Transitioning to active-controlled trials to evaluate cardiovascular safety and efficacy of medications for type 2 diabetes.

Cardiovascular (CV) outcome trials (CVOTs) of type 2 diabetes mellitus (T2DM) therapies have mostly used randomized comparison with placebo to demonstrate non-inferiority to establish that the investigational drug does not increase CV risk. Recently, several glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter 2 inhibitors (SGLT-2i) demonstrated reduced CV risk. Consequently, future T2DM therapy trials could face new ethical and clinical challenges if CVOTs continue with the traditional, placebo-controlled design.

Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial.

Background: We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist tirzepatide versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications.

Methods: This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on five continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA) of 7·5-10·5% (58-91 mmol/mol), body-mass index of 25 kg/m or greater, and established cardiovascular disease or a high risk of cardiovascular events.

The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes.

Aim: To better understand the marked decrease in serum triglycerides observed with tirzepatide in patients with type 2 diabetes, additional lipoprotein-related biomarkers were measured post hoc in available samples from the same study.

Materials And Methods: Patients were randomized to receive once-weekly subcutaneous tirzepatide (1, 5, 10 or 15 mg), dulaglutide (1.5 mg) or placebo.

Effect of C-Reactive Protein on Lipoprotein(a)-Associated Cardiovascular Risk in Optimally Treated Patients With High-Risk Vascular Disease: A Prespecified Secondary Analysis of the ACCELERATE Trial.

Importance: Although lipoprotein(a) (Lp[a]) is a causal genetic risk factor for atherosclerotic cardiovascular disease, it remains unclear which patients with established atherosclerotic cardiovascular disease stand to benefit the most from Lp(a) lowering. Whether inflammation can modulate Lp(a)-associated cardiovascular (CV) risk during secondary prevention is unknown.

Objective: To examine whether Lp(a)-associated CV risk is modulated by systemic inflammation in optimally treated patients at high risk of CV disease.

Designing, Conducting, Monitoring, and Analyzing Data from Pragmatic Randomized Clinical Trials: Proceedings from a Multi-stakeholder Think Tank Meeting.

In late 2018, the Food and Drug Administration (FDA) outlined a framework for evaluating the possible use of real-world evidence (RWE) to support regulatory decision-making. This framework was created to facilitate studies that would generate high-quality RWE, including pragmatic clinical trials (PCTs), which are randomized trials designed to inform clinical or policy decisions by assessing the real-world effectiveness of an intervention. There is general agreement among experts that the use of existing healthcare and patient-generated data holds promise for making randomized trials more efficient, less costly, and more generalizable.

Effect of CETP inhibition with evacetrapib in patients with diabetes mellitus enrolled in the ACCELERATE trial.

Background: High-density lipoprotein (HDL) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition with evacetrapib results in a marked increase in HDL and reduction in low-density lipoprotein (LDL) levels. We evaluated the impact of treatment with evacetrapib versus placebo in the subset of 8236 patients with diabetes mellitus (DM) enrolled in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes trial.

Impact of Regulatory Guidance on Evaluating Cardiovascular Risk of New Glucose-Lowering Therapies to Treat Type 2 Diabetes Mellitus: Lessons Learned and Future Directions.

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes.

Genome-Wide Polygenic Score and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease: A Nested Case-Control Study.

Genome-wide polygenic scores (GPSs) integrate information from many common DNA variants into a single measure of inherited susceptibility, and can identify individuals who are at substantially elevated risk of developing important common diseases. For coronary artery disease, about 8% of the population can be identified who are at triple the normal risk based on genetic variation alone. Among these high polygenic score individuals, adherence to a healthy lifestyle or use of statins may offset increased inherited risk.

Impact of Baseline Glycemic Control on Residual Cardiovascular Risk in Patients With Diabetes Mellitus and High-Risk Vascular Disease Treated With Statin Therapy.

Background The contemporary impact of glycemic control on patients with diabetes mellitus at high cardiovascular risk remains unclear. We evaluated the utility of hemoglobin A1c (HbA1c) as a marker of risk on the composite end point of cardiovascular death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization in an optimally treated population with diabetes mellitus and established coronary artery disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods and Results We included all patients with established diabetes mellitus and measured HbA1c (N=8145) and estimated Kaplan-Meier (KM) events rates, stratified by increasing baseline HbA1c levels censored at 30 months.

Plasma Aldosterone Levels Are Not Associated With Cardiovascular Events Among Patients With High-Risk Vascular Disease: Insights From the ACCELERATE Trial.

Background The failure of cholesteryl ester transfer protein inhibitor torcetrapib was associated with an off-target increase in plasma aldosterone. We sought to evaluate the impact of evacetrapib on plasma aldosterone level and determine the association between plasma aldosterone level and major adverse cardiovascular events among patients with stable high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods and Results We included all patients with a plasma aldosterone level (N=1624) and determined the impact of evacetrapib exposure compared with placebo on plasma aldosterone levels after 12 months of treatment.

Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.

Background: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A (HbA) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control.

Methods: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries.

Baseline fasting plasma insulin levels predict risk for major adverse cardiovascular events among patients with diabetes and high-risk vascular disease: Insights from the ACCELERATE trial.

Background: Despite optimal treatment, type II diabetes mellitus remains associated with an increased risk for future cardiovascular events. We sought to determine the association between baseline fasting plasma insulin levels and major adverse cardiovascular outcomes in patients with type II diabetes mellitus and high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial.

Methods: We included all patients with type II diabetes mellitus who had a central laboratory measured fasting plasma insulin level drawn at baseline as part of the study protocol.

ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease: A Nested Case-Control Study.

Importance: A pharmacogenetic analysis of dalcetrapib, a cholesteryl ester transfer protein inhibitor, reported an association between a single-nucleotide polymorphism (SNP) in the ADCY9 gene (rs1967309) and reduction in major adverse cardiovascular events despite a neutral result for the overall trial.

Objective: To determine whether the association between the SNP in the ADCY9 gene and a reduction in major adverse cardiovascular events could be replicated for another cholesteryl ester transfer protein inhibitor, evacetrapib, in patients with high-risk vascular disease.

Design, Setting, And Participants: A nested case-control study examining the rs1967309 SNP in 1427 cases and 1532 matched controls selected from the 12 092-patient Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial, a randomized, double-blind, placebo-controlled phase 3 trial conducted in patients with high-risk vascular disease randomized from October 2012 through December 2013.

Efficacy and Safety of the Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib in Combination With Atorvastatin in Japanese Patients With Primary Hypercholesterolemia.

Background: Inhibition of cholesteryl ester transfer protein by evacetrapib when added to atorvastatin may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal.

Methods and results: This multicenter, randomized, 12-week, double-blind, parallel-group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib with atorvastatin in reducing LDL-C in 149 Japanese patients (evacetrapib/atorvastatin, n=53; ezetimibe/atorvastatin, n=50; placebo/atorvastatin, n=46) with primary hypercholesterolemia. The primary efficacy measure was percent change from baseline to week 12 in LDL-C (β quantification).

Navigating the Future of Cardiovascular Drug Development-Leveraging Novel Approaches to Drive Innovation and Drug Discovery: Summary of Findings from the Novel Cardiovascular Therapeutics Conference.

Purpose: The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease.

Methods: The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe.

Efficacy and Safety of Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib Administered as Monotherapy in Japanese Patients With Primary Hypercholesterolemia.

Background: Inhibition of cholesteryl ester transfer protein with evacetrapib may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal with statins or patients who cannot tolerate statins.

Methods and results: This multicenter, randomized, 12-week, double-blind, parallel group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib in reducing LDL-C in 54 Japanese patients (27 evacetrapib, 27 placebo) with primary hypercholesterolemia. Primary efficacy measure was the percent change from baseline to week 12 in LDL-C (β quantification).

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease.

Background: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease.

Methods: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease.

Comparative effects of cholesteryl ester transfer protein inhibition, statin or ezetimibe on lipid factors: The ACCENTUATE trial.

Background And Aims: The optimal approaches to management of patients treated with moderate statin doses on lipid parameters are unknown. The ACCENTUATE study aimed to compare the effects of adding the cholesteryl ester transfer protein inhibitor (CETP) evacetrapib, ezetimibe or increasing statin dose in atorvastatin-treated high-vascular risk patients on lipid parameters.

Methods: 366 patients with atherosclerotic cardiovascular disease (ASCVD) and/or diabetes were treated with atorvastatin 40 mg/day for 28 days prior to randomization to atorvastatin 40 mg plus evacetrapib 130 mg, atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe 10 mg or atorvastatin 40 mg plus placebo, daily for 90 days at 64 centers in the United States.

Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: Rationale and design of the ACCELERATE trial.

Background: Potent pharmacologic inhibition of cholesteryl ester transferase protein by the investigational agent evacetrapib increases high-density lipoprotein cholesterol by 54% to 129%, reduces low-density lipoprotein cholesterol by 14% to 36%, and enhances cellular cholesterol efflux capacity. The ACCELERATE trial examines whether the addition of evacetrapib to standard medical therapy reduces the risk of cardiovascular (CV) morbidity and mortality in patients with high-risk vascular disease.

Study Design: ACCELERATE is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial.

A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease.

Background: Platelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study.

Methods: The primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention.

TRITON and beyond: new insights into the profile of prasugrel.

Prasugrel, a third-generation thienopyridine antiplatelet agent, demonstrated superior efficacy to clopidogrel but with an increased risk of bleeding in the phase III pivotal registration Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). This article reviews and discusses select components of a large literature of prasugrel data that has emerged since the TRITON-TIMI 38 (TRITON) study primary disclosure.

Relationship between exposure to prasugrel active metabolite and clinical outcomes in the TRITON-TIMI 38 substudy.

In TRITON-TIMI 38, levels of the prasugrel active metabolite (pras-AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pras-AM was observed in low-weight or very elderly patients. The authors hypothesized that this higher exposure might explain the higher risk of non-coronary artery bypass graft (CABG)-related TIMI-related bleeding observed in these 2 patient populations.

Population pharmacokinetic analyses to evaluate the influence of intrinsic and extrinsic factors on exposure of prasugrel active metabolite in TRITON-TIMI 38.

Serial pharmacokinetic (PK) sampling in 1159 patients from TRITON-TIMI 38 was undertaken. A multilinear regression model was used to quantitatively predict prasugrel's active metabolite (Pras-AM) concentrations from its 2 downstream inactive metabolites. Population-based methods were then applied to Pras-AM concentration data to characterize the PK.