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Effect of CETP Inhibition with Evacetrapib in Patients with Diabetes Mellitus Enrolled in the ACCELERATE Trial

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Effect of CETP Inhibition with Evacetrapib in Patients with Diabetes Mellitus Enrolled in the ACCELERATE Trial Cardiovascular and Metabolic Risk BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2019-000943 on 15 March 2020. Downloaded from Open access Original research Effect of CETP inhibition with evacetrapib in patients with diabetes mellitus enrolled in the ACCELERATE trial Venu Menon ,1 Anirudh Kumar ,1 Divyang R Patel,1 Julie St John,1 Jeffrey Riesmeyer,2 Govinda Weerakkody,2 Giacomo Ruotolo,2 Kathy E Wolski,1 Ellen McErlean,1 Paul C Cremer,1 Stephen J Nicholls,3 A Michael Lincoff,1 Steven E Nissen1 To cite: Menon V, Kumar A, ABSTRACT Patel DR, et al. Effect of CETP Background High- density lipoprotein (HDL) levels are Significance of this study inhibition with evacetrapib in inversely associated with cardiovascular risk. Cholesteryl patients with diabetes mellitus ester transfer protein inhibition with evacetrapib results What is already known about this subject? enrolled in the ACCELERATE in a marked increase in HDL and reduction in low- density ► Despite contemporary optimal medical therapy, pa- trial. BMJ Open Diab Res Care lipoprotein (LDL) levels. We evaluated the impact of tients with diabetes remain at elevated risk for car- 2020;8:e000943. doi:10.1136/ diovascular events compared with their counterparts bmjdrc-2019-000943 treatment with evacetrapib versus placebo in the subset of 8236 patients with diabetes mellitus (DM) enrolled in the without diabetes. As such, they are important targets Assessment of Clinical Effects of Cholesteryl Ester Transfer for novel agents which may mitigate cardiovascular ► Additional material is Protein Inhibition with Evacetrapib in Patients at a High risk. published online only. To view Risk for Vascular Outcomes trial. What are the new findings? please visit the journal online Methods and results Time to first occurrence of ► Among patients with diabetes, use of evacetrapib (http:// dx. doi. org/ 10. 1136/ any component of the primary composite endpoint of bmjdrc- 2019- 000943). resulted in significant and sustained improvements cardiovascular death, myocardial infarction, stroke, in low-density lipoprotein, high-density lipoprotein revascularization, and hospitalization for unstable angina (HDL), and hemoglobin A1c. Received 1 October 2019 was compared among patients with DM randomized ► Despite this, there were no benefits of treatment to treatment with evacetrapib (n=4127) or placebo Revised 23 January 2020 with evacetrapib on prespecified clinical outcomes Accepted 31 January 2020 (n=4109) over a median of 26 months of follow-up. The in this high-risk population. mean baseline LDL at initiation was 80 mg/dL with a mean baseline HDL of 44 mg/dL. In patients with DM, How might these results change the focus of http://drc.bmj.com/ evacetrapib resulted in a 131% mean increase in HDL research or clinical practice? levels and a 32% mean decrease in LDL at 3 months ► Why do patients with diabetes remain at elevat- that was sustained during the course of the trial. At 6 ed risk for cardiovascular events despite optimal, months, hemoglobin A1c (HbA1c) levels were lower with guideline-recommended medical therapy? evacetrapib than placebo (7.08% vs 7.15%, p=0.023). ► Why did cholesteryl ester transfer protein inhibition Composite event rates were higher in patients with DM fail to reduce cardiovascular events among patients on September 28, 2021 by guest. Protected copyright. than without DM (Kaplan-Meier estimates: 15.2% vs with diabetes? © Author(s) (or their 10.6%, HR 1.46, 95% CI 1.30 to 1.64, p<0.001). In the employer(s)) 2020. Re- use ► Is there another therapeutic mechanism by which DM group, event rates for the composite endpoint (14.5% increasing HDL can translate into improved cardio- permitted under CC BY-NC. No evacetrapib vs 16% placebo, HR 0.95, 95% CI 0.85 to vascular outcomes? commercial re- use. See rights 1.07, p=0.38) and individual components of the composite and permissions. Published by BMJ. were similar for both evacetrapib and placebo groups. No significant treatment interaction between treatment 1Heart and Vascular Institute, assignment and diabetes status was noted. Cleveland Clinic Foundation, Cleveland, Ohio, USA Conclusion Despite a favorable increase in HDL, and 2Eli Lilly and Company, decreases in LDL and HbA1c levels in patients with DM, Indianapolis, Indiana, USA we observed no benefits of treatment with evacetrapib on affected by type 2 diabetes mellitus (DM).1 3 prespecified clinical outcomes in this high-risk population. Monash Cardiovascular Worldwide, over 400 million adults are Research Centre, Monash University, Melbourne, Victoria, currently affected with DM and this number Australia INTRODUCTION is expected to increase to 642 million by 2040. A new diagnosis of DM in the fifth decade Correspondence to Urbanization, rising living standards and Dr Venu Menon; increased rates of obesity have all contrib- is associated with 5–6 years of reduction in menonv@ ccf. org uted to a marked increase in the population longevity in both men and women, mainly BMJ Open Diab Res Care 2020;8:e000943. doi:10.1136/bmjdrc-2019-000943 1 BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2019-000943 on 15 March 2020. Downloaded from Cardiovascular and Metabolic Risk as a consequence of complications from cardiovascular endpoints committee blinded to treatment assignment disease.2 using prespecified standardized definitions. Epidemiological studies have suggested a strong inverse relationship between high-density lipoprotein (HDL) Statistical methods cholesterol levels and observed cardiovascular risk.3–6 A All randomized patients were included in this prespeci- cardioprotective benefit of elevated HDL levels has also fied analysis on an intention- to- treat basis. Patients with been suggested in some, but not all, genetic studies.7–10 DM were defined as those receiving treatment with an Diabetic dyslipidemia is characterized by a high preva- oral or parenteral antiglycemic agent and/or insulin or lence of low HDL levels, elevated triglycerides, increased being managed by diet alone as a result of a pre-existing lipoprotein(a), and dense low-density lipoprotein (LDL) diagnosis of DM. A new diagnosis of DM was based levels.11 While patients with DM benefit greatly from on fasting plasma glucose measurements ≥126 mg/ intense statin therapy, these agents have a minor impact dL, 2-hour plasma glucose ≥200 mg/dL during an oral on observed HDL levels.12 glucose tolerance test, or hemoglobin A1c (HbA1c) level Evacetrapib, a potent cholesteryl ester transfer protein ≥6.5%. Baseline clinical characteristics in patients with (CETP) inhibitor, when added to a high- dose statin, has and without DM were compared. Treatment groups were been shown to increase HDL levels by approximately compared on major side effects in patients with DM as 130%, lower LDL levels by 30%–35%, and decrease levels well as on the incidence of those with new-onset diabetes. of lipoprotein(a).13 These biochemical actions mediated Continuous variables were compared between groups via inhibiting the transfer of cholesterol ester from HDL using Student’s t-test for normally distributed variables or to apolipoprotein B (ApoB) containing lipoproteins were Wilcoxon rank- sum test for non-normally distributed vari- expected to translate into favorable clinical outcomes ables. Mean±SD or median with IQR are reported respec- in high-risk cardiovascular patients. However, no bene- tively. Categorical variables were compared between fits were noted in the Assessment of Clinical Effects of groups using Pearson χ2 or Fisher’s exact test. Frequency Cholesteryl Ester Transfer Protein Inhibition with Evace- and percent are reported. trapib in Patients at a High Risk for Vascular Outcomes The primary composite endpoint was defined as the (ACCELERATE) trial.14 In this manuscript, we detail the time to first occurrence of cardiovascular death, myocar- lipid modification and clinical impact of treatment with dial infarction, stroke, hospitalization for unstable evacetrapib compared with placebo in the large subset of angina, or coronary revascularization. Additionally, a trial participants with DM enrolled in this clinical trial. triple composite endpoint of time to first occurrence of cardiovascular death, myocardial infarction, or stroke was also included. Survival analysis was performed to METHODS assess the incidence of primary composite and individual Study design endpoints within and across DM and treatment group The design, conduct and outcomes of the overall combinations. Kaplan- Meier (KM) estimates of event results of the ACCELERATE trial have been previously rates are reported and compared between groups using published.14 15 Briefly, this international, multicenter trial a log- rank test. Cox proportional hazards modeling was http://drc.bmj.com/ prospectively randomized 12 092 subjects with a prior used to compare evacetrapib to placebo within DM and acute coronary syndrome, stroke, symptomatic periph- non- DM patients as well as test the treatment by DM inter- eral vascular disease, or diabetes with established coro- action for each endpoint. HRs with 95% CIs are reported. nary artery disease to treatment with evacetrapib 130 mg KM curves illustrate the incidence of the primary and daily or placebo. Nearly all study participants with the triple composite endpoints over time. The clinical exception of those intolerant to statin (96.5%) were endpoints were truncated at 915 days (30 months) due on September 28, 2021 by guest. Protected copyright. treated with these agents at trial onset. The primary effi- to study termination. Changes in HDL, LDL, and HbA1c cacy endpoint was the first occurrence of any component were assessed over time within treatment and DM groups of the composite of cardiovascular death, myocardial using mixed modeling with repeated measures while infarction, stroke, revascularization, and hospitaliza- adjusting for respective baseline measures. Least squares tion for unstable angina. Due to clinical futility for the (LS) means with SE bars are plotted over time. Tests primary composite endpoint, the trial was terminated were two tailed with a 0.05 significance level. Analysis was prematurely. The median exposure to study drug/ performed using SAS V.9.4 (SAS Institute).
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