etc-1002 reduces blood pressure in hypercholesterolemic patients with mildly elevated blood pressure
TRANSCRIPT
Change in Blood Pressure from Baseline (mmHg)
LS MeanDifference from
350 Journal of Clinical Lipidology, Vol 8, No 3, June 2014
Methods: Normal human primary hepatocytes (LonzaWalkersville Inc.) were first incubated with palmitic acid(0.5 mM) for 24 h to induce fat accumulation. Cells werethen treated with niacin (0-0.5 mM) for 24 h. Cellular fataccumulation and formation of reactive oxygen species(ROS, as an index of oxidative stress) were measured bystaining with Nile Red O and DCFDA fluorescencerespectively. In-vivo effect of niacin on prevention andregression of hepatic steatosis was assessed in high-fat fedrat model of NAFLD. The histology of liver tissue fromanimals was examined in paraffin embedded hematoxylinand eosin (H&E) stained sections.
Results: Niacin (at 0.25 and 0.5 mM doses) significantlyinhibited palmitic acid-induced fat accumulation in hepa-tocytes by 45-62%. This effect was associated with robustinhibition of diacylglycerol acyltransferase 2 (DGAT2)mRNA expression by niacin. Niacin, in a dose-dependentmanner, significantly inhibited ROS production in hepato-cytes. In experimental rat model of NAFLD, inclusion ofniacin at 0.5% and 1% in the high-fat diet significantlydecreased liver fat content, hepatic oxidative products, andprevented hepatic steatosis. Niacin treatment to rats withpreexisting hepatic steatosis induced by the high-fat dietsignificantly regressed steatosis.
Conclusion: These novel findings suggest that niacin,through inhibiting hepatocyte fat accumulation and lipidperoxidation products, effectively prevents and causes theregression of hepatic steatosis and NAFLD. Clinicaldevelopment of niacin formulations and niacin-relatedcompounds for the treatment of NAFLD may offer a verycost-effective opportunity in addressing the unmet need forthe development of therapeutic agents for NAFLD andother fatty liver disease.
N† PBO (95% CI) p-value
ANCOVA with Treatment as CovariateSBP 185 -3.64 (-7.24, -0.04) 0.0478DBP 109 -1.26 (-4.01, 1.49) 0.3660ANCOVA with Baseline, Study and Study TreatmentInteraction as CovariateSBP 149 -6.68 (-11.27, -2.08) 0.0047DBP 87 -2.24 (-5.85, 1.37) 0.2204
†Modified Intent-to-Treat (mITT) population, active and PBO
combined.
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ETC-1002 Reduces Blood Pressure inHypercholesterolemic Patients with Mildly ElevatedBlood Pressure
Roger S. Newton, PhD, Diane E. MacDougall, MS, JeffreyC. Hanselman, MS, Janice R. Margulies, MS, JamesRoy Johnson, PhD, Christie M. Ballantyne, MD, PaulDavis Thompson, MD, Michael A. Weber, MD, NoahL. Rosenberg, MD, (Plymouth, MI)
Lead Author’s Financial Disclosures: Dr. Newtonis employed by and is an owner (stock and stock options) inEsperion Therapeutics Inc., the company that is developingETC-1002 and sponsored the studies.
Study Funding: YesFunding Sources: This study was funded by EsperionTherapeutics, Inc.
Background/Synopsis: ETC-1002 is an oral investi-gational drug being developed to lower LDL-cholesterol(LDL-C) and improve other cardiometabolic risk factors.
ETC-1002 inhibits ATP-citrate lyase (ACL) and activatesAMP-activated protein kinase (AMPK) in the liver.
Objective/Purpose: Four Phase 2a, double-blind, par-allel group, placebo (PBO)-controlled studies were pooledto assess the blood pressure effects of ETC-1002 inhypercholesterolemic patients with systolic blood pressure(SBP) $ 120 mmHg and/or diastolic blood pressure (DBP)$ 80 mmHg at baseline.
Methods: Patients with hypercholesterolemia and abaseline SBP $ 120 mmHg and/or DBP $ 80 mmHgreceiving ETC-1002 in 4 PBO-controlled studies werepooled for analysis. Data were analyzed using mixed modelANCOVA with treatment as a covariate. Additional sensi-tivity analyses were conducted to investigate the effect ofbaseline blood pressure value, study and study treatmentinteraction as model covariates.
Results: ETC-1002 reduced SBP by -3.64 mmHg (95%CI 5 -7.24, -0.04, p50.05) and DBP by -1.26 mmHg (95%CI 5 -4.01, 1.49, p50.37). When baseline blood pressureand study were included as covariates, ETC-1002 reducedSBP by –6.68 mmHg (95% CI 5 -11.27, -2.08, p50.005)and DBP by -2.24 mmHg (95% CI 5 -5.85, 1.37, p50.22).Results shown are placebo corrected least squares meanchange from baseline across the 4 pooled studies.
Conclusion: ETC-1002 significantly reduced systolicblood pressure in patients with mildly elevated baselineblood pressure. These data support further clinical evaluationof the effects of ETC-1002 on blood pressure in patients.
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Effects of Evolocumab on Lipoprotein Particles &Subclasses in Hypercholesterolemic & HeterozygousFamilial Hypercholesterolemia Subjects on Statin†
Ren Xu, MSc, Clapton Dias, PhD, Matt Peach, MSc,Lisa Hamilton, MSc, Bing Gao, PhD, Brian Smith, PhD,Blaire Cooke, PhD, Simon Jackson, PhD, Adam Shaywitz,MD, PhD, Dan Fitzpatrick, PhD, Rob Scott, MD, ScottM. Wasserman, MD, (Seattle, WA)
Lead Author’s Financial Disclosures: Ren Xu,MSc is employed by Amgen Inc.