Icosapent ethyl: safely reducing cardiovascular risk in adults with elevated triglycerides.

INTRODUCTION: In patients at high cardiovascular risk, the rate of events remains elevated despite traditional, evidence-based lipid-lowering therapy. Residual hypertriglyceridemia is an important contributor to this risk. However, prior medications with triglyceride-lowering effects have not reduced adverse clinical outcomes in the statin era. AREAS COVERED: The present review summarizes evidence and recommendations related to triglyceride-lowering therapy in the primary and secondary preventive settings. We provide an overview of findings from recent meta-analyses, important observational studies, and a detailed description of landmark trials, including the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT). We further review recommendations from current guidelines. EXPERT OPINION: Icosapent ethyl is a stable, highly purified ethyl ester of eicosapentaenoic acid that safely and effectively reduces cardiovascular events in the contemporary setting. It is prescribed at a dose of 2 grams twice daily and is indicated in patients at high cardiovascular risk who have fasting or non-fasting triglyceride levels ≥150 mg/dl despite maximally tolerated statin treatment, or in individuals with triglyceride levels ≥500 mg/dl. Conversely, omega-3 fatty acid preparations containing a combination of eicosapentaenoic acid and docosahexaenoic acid are not indicated for reduction of cardiovascular risk and should be actively deprescribed.

A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH. METHODS: In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19). RESULTS: At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. -1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients. CONCLUSION: MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. LAY SUMMARY: Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced.

Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results.

AIMS: Though statin therapy is known to slow coronary atherosclerosis progression and reduce cardiovascular (CV) events, significant CV risk still remains. In the REDUCE-IT study, icosapent ethyl (IPE) added to statin therapy reduced initial CV events by 25% and total CV events by 30%, but its effects on coronary atherosclerosis progression have not yet been fully investigated. Therefore, this study is to determine whether IPE 4 g/day will result in a greater change from baseline in plaque volume measured by serial multidetector computed tomography than placebo in statin-treated patients. METHODS AND RESULTS: EVAPORATE is a randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis by coronary computed tomographic angiography (CCTA) (≥1 angiographic stenoses with ≥20% narrowing), on stable statin therapy with low-density lipoprotein cholesterol levels 40-115 mg/dL, and persistently high triglyceride levels (135-499 mg/dL). Patients underwent an interim scan at 9 months and were followed for an additional 9 months with CCTA at 0, 9, and 18 months. Here, we present the protocol-specified interim efficacy results. A total of 80 patients were enrolled, with 67 completing the 9-month visit and having interpretable CCTA at baseline and at 9 months (age = 57 ± 6 years, male = 36, 63%). At the 9-month interim analysis, there was no significant change in low attenuation plaque (LAP) between active and placebo groups (74% vs. 94%, P = 0.469). However, there was slowing of total non-calcified plaque (sum of LAP, fibrofatty, and fibrous plaque) (35% vs. 43%, P = 0.010), total plaque (non-calcified + calcified plaque) (15% vs. 26%, P = 0.0004), fibrous plaque (17% vs. 40%, P = 0.011), and calcified plaque (-1% vs. 9%, P = 0.001), after adjustment by baseline plaque, age, sex, diabetes, baseline triglyceride levels, and statin use. CONCLUSION: EVAPORATE is the first study using CCTA to evaluate the effects of IPE as an adjunct to statin therapy on atherosclerotic plaque characteristics in a high-risk CV population with persistently high triglyceride levels. It provides important mechanistic data in regards to the reduction in CV events in the REDUCE-IT clinical trial. CLINICALTRIALS. GOVIDENTIFIER: NCT029226027.

Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study.

BACKGROUND & AIMS: Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that has been hypothesized to improve non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic bile acid production. We studied the safety, tolerability and efficacy of volixibat in patients with NASH. METHODS: In this double-blind, phase II dose-finding study, adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive volixibat (5, 10 or 20 mg) or placebo once daily for 48 weeks. The endpoints of a predefined interim analysis (n = 80), at week 24, were: ≥5% reduction in MRI-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was a ≥2-point reduction in non-alcoholic fatty liver disease activity score without worsening fibrosis at week 48. RESULTS: Volixibat did not meet either interim endpoint; the study was terminated owing to lack of efficacy. In participants receiving any volixibat dose, mean serum 7-alpha-hydroxy-4-cholesten-3-one (C4; a biomarker of bile acid synthesis) increased from baseline to week 24 (+38.5 ng/ml [SD 53.18]), with concomitant decreases in serum total cholesterol (-14.5 mg/dl [SD 28.32]) and low-density lipoprotein cholesterol (-16.1 mg/dl [SD 25.31]). These changes were generally dose-dependent. On histological analysis, a greater proportion of participants receiving placebo (38.5%, n = 5/13) than volixibat (30.0%, n = 9/30) met the primary endpoint. Treatment-emergent adverse events (TEAEs) were mainly mild or moderate. No serious TEAEs were related to volixibat. Diarrhoea was the most common TEAE overall and the most common TEAE leading to discontinuation. CONCLUSIONS: Increased serum C4 and decreased serum cholesterol levels provide evidence of target engagement. However, inhibition of ASBT by volixibat did not elicit a liver-related therapeutic benefit in adults with NASH. LAY SUMMARY: A medicine called volixibat has previously been shown to reduce cholesterol levels in the blood. This study investigated whether volixibat could reduce the amount of fat in the liver and reduce liver injury in adults with an advanced form of non-alcoholic fatty liver disease. Volixibat did not reduce the amount of fat in the liver, nor did it have any other beneficial effect on liver injury. Participants in the study generally tolerated the side effects of volixibat and, as in previous studies, the main side effect was diarrhoea. These results show that volixibat is not an effective treatment for people with fatty liver disease. CLINICAL TRIAL IDENTIFIER: NCT02787304.

Pharmacologic and Pharmacodynamic Equivalence of 2 Formulations of Orlistat.

We sought to establish the bioequivalence of 2 weight-loss aids: orlistat 27-mg chewable tablet and orlistat 60-mg capsule, measured pharmacodynamically as percentage fecal fat excretion. Two open-label, single-center, randomized, 3-period, 3-treatment crossover studies were conducted in adults with body mass index 25-33 kg/m2 . For each 9-day treatment period, subjects received orlistat 27-mg chewable tablet, 60-mg capsule, or 120-mg capsules (2 60-mg capsules) 3 times daily; a 2-day washout separated treatments. Primary bioequivalence analyses were based on 2 1-sided tests of the 90% CI of the ratio of geometric means using log-transformed data (study 1) and by the dose-scale method to calculate bias-corrected and accelerated 90% CI of relative bioavailability (f) using nontransformed data (study 2). Bioequivalence was established if 90% CIs fell within 0.80-1.25. In total, 48 and 144 subjects were randomized in study 1 and study 2, respectively. Bioequivalence between the formulations was established in both studies: study 1 ratio of geometric means of percentage fecal fat excretion was 0.96 (2 1-sided tests, 90% CI 0.87-1.06); study 2-point estimate of f was 1.09 (bias-corrected and accelerated 90% CI 0.98-1.22). Tolerability of the 27-mg tablet was consistent with the 60-mg capsule; mild gastrointestinal effects were most common.

A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis.

BACKGROUND: Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat. METHODS: Overweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids. RESULTS: All 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0-4) to 2 (0-8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 µmol (standard deviation [SD] 468.965) with volixibat and 224.75 µmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of - 0.70 mmol/L (range - 2.8 to 0.4) and - 0.6990 mmol/L (- 3.341 to 0.570), respectively. CONCLUSIONS: This study indicates that maximal inhibition of bile acid reabsorption, as assessed by FBA excretion, occurs at volixibat doses of ≥20 mg/day in obese and overweight adults, without appreciable change in gastrointestinal tolerability. These findings guided dose selection for an ongoing phase 2 study in patients with non-alcoholic steatohepatitis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02287779 (registration first received 6 November 2014).

Mean common or mean maximum carotid intima-media thickness as primary outcome in lipid-modifying intervention studies.

AIM: Carotid intima-media thickness (CIMT) measurements are used as a disease outcome in randomized controlled trials that assess the effects of lipid-modifying treatment. It is unclear whether common CIMT or mean maximum CIMT should be used as the primary outcome. We directly compared both measurements using aspects that are of great importance in deciding which is most favorable for use in clinical trials. METHODS: A literature search was performed (PUBMED, up to March 31, 2008). Fifteen trials with lipid-modifying treatment were identified that had information on both outcome measures. Common CIMT and mean maximum CIMT were compared on reproducibility, strength of relation with LDL and HDL cholesterol and congruency of their results (harm/neutral/beneficial) with data from event trials. RESULTS: Findings showed that the reported reproducibility was high for both measurements, although a direct comparison was not possible. The relationship between the achieved LDL-C and HDL-C levels with CIMT progression was modest and showed no difference in magnitude between CIMT measurements. CIMT progression rates differed across carotid segments with the highest progression rates observed in the bifurcation segment. Treatment effects differed across carotid segments without a clear preference pattern. Trials using mean maximum CIMT progression more often (12 out of 15 studies) paralleled the findings of event trials in contrast to the mean common CIMT (11 out of 15 studies), a difference not reaching statistical significance. CONCLUSIONS: Based on the literature, with equal results for reproducibility (assumed), lipid relationship and congruency with event findings, but with treatment effects that differ across carotid segments that can not be predicted, the mean maximum CIMT as the primary outcome may be preferred in trials on the impact of lipid-modifying interventions. One advantage is that information on mean common CIMT can generally be obtained easily in protocols assessing mean maximum CIMT, but not the other way around.

Anacetrapib and dalcetrapib: two novel cholesteryl ester transfer protein inhibitors.

OBJECTIVE: To evaluate the role of cholesteryl ester transfer protein (CETP) in the cholesterol transport system and review the pharmacology, pharmacokinetic properties, efficacy, and adverse effects of the CETP inhibitors, anacetrapib and dalcetrapib, for the treatment of dyslipidemia. DATA SOURCES: A literature search was conducted in Ovid/MEDLINE (1950 to week 4 December 2010), PubMed/MEDLINE (up to December 2010), EMBASE (2000 to December 2010), and International Pharmaceutical Abstracts (1970 to December 2010) using the MeSH terms and key words anacetrapib, MK 0859, dalcetrapib, and JTT 705. The search was limited to publications in English. STUDY SELECTION AND DATA EXTRACTION: Studies evaluating the pharmacology, pharmacokinetics, safety, and efficacy of anacetrapib and dalcetrapib for the treatment of dyslipidemia were included. Clinical reviews evaluating the characterization of CETP and its inhibition as a mechanism for reducing cardiovascular risk were also included. DATA SYNTHESIS: Anacetrapib and dalcetrapib represent a novel treatment option for patients who have dyslipidemia and low levels of high-density lipoprotein cholesterol (HDL-C). Anacetrapib and dalcetrapib increase HDL-C by inhibiting CETP-mediated transfer of cholesteryl ester and triglyceride. Studies evaluating the safety and efficacy of anacetrapib and dalcetrapib concluded that both agents safely and effectively augment HDL-C. Their mechanism of action, potential for significant raising of HDL-C, once-daily dosing regimen, and favorable lipid-altering effects when added to hydroxymethylglutaryl-CoA reductase inhibitors are key elements. Anacetrapib and dalcetrapib are well tolerated, with mild gastrointestinal complaints reported more than with placebo. Although another CETP inhibitor, torcetrapib, was withdrawn from clinical development secondary to increased morbidity and mortality, neither anacetrapib nor dalcetrapib has demonstrated the adverse off-target effects portrayed with torcetrapib. CONCLUSIONS: Inhibition of CETP by anacetrapib and dalcetrapib represents an encouraging development in the management of dyslipidemia, particularly in patients with low HDL-C levels. Results of future trials are much anticipated, as these will clarify the role of anacetrapib and dalcetrapib in reduction of cardiovascular disease.

The role of red yeast rice for the physician.

Red yeast rice is an ancient Chinese dietary staple and medication used by millions of patients as an alternative therapy for hypercholesterolemia. In recent years, the use of red yeast rice has grown exponentially due to increased public interest in complementary and alternative medications and the publication of several randomized, controlled trials demonstrating its efficacy and safety in different populations. The most promising role for red yeast rice is as an alternative lipid-lowering therapy for patients who refuse to take statins because of philosophical reasons or patients who are unable to tolerate statin therapy due to statin-associated myalgias. However, there is limited government oversight of red yeast rice products, wide variability of active ingredients in available formulations, and the potential of toxic byproducts. Therefore, until red yeast rice products are regulated and standardized, physicians and patients should be cautious in recommending this promising alternative therapy for hyperlipidemia.

Thyroid hormone receptor and lipid regulation.

The concept of thyroid hormone (TH) analogs that retain the beneficial effects of TH excess on lipid lowering and fat metabolism, while avoiding any harmful effects on the heart, muscle, bone and other tissues, has interested scientists and physicians for several decades. While there have been many attempts to develop selective TH receptor (TR) modulators (STRMs) for safe lipid lowering, these approaches have failed consistently. This review details recent advances in the development of TRß subtype- and liver-selective STRM analogs, and presents the results of preliminary clinical trials with one of these compounds, eprotirome (KB-2115; Karo Bio AB).

HDL therapy: two kinds of right?

Cardiovascular disease remains the leading cause of morbidity and mortality globally. The disease is largely controlled with interventions managing atherogenic lipids including LDL and triglycerides. However a number of studies have shown that increasing HDL levels is likely to provide better outcomes for patients suffering from this disease. There has been an extensive research effort into understanding how HDL levels are regulated in the body and which pathways can be targeted therapeutically. The HDL metabolic pathway is however overwhelmingly complex. This has provided only limited success in trialing drugs designed to raise HDL. To add to the complexity HDL itself is a heterogeneous population of particles and there is controversy surrounding which HDL particle is the most cardio-protective. In addition there is varying opinions on which of the HDL cellular receptors are more important in humans (as opposed to what has been discovered in mice) in regulating these effects. In this article we explore the evidence for and against using the currently suggested methods of raising HDL and provide some evidence for how the adverse effects of these drugs could be corrected.