evacetrapib (LY2484595) / Eli Lilly - LARVOL DELTA

High throughput screens identify genotype-specific therapeutics for channelopathies. (PubMed, JCI Insight) - "We then use deep mutational scanning to prospectively identify all KV11.1 missense variants in a LQTS hotspot region responsive to treatment with evacetrapib. Combining high-throughput drug screens with deep mutational scanning establishes a new paradigm for mutation-specific drug discovery translatable to personalized treatment of patients with rare genetic disorders."

Journal • Cardiovascular • Genetic Disorders

Comparative Effectiveness of Cholesteryl Ester Transfer Protein (CETP) Inhibitors on Lipid Profiles in Adults With Hyperlipidemia: A Comprehensive Systematic Review and Frequentist Network Meta-Analysis of Randomized Controlled Trials. (PubMed, Clin Cardiol) - "CETP inhibitors, particularly anacetrapib and obicetrapib combined with statins, significantly improve lipid profiles, offering potential therapeutic benefits for hyperlipidemia management and cardiovascular risk reduction."

HEOR • Journal • Retrospective data • Review • Cardiovascular • Dyslipidemia

Low HDL-The Challenge. (PubMed, Clin Med Res) - "Several products were tested in large controlled studies, such as dalcetrapib and evacetrapib; neither resulted in any clinical benefit. Anacetrapib only resulted in very limited benefit and is no longer under active development...There was no benefit in the primary end point of myocardial infarction, stroke, or death. In patients with low HDL, a strategy of having LDL as low as can be possibly achieved may be the most appropriate approach."

Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Metabolic Disorders • Myocardial Infarction • Tobacco Cessation • APOA1

Cholesteryl ester transfer protein activity correlates inversely with apolipoprotein A5 levels. (PubMed, J Clin Lipidol) - "Our results uncover a previously unrecognized link between CETP and ApoA5 by showing that CETP overexpression reduces ApoA5 levels while CETP inhibition increases ApoA5 concentrations."

Journal • Dyslipidemia • ANGPTL3 • APOA5 • APOB • LPL

Targeting to High-Density Lipoprotein Cholesterol: New Insights for Inflammatory Bowel Disease Treatment. (PubMed, J Lipid Res) - "Together, these results demonstrate an important role of HDL-C in IBD and indicate the potential pharmacological effects of CETPi for future IBD therapy through elevation of HDL-C."

Journal • Cardiovascular • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • Septic Shock • ATF3

Chikungunya Replication and Infection Is Dependent upon and Alters Cellular Hexosylceramide Levels in Vero Cells. (PubMed, Viruses) - "CHIKV was also sensitive to evacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, though the mechanism of inhibition appeared independent of CETP itself, suggesting an off-target effect. These findings highlight specific lipid pathways, particularly glycosphingolipid metabolism, as critical for CHIKV replication and further refine our understanding of how CHIKV exploits host lipid networks. This study provides new insights into CHIKV biology and suggests that targeted investigation of host lipid pathways may inform future therapeutic strategies."

Journal • Chikungunya • Infectious Disease • Metabolic Disorders • Musculoskeletal Pain

REDUCING CETP ACTIVITY PREVENTS MEMORY DECLINE IN AN ALZHEIMER'S DISEASE MOUSE MODEL (ADPD 2025) - "Our findings support the idea that CETP activity may affect endothelial function and that lipid metabolism modulates AD risk. This study offers preclinical evidence that CETP inhibitors like evacetrapib could delay or prevent AD as a novel therapeutic opti on."

Preclinical • Alzheimer's Disease • Amyloidosis • CNS Disorders • Metabolic Disorders

CEA-induced PI3K/AKT pathway activation through the binding of CEA to KRT1 contributes to oxaliplatin resistance in gastric cancer. (PubMed, Drug Resist Updat) - "In summary, the CEA-KRT1-PI3K/AKT axis regulates oxaliplatin sensitivity in GC cells. Treatment with small molecule inhibitors such as evacetrapib to inhibit this interaction constitutes a novel therapeutic strategy."

Journal • Gastric Cancer • Oncology • Solid Tumor • CEACAM5 • KRT1

Prevalence of Familial Hypercholesteremia (FH) Among Participants in the ACCELERATE Trial: Implications for Opportunistic FH Screening and Prognostication (AHA 2024) - "Participants of ASCVD trials may be enriched for FH, so ASCVD trial enrollment may be a unique contact point to opportunistically diagnose FH.Hypothesis: The population of the ACCELERATE trial of evacetrapib and ASCVD outcomes is enriched for FH. ACCELERATE is a phase 3 cardiovascular outcomes trial which randomized 12,092 patients with high-risk vascular disease to receive evacetrapib or placebo... In a participant-level analysis of a rigorous, independently adjudicated ASCVD outcomes trial, severe hypercholesterolemia and FH were more prevalent in the trial population than the general population based on pretreatment LDL-C calculation. Severe hypercholesterolemia was significantly associated with higher ASCVD incidence. ASCVD trial enrollment may be a novel high-yield contact point for index FH case identification using simple pretreatment LDL-C calculation."

Atherosclerosis • Dyslipidemia • Metabolic Disorders

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. (PubMed, J Cardiovasc Dev Dis) - "Our meta-analysis shows, for the first time, that CETPis are associated with reduced CVD-related mortality and MI."

Journal • Retrospective data • Review • Acute Coronary Syndrome • Atherosclerosis • Cardiovascular • Dyslipidemia • Myocardial Infarction

CARDIOVASCULAR SAFETY PROFILE OF CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF 17 RANDOMIZED CONTROLLED TRIALS (ACC 2024) - "Six trials examined dalcetrapib (n=23,057), 7 anacetrapib (n=33,643), two torcetrapib (n=16,255), one obicetrapib (n=66), and one evacetrapib (n=12092). The use of anacetrapib resulted in a lower incidence of MACE and MI events than placebo. Besides its robust effects on LDL and HDL cholesterol, it has an acceptable safety profile."

Retrospective data • Review • Cardiovascular

CETP INHIBITOR EVACETRAPIB PREVENTS MEMORY DECLINE IN ALZHEIMER'S DISEASE MOUSE MODEL (ADPD 2024) - "This study provides preclinical evidence that repurposing of CETP inhibitors such as evacetrapib could delay or prevent AD. Our findings add to the ever-growing evidence that lipid metabolism modulates AD risk and that CETP inhibition is an effective therapeutic avenue."

Preclinical • Alzheimer's Disease • Cardiovascular • CNS Disorders • Dyslipidemia • Metabolic Disorders • APOB • THY1

CETP inhibitor evacetrapib enters mouse brain tissue. (PubMed, Front Pharmacol) - "We show that evacetrapib crosses the blood-brain barrier and is detectable in brain tissue 0.5 h after a 40 mg/kg i.v. injection in a non-linear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer's disease."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Dyslipidemia

Structure-based mechanism and inhibition of cholesteryl ester transfer protein. (PubMed, Curr Atheroscler Rep) - "CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, were designed and evaluated in phase III clinical trials for the treatment of ASCVD or dyslipidemia. Insights into the structural-based CETP-lipoprotein interactions can unravel CETP inhibition machinery, which can hopefully guide the design of more effective CETP inhibitors that combat ASCVD. Individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer and which in turn, guide the rational design of new anti-ASCVD therapeutics."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders

CETP INHIBITOR EVACETRAPIB SHOWS BENEFICIAL EFFECTS IN AN AD MOUSE MODEL (ADPD 2023) - "As expected, hAPP and hAPP/hCETPtg mice showed cognitive impa irment. Interestingly, evacetrapib rescued cognition in hAPP/hCETPtg mice. Good cognition correlated positively with higher HDL and lower LDL levels, but APP and Aß levels did not correlate with cognition."

Preclinical • Alzheimer's Disease • Amyloidosis • CNS Disorders • THY1

Evacetrapib Elicits Antitumor Effects on Colorectal Cancer by Inhibiting the Wnt/β-Catenin Signaling Pathway and Activating the JNK Signaling Pathway. (PubMed, Biol Pharm Bull) - "We found that Evacetrapib, a CETP inhibitor, suppressed CRC cell growth by inhibiting the Wnt/β-catenin signaling pathway and activating the c-Jun NH2-terminal kinase (JNK) signaling pathway in CRC. Therefore, Evacetrapib displays an anti-cancer effect and is a possible option for treating CRC."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Longitudinal High-Sensitivity C-Reactive Protein and Longer-Term Cardiovascular Outcomes in Optimally-Treated Patients With High-Risk Vascular Disease. (PubMed, Am J Cardiol) - "We performed a post hoc analysis of ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibitor with Evacetrapib in Patients with High-Risk for Vascular Outcomes), involving optimally-treated patients with high-risk vascular disease, with available baseline and at least 1 follow-up hsCRP level...In the setting of established medical therapies, longitudinal follow-up hsCRP was independently associated with long-term MACE. In conclusion, these findings suggest that longitudinal hsCRP represents a novel approach of residual cardiovascular risk even when on-treatment hsCRP levels remain <2 mg/L."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Myocardial Infarction • CRP

High-affinity SOAT1 ligands remodeled cholesterol metabolism program to inhibit tumor growth. (PubMed, BMC Med) - "Taken together, we reported several high-affinity SOAT1 ligands and demonstrated their clinical potential in the precision therapy of liver cancer, and also reveal the potential antitumor mechanism of SOAT1-targeting compounds."

Journal • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CD8

Cholesterol metabolism in Alzheimer's disease. (PubMed, Alzheimers Dement) - "CETP may play an aggravating role in AD, which has not yet been investigated since mice naturally lack CETP. We propose that CETP inhibitors such as evacetrapib may be promising pharmacological treatments contributing to the prevention of cognitive decline in AD."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Dyslipidemia • THY1

"We can start with the futility of evacetrapib." (@Seyi59919941)

Pharmacological Inhibition of CETP (Cholesteryl Ester Transfer Protein) Increases HDL (High-Density Lipoprotein) That Contains ApoC3 and Other HDL Subspecies Associated With Higher Risk of Coronary Heart Disease. (PubMed, Arterioscler Thromb Vasc Biol) - "CETP inhibitors evacetrapib and torcetrapib increase apoA1 in HDL subspecies that contain apoC3 and other HDL subspecies associated with higher risk of coronary heart disease. Subspecies-specific effects shift HDL subspecies concentrations toward a profile associated with higher risk, which may contribute to lack of clinical benefit from raising HDL by pharmaceutical CETP inhibition."

Clinical • Journal • Cardiovascular • Coronary Artery Disease • Heart Failure • Immunology • Inflammation • A2M • APOA1 • APOE

CETP-inhibitors: from HDL-C to LDL-C lowering agents? (PubMed, Cardiovasc Res) - "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 (PCSK9) inhibitors. Whereas 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...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."

Journal • Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Metabolic Disorders • APOB

[VIRTUAL] Cholesterol Metabolism in Alzheimer’s Disease (AAIC 2021) - "CETP may play an aggravating role in AD, which has not yet been investigated since mice naturally lack CETP. We propose that CETP inhibitors such as evacetrapib may be promising pharmacological treatments contributing to the prevention of cognitive decline in AD."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Dyslipidemia • THY1

Safety and Efficacy of Evacetrapib in Patients with Inadequately-controlled Hypercholesterolemia and High Cardiovascular Risk; A meta-analysis of Randomized Placebo-controlled Trials. (PubMed, Prostaglandins Leukot Essent Fatty Acids) - "Current evidence from five RCTs (12,539 participants) suggests that evacetrapib has favorable outcomes in patients with inadequately-controlled Hypercholesterolemia and high cardiovascular risks. Evacetrapib could significantly increase the HDL and Apo-A1 levels and lower the LDL cholesterol and Apo-B levels with an acceptable safety profile."

Journal • Retrospective data • Review • Cardiovascular • Dyslipidemia • Metabolic Disorders • APOA1

Effect of CETP inhibition with evacetrapib in patients with diabetes mellitus enrolled in the ACCELERATE trial. (PubMed, BMJ Open Diabetes Res Care) - "No significant treatment interaction between treatment assignment and diabetes status was noted. Despite a favorable increase in HDL, and decreases in LDL and HbA1c levels in patients with DM, we observed no benefits of treatment with evacetrapib on prespecified clinical outcomes in this high-risk population."

Clinical • Journal • Cardiovascular • Diabetes • Dyslipidemia • Metabolic Disorders • Myocardial Infarction