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Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management., Central Illustration

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication. Molecular docking investigations suggested that dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta G value of −8.5 kcal/mol. Dalcetrapib inhibited both 3CL protease activity in vitro and viral replication in Vero E6 cells with IC50 values of 14.4 ± 3.3 μM and an EC50 of 17.5 ± 3.5 μM (mean ± SD). Near-complete inhibition of protease activity persisted despite 1000-fold dilution after ultrafiltration with a nominal dalcetrapib-thiol concentration of approximately 100 times below the IC50 of 14.4 μM, suggesting stable protease–drug interaction. The inhibitory effect of dalcetrapib on the SARS-CoV-2 3CL protease and viral replication warrants its clinical evaluation for the treatment of COVID-19.

Dyslipidemia is associated with atherosclerosis and cardiovascular disease development, posing serious risks to human health. Cholesteryl ester transfer protein (CETP) is responsible for exchange of neutral lipids, such as cholesteryl ester and TG, between plasma high density lipoprotein (HDL) particles and Apolipoprotein B-100 (ApoB-100) containing lipoprotein particles. Genetic studies suggest that single-nucleotide polymorphism (SNPs) with loss of activity CETP is associated with increased HDL-C, reduced LDL-C, and cardiovascular risk. In animal studies, mostly in rabbits, which have similar CETP activity to humans, inhibition of CETP through antisense oligonucleotides reduced aortic arch atherosclerosis. Concerning this notion, inhibiting the CETP is considered as a promise approach to reduce cardiovascular events, and several CETP inhibitors have been recently studied as a cholesterol modifying agent to reduce cardiovascular mortality in high risk cardiovascular disease patients. However, in Phase III cardiovascular outcome trials, three CETP inhibitors, named Torcetrapib, Dalcetrapib, and Evacetrapib, did not provide expected cardiovascular benefits and failed to improve outcomes of patient with cardiovascular diseases (CVD). Although REVEAL trail has recently shown that Anacetrapib could reduce major coronary events, it was also shown to induce excessive lipid accumulation in adipose tissue; thereby, the further regulatory approval will not be sought. On the other hand, growing evidence indicated that the function of CETP inhibitors on modulating the cardiovascular events are determined by correlated single nucleotide polymorphism (SNP) in the ADCY9 gene. However, the underlying mechanisms whereby CETP inhibitors interact with the genotype are not yet elucidated, which could potentially be related to the genotype-dependent cholesterol efflux capacity of HDL particles. In the present review, we summarize the current understanding of the functions of CETP and the outcomes of the phase III randomized controlled trials of CETP inhibitors. In addition, we also put forward the implications from results of the trials which potentially suggest that the CETP inhibitors could be a promising precise therapeutic medicine for CVD based on genetic background.

peer-reviewed The full text of this article will not be available in ULIR until the embargo expires on the 14/04/2021 This work aims to transfer the fast dissolution performances of drug nanosuspensions into the solid state via a carrier particle-mediated isolation method and explores the factors affecting the maximum achievable drug loading of the prepared nanocomposite microparticles. The solid composites of fast dissolving dalcetrapib (DCP) nanoparticles on larger montmorillonite (MMT) carrier microparticles have been prepared by an antisolvent precipitation method. The very high dissolution rate of the DCP nanoparticles is combined with the simple solid–liquid separation and drying of the MMT composite microparticles. The fast dissolution rate of DCP from the solid-state nanocomposite microparticles was maintained up to a drug loading of 20.9%, and the formulation was stable for a minimum of 10 weeks in the solid state. Surface functionalization of the MMT particles was not needed for a high and uniform attachment of nanoparticles. Addition of soluble surfactant and polymeric additives, generally used for stabilization of nanosuspensions, was not required and even decreased the DCP nanoparticle attachment and thus limited drug loading

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3400 Peruvians. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues, which also differs between males and females. We also detected interaction effects of the two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. We propose that ADCY9 and CETP coevolved during recent human evolution due to sex-specific selection, which points toward a biological link between dalcetrapib’s pharmacogene ADCY9 and its therapeutic target CETP.

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.

Background: Cholesteryl ester transfer protein (CETP) inhibitors increase serum high-density lipoprotein cholesterol (HDL-c) concentration; however, their impact on cardiovascular outcomes is not clear. This systematic review examines the effect of CETP inhibitors on serum lipid profiles, cardiovascular events, and all-cause mortality. Methods: We searched MEDLINE, Embase, and the Cochrane Library of Clinical Trials for placebo-controlled randomized controlled trials (RCTs) that examined the effect of a CETP inhibitor (dalcetrapib, anacetrapib, evacetrapib, or TA-8995) on all-cause mortality, major adverse cardiovascular events (MACE), or the components of MACE at ≥6 months. Data were pooled using random-effects models. Results: A total of 11 RCTs (n = 62,431) were included in our systematic review; 4 examined dalcetrapib (n = 16,612), 6 anacetrapib (n = 33,682), and 1 evacetrapib (n = 12,092). Compared to dalcetrapib, ana­cetrapib and evacetrapib were more efficacious at raising HDL-c levels (∼100–130 vs. ∼30%). Anacetrapib and evacetrapib also decreased low-density lipoprotein cholesterol (LDL-c) by approximately 30% while dalcetrapib did not affect the LDL-c level. Overall, CETP inhibitors were not associated with the incidence of MACE (pooled relative risk [RR]: 0.97; 95% confidence interval [CI]: 0.91–1.04). CETP inhibitors may decrease the risks of nonfatal myocardial infarction (MI) (RR: 0.93; 95% CI: 0.87–1.00) and cardiovascular death (RR: 0.92; 95% CI: 0.83–1.01), though these trends did not reach statistical significance. Conclusions: CETP inhibitors are not associated with an increased risk of MACE or all-cause mortality. There is a trend towards small reductions in nonfatal MI and cardiovascular death, though the clinical im­portance of such reductions is likely modest.

Cholesteryl ester transfer protein (CETP) is a liver-synthesized glycoprotein whose main functions are facilitating transfer of both cholesteryl esters from high-density lipoprotein (HDL) particles to apolipoprotein B (apoB)-containing particles as well as transfer of triglycerides from apoB-containing particles to HDL particles. Novel crystallographic data have shown that CETP exchanges lipids in the circulation by a dual molecular mechanism. Recently, it has been suggested that the atherosclerotic cardiovascular disease (ASCVD) benefit from CETP inhibition is the consequence of the achieved low-density lipoprotein cholesterol (LDL-C) and apoB reduction, rather than through the HDL cholesterol (HDL-C) increase. The use of CETP inhibitors is supported by genetic evidence from Mendelian randomization studies, showing that LDL-C lowering by CETP gene variants achieves equal ASCVD risk reduction as LDL-C lowering through gene proxies for statins, ezetimibe, and proprotein convertase subtilisin–kexin Type 9 inhibitors. Although first-generation CETP inhibitors (torcetrapib, dalcetrapib) were mainly raising HDL-C or had off-target effects, next generation CETP inhibitors (anacetrapib, evacetrapib) were also effective in reducing LDL-C and apoB and have been proven safe. Anacetrapib was the first CETP inhibitor to be proven effective in reducing ASCVD risk. In addition, CETP inhibitors have been shown to lower the risk of new-onset diabetes, improve glucose tolerance, and insulin sensitivity. The newest-generation CETP inhibitor obicetrapib, specifically designed to lower LDL-C and apoB, has achieved significant reductions of LDL-C up to 45%. Obicetrapib, about to enter phase III development, could become the first CETP inhibitor as add-on therapy for patients not reaching their guideline LDL-C targets.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management.

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.

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 final chapter of the book demonstrates two case studies in which the essential messages from the preceding chapters are projected onto real-life cases. Both a successful and a failed translational project were chosen from the cardiovascular arena. Torcetrapib—an HDL-cholesterol increasing drug—was developed despite a considerable translational risk because the main biomarker, HDL-cholesterol concentration in human plasma, had never before been firmly established as a risk factor with therapeutic implications. The phase III pivotal trial not only failed but also produced excess mortality. The latter was attributable to off-target toxicity (an increase of blood pressure) as shown by the congener drug dalcetrapib. This drug was developed at an even higher translational risk because the main biomarker had been devalidated by the first drug in the field, but at least it proved to be nontoxic—although also not successful regarding the reduction of cardiovascular endpoints. The failure of this second drug was clearly foreseeable. At the other end of the spectrum, varenicline was analyzed as a smoke cessation aid that scored high in translatability assessment. The main reasons for this were a clear biomarker indicating smoke cessation and a positive congener experience in the past.

Drug development of cholesteryl ester transfer protein (CETP) inhibition to prevent coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and Mendelian randomization (MR) results. Findings from meta-analyses of CETP inhibitor trials (≥ 24 weeks follow-up) were used to judge between-compound heterogeneity in treatment effects. Genetic data were extracted on 190+ pharmacologically relevant outcomes; spanning 480,698-21,770 samples and 74,124-4,373 events. Drug target MR of protein concentration was used to determine the on-target effects of CETP inhibition and compared to that of PCSK9 modulation. Fifteen eligible CETP inhibitor trials of four compounds were identified, enrolling 79,961 participants. There was a high degree of heterogeneity in effects on lipids, lipoproteins, blood pressure, and clinical events. For example, dalcetrapib and evacetrapib showed a neutral effect, torcetrapib increased, and anacetrapib decreased cardiovascular disease (CVD); heterogeneity p-value < 0.001. In drug target MR analysis, lower CETP concentration (per μg/ml) was associated with CHD (odds ratio 0.95; 95%CI 0.91; 0.99), heart failure (0.95; 95%CI 0.92; 0.99), chronic kidney disease (0.94 95%CI 0.91; 0.98), and age-related macular degeneration (1.69; 95%CI 1.44; 1.99). Lower PCSK9 concentration was associated with a lower risk of CHD, heart failure, atrial fibrillation and stroke, and increased risk of Alzheimer’s disease and asthma. In conclusion, previous failures of CETP inhibitors are likely compound related. CETP inhibition is expected to reduce risk of CHD, heart failure, and kidney disease, but potentially increase risk of age-related macular disease.

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. [Abstract copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.]

Background: Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined. Methods: Adcy9 -inactivated ( Adcy9 Gt/Gt ) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETPtg Adcy9 Gt/Gt and CETPtg Adcy9 WT ), were submitted to an atherogenic protocol (injection of an AAV8 [adeno-associated virus serotype 8] expressing a PCSK9 [proprotein convertase subtilisin/kexin type 9] gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, vasorelaxation, telemetry, and adipose tissue magnetic resonance imaging were evaluated. Results: Adcy9 Gt/Gt mice had a 65% reduction in aortic atherosclerosis compared to WT ( P Adcy9 Gt/Gt mice compared to WT animals ( P Adcy9 Gt/Gt mice (versus WT, P Adcy9 Gt/Gt ( P Adcy9 Gt/Gt mice allowed significantly less adhesion of splenocytes compared to WT ( P Adcy9 Gt/Gt mice gained more weight than WT with the atherogenic diet; this was associated with an increase in whole body adipose tissue volume ( P Adcy9 Gt/Gt compared to WT mice ( P P P =0.0572). Adcy9 inactivation–induced effects on atherosclerosis, endothelial function, weight gain, adipose tissue volume, and feed efficiency were lost in CETPtg Adcy9 Gt/Gt mice ( P >0.05 versus CETPtg Adcy9 WT ). Conclusions: Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone.