Abstract Aims In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. Methods and results dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1–3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75–1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65–0.96) for myocardial infarction, 0.92 (95% CI 0.64–1.33) for stroke, 1.21 (95% CI 0.91–1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60–9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70–0.98). Conclusion Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. Clinical Trial Registration Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 ( ADCY9 ) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

Abstract: Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor.

The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene.

OBJECTIVE Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. RESEARCH DESIGN AND METHODS In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4–12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random). RESULTS At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68–0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes. CONCLUSIONS In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.

Background High-density lipoprotein cholesterol (HDL-C) concentration is inversely related to risk of major adverse cardiovascular events (MACE) in epidemiologic studies but is a poorer predictor of MACE in patients with established coronary heart disease. HDL particle concentration (HDLP) has been proposed as a better predictor of risk. We investigated whether HDLP is associated with risk of MACE after acute coronary syndrome (ACS). Methods The dal-Outcomes trial compared the CETP inhibitor dalcetrapib with placebo in patients with recent ACS. In a nested case-cohort analysis, total, large, medium, and small HDLPs were measured by nuclear magnetic resonance spectroscopy at baseline (4-12 weeks after ACS) in 476 cases with MACE and 902 controls. Hazard ratios (HRs; case-control) for 1-SD increment of HDLP or HDL-C at baseline were calculated with and without adjustment for demographic, clinical, laboratory, and treatment variables. Similarly, HRs for MACE were calculated for changes in HDLP or HDL-C from baseline to month 3 of assigned treatment. Results Over median follow-up of 28 months, the risk of MACE was not associated with baseline HDLP (adjusted HR = 0.98, 95% CI = 0.84-1.15, P =.81), any HDLP subclass, or HDL-C. Dalcetrapib increased HDL-C and total, medium, and large HDLP and decreased small HDLP but had no effect on MACE compared with placebo. There were no association of risk of MACE with change in HDLP or HDL-C and no interaction with assigned study treatment. Conclusions Neither baseline HDLP nor the change in HDLP on treatment with dalcetrapib or placebo was associated with risk of MACE after ACS.

The cholesterol ester transfer protein (CETP) inhibitor dalcetrapib has been under evaluation for its potential to prevent cardiovascular (CV) events for almost two decades. The current clinical development program, representing new advances in precision medicine and focused on a genetically defined population with acute coronary syndrome (ACS), is supported by a large body of pharmacokinetic and pharmacodynamic data as well as substantial clinical experience in over 13,000 patients and volunteers. Dalcetrapib treatment of 600 mg/day produces significant inhibition of CETP activity, and has been utilized in phase II and III studies, including CV endpoint trials. Numerous studies have investigated the interactions between dalcetrapib and most drugs commonly prescribed to CV patients and have not demonstrated any clinically significant effects. Evaluations in patients with renal and hepatic impairment demonstrate a greater exposure to dalcetrapib than in the non-impaired population, but long-term clinical studies including patients with mild to moderate hepatic and renal dysfunction demonstrate no increase in adverse events. Safety pharmacology and toxicology studies as well as the clinical safety experience support the continuing development of dalcetrapib as an adjunct to 'standard of care' for the ACS population. This article provides a full review of the pharmacokinetics, as well as pharmacodynamics and pharmacology, of dalcetrapib in the context of a large clinical program.

Biomarkers have proven to be critical tools in both cardiovascular clinical practice and clinical research. In clinical practice, biomarkers are used to identify patients at risk for disease, stratify disease severity, guide intervention decisions and monitor patient response to therapy. Biomarkers are also used extensively to improve the design of cardiovascular clinical trials, identify 'at-risk' populations, allow for preliminary screening for response, identify appropriate dose ranges, study subgroup differences and identify early safety concerns. The purpose of this paper is to describe current key cardiovascular biomarker initiatives and to outline some of the important considerations in applying these biomarkers in a clinical trial setting, utilizing the examples of HDL cholesterol, HDL-targeted therapies and imaging tools used to assess HDL-targeted therapies as a case study.

The purpose of this article is to review the current landscape of new therapeutic targets, advances in biomarkers and imaging technologies, regulatory sciences, and their collective potential impact on the development of novel anti-atherosclerosis drugs. Current development challenges such as the design of pharmacodynamic (indicative or surrogate biomarker) and ‘hard’ end point studies are reviewed. The reader can also expect to learn about advanced collaborative efforts that will likely have an impact on future initiatives.

The complexity of medical care has led to a dramatic increase in the number of drugs taken by patients. In an effort to improve patient compliance and the effectiveness of clinical care, many drugs are being studied for combination in a single capsule or tablet. The recent success of many combination drugs for hypertension has accelerated the interest in combination drugs for lipids and atherosclerosis. Advicor (Kos Pharmaceuticals, Miami, FL), a combination of nicotinic acid and a statin (mevacor), is the first combination lipid drug. Recently, the United States Food and Drug Administration approved the combination of another statin, pravachol, with aspirin. Therefore, combination drugs are likely to be a significant contribution to clinical practice and drug development.

The conference on regression and progression discussed in this supplement to The American Journal of Cardiology presents the latest information on invasive and noninvasive measurement of structural vascular disease. Many groups are currently seeking to validate new techniques. Several of these new methods are described in this supplement and continue to improve yearly and alter our perception of the atherosclerotic process. The question is, do these methods quantify the same or different aspects of the atherosclerotic process? And if they characterize different aspects, which are most promising for the study of vascular disease progression and regression, and which are most likely to correlate with clinical events and thus to be developed to enhance earlier diagnosis and treatment?