was also adjusted for the variables in model 2 plus use of met- Results formin, sulfonylureas, sodium–glucose cotransporter-2 Te analysis cohort comprised 2418
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