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The effect of twelve weeks of treatment with ezetimibe on HDV RNA level in patients with chronic hepatitis D.
Abbas, Z, Saad, M, Asim, M, Abbas, M, Samejo, SA
The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology. 2020;(2):136-141
Abstract
BACKGROUND/AIMS: Sodium taurocholate co-transporting polypeptide (NTCP) is the receptor for the hepatitis B virus (HBV) and hepatitis D virus (HDV) entry into hepatocytes. Ezetimibe is a cholesterol-lowering drug that possesses the pharmacophore features to inhibit NTCP. This study evaluates the efficacy of ezetimibe in patients with chronic HDV infection in a nonrandomized trial. MATERIALS AND METHODS This proof of concept phase 2 trial evaluated the efficacy and safety of ezetimibe 10 mg daily in (interferon treatment-experienced or interferon ineligible) patients with chronic hepatitis D (CHD). Forty-four patients with CHD were recruited, 38 male and 6 female patients, mean age 35.2±8.7 (range 19-64). Fifteen (34%) patients were on concomitant nucleoside therapy, and cirrhosis was present in 14 subjects. The primary therapeutic endpoint was a decline in HDV RNA at one log or more from the baseline at week 12. RESULTS The mean HDV RNA level was 5.4±1.3 log10 IU/mL. HBeAg was non-reactive in 43 (98%). HBV DNA was undetectable in 28 (64%). One patient stopped treatment at week 4, and one patient did not follow-up. One log or more reduction in the HDV RNA levels was observed in 18/44 (41%) patients. No log reduction occurred in 16 patients, and 8 experienced a log increase. No adverse effects from the concomitant nucleoside analogue use or clinical cirrhosis were observed. The drug exhibited a positive safety profile. CONCLUSION Treatment of CHD patients with ezetimibe resulted in a one log reduction of viral load in 43% (18/42) of the patients who completed the 12 weeks of therapy.
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Efficacy and Safety of Alirocumab Versus Ezetimibe Over 2 Years (from ODYSSEY COMBO II).
El Shahawy, M, Cannon, CP, Blom, DJ, McKenney, JM, Cariou, B, Lecorps, G, Pordy, R, Chaudhari, U, Colhoun, HM
The American journal of cardiology. 2017;(6):931-939
Abstract
The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab has been shown to substantially reduce low-density lipoprotein cholesterol (LDL-C). Demonstrating whether efficacy and safety are maintained over a long duration of exposure is vital for clinical decision-making. The COMBO II trial compared the efficacy and safety of alirocumab versus ezetimibe over 2 years. A prespecified first analysis was reported at 52 weeks. Here we report the final end-of-study data (on-treatment) and evaluate post hoc the safety profile with longer versus shorter duration of alirocumab exposure. Patients (n = 720) on maximally tolerated statin dose were treated with alirocumab (75/150 mg every 2 weeks) or ezetimibe (10 mg/day). Overall mean adherence for both treatment groups during the first and second year was >97%. At 2 years, LDL-C was reduced by 49% (alirocumab) versus 17% (ezetimibe; p <0.0001), and LDL-C <70 mg/dl was achieved by 73% of alirocumab-treated versus 40% of ezetimibe-treated patients. Overall safety was similar in both treatment groups at 2 years and during the first versus the second year. Local injection-site reactions were reported by 2.5% (alirocumab) versus 0.8% (ezetimibe) during the first year, and 0.2% versus 0.5% during the second year, indicating early occurrence during prolonged alirocumab exposure. Two consecutive calculated LDL-C values <25 mg/dl were observed in 28% of alirocumab-treated patients (vs 0.4% with ezetimibe). Persistent anti-drug antibody responses were observed in 1.3% (6 of 454) of alirocumab-treated versus 0.4% (1 of 231) of ezetimibe-treated patients. Neutralizing antibodies (that inhibit binding in vitro) were observed in 1.5% (7 of 454) of alirocumab-treated patients (0 with ezetimibe), mostly at isolated time points. Alirocumab sustained substantial LDL-C reductions and was well tolerated up to 2 years in the COMBO II trial.
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Thyroid Hormone Status in Sitosterolemia Is Modified by Ezetimibe.
Othman, RA, Myrie, SB, Mymin, D, Roullet, JB, DeBarber, AE, Steiner, RD, Jones, PJH
The Journal of pediatrics. 2017;:198-204.e1
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OBJECTIVES To assess the association between biomarkers of thyroid status and 5α-stanols in patients with sitosterolemia treated with ezetimibe (EZE). STUDY DESIGN Eight patients with sitosterolemia (16-56 years of age) were studied during 14 weeks off EZE therapy and 14 weeks on EZE (10 mg/day). Serum thyroid biomarkers (free triiodothyronine [FT3], free thyroxine [FT4], FT3/FT4 ratio, thyroid-stimulating hormone), 5α-stanols (sitostanol and cholestanol), and cholestanol precursors (total cholesterol and its synthesis marker lathosterol, and 7α-hydroxy-4-cholesten-3-one cholestenol) were measured at baseline and during the 14 weeks off EZE and on EZE. RESULTS EZE increased FT3/FT4 (10% ± 4%; P = .02). EZE reduced plasma and red blood cells sitostanol (-38% ± 6% and -20% ± 4%; all P < .05) and cholestanol (-18% ± 6% and -13% ± 3%; all P < .05). The change in plasma cholestanol level on EZE inversely correlated with the change in FT3/FT4 (r = -0.86; P = .01). EZE lowered total cholesterol (P < .0001) and did not affect 7α-hydroxy-4-cholesten-3-one cholestanol. EZE increased (P < .0001) lathosterol initially, but the level was not sustained, resulting in similar levels at week 14 off EZE and on EZE. CONCLUSION In patients with STSL, 5α-stanols levels might be associated with thyroid function. EZE reduces circulating 5α-stanols while increasing FT3/FT4, implying increased conversion of T4 to T3, thus possibly improving thyroid hormone status. TRIAL REGISTRATION ClinicalTrials.govNCT01584206.
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Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial.
Farnier, M, Jones, P, Severance, R, Averna, M, Steinhagen-Thiessen, E, Colhoun, HM, Du, Y, Hanotin, C, Donahue, S
Atherosclerosis. 2016;:138-46
Abstract
OBJECTIVE To compare lipid-lowering efficacy of adding alirocumab to rosuvastatin versus other treatment strategies (NCT01730053). METHODS Patients receiving baseline rosuvastatin regimens (10 or 20 mg) were randomized to: add-on alirocumab 75 mg every-2-weeks (Q2W) (1-mL subcutaneous injection via pre-filled pen); add-on ezetimibe 10 mg/day; or double-dose rosuvastatin. Patients had cardiovascular disease (CVD) and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL (1.8 mmol/L) or CVD risk factors and LDL-C ≥100 mg/dL (2.6 mmol/L). In the alirocumab group, dose was blindly increased at Week 12 to 150 mg Q2W (also 1-mL volume) in patients not achieving their LDL-C target. Primary endpoint was percent change in calculated LDL-C from baseline to 24 weeks (intent-to-treat). RESULTS 305 patients were randomized. In the baseline rosuvastatin 10 mg group, significantly greater LDL-C reductions were observed with add-on alirocumab (-50.6%) versus ezetimibe (-14.4%; p < 0.0001) and double-dose rosuvastatin (-16.3%; p < 0.0001). In the baseline rosuvastatin 20 mg group, LDL-C reduction with add-on alirocumab was -36.3% compared with -11.0% with ezetimibe and -15.9% with double-dose rosuvastatin (p = 0.0136 and 0.0453, respectively; pre-specified threshold for significance p < 0.0125). Overall, ∼80% alirocumab patients were maintained on 75 mg Q2W. Of alirocumab-treated patients, 84.9% and 66.7% in the baseline rosuvastatin 10 and 20 mg groups, respectively, achieved risk-based LDL-C targets. Treatment-emergent adverse events occurred in 56.3% of alirocumab patients versus 53.5% ezetimibe and 67.3% double-dose rosuvastatin (pooled data). CONCLUSIONS The addition of alirocumab to rosuvastatin provided incremental LDL-C lowering versus adding ezetimibe or doubling the rosuvastatin dose.
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Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study.
Stroes, E, Guyton, JR, Lepor, N, Civeira, F, Gaudet, D, Watts, GF, Baccara-Dinet, MT, Lecorps, G, Manvelian, G, Farnier, M, et al
Journal of the American Heart Association. 2016;(9)
Abstract
BACKGROUND The PCSK9 antibody alirocumab (75 mg every 2 weeks; Q2W) as monotherapy reduced low-density lipoprotein-cholesterol (LDL-C) levels by 47%. Because the option of a monthly dosing regimen is convenient, ODYSSEY CHOICE II evaluated alirocumab 150 mg Q4W in patients with inadequately controlled hypercholesterolemia and not on statin (majority with statin-associated muscle symptoms), receiving treatment with fenofibrate, ezetimibe, or diet alone. METHODS AND RESULTS Patients were randomly assigned to placebo, alirocumab 150 mg Q4W or 75 mg Q2W (calibrator arm), with dose adjustment to 150 mg Q2W at week (W) 12 if W8 predefined LDL-C target levels were not met. The primary efficacy endpoint was LDL-C percentage change from baseline to W24. Mean baseline LDL-C levels were 163.9 mg/dL (alirocumab 150 mg Q4W, n=59), 154.5 mg/dL (alirocumab 75 mg Q2W, n=116), and 158.5 mg/dL (placebo, n=58). In the alirocumab 150 mg Q4W and 75 mg Q2W groups (49.1% and 36.0% of patients received dose adjustment, respectively), least-squares mean LDL-C changes from baseline to W24 were -51.7% and -53.5%, respectively (placebo [+4.7%]; both groups P<0.0001 versus placebo). In total, 63.9% and 70.3% of alirocumab-treated patients achieved their LDL-C targets at W24. Treatment-emergent adverse events occurred in 77.6% (alirocumab 150 mg Q4W), 73.0% (alirocumab 75 mg Q2W), and 63.8% (placebo) of patients, with injection-site reactions among the most common treatment-emergent adverse events. CONCLUSIONS Alirocumab 150 mg Q4W can be considered in patients not on statin with inadequately controlled hypercholesterolemia as a convenient option for lowering LDL-C. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT02023879.
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Modulation of adhesion molecules by cholesterol-lowering therapy in mononuclear cells from hypercholesterolemic patients.
Cerda, A, Rodrigues, AC, Alves, C, Genvigir, FD, Fajardo, CM, Dorea, EL, Gusukuma, MC, Pinto, GA, Hirata, MH, Hirata, RD
Cardiovascular therapeutics. 2015;(4):168-76
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INTRODUCTION Cholesterol-lowering therapy has been related with several pleiotropic effects including anti-inflammatory action in vascular endothelium; however, their influence on monocyte adhesion molecules is poorly described. AIMS To investigate the effect of inhibitors of synthesis (statins) and absorption (ezetimibe) of cholesterol on expression of adhesion molecules L-selectin, PSGL-1, VLA-4, LFA-1, and Mac-1 in mononuclear cells in vivo and in vitro using THP-1 cells. METHODS The influence of simvastatin (10 mg/day), ezetimibe (10 mg/day), and their combination (10 mg each/day) on mRNA expression of adhesion molecules was analyzed in peripheral blood mononuclear cells (PBMC) from hypercholesterolemics. The effects of atorvastatin, simvastatin, and ezetimibe on mRNA and protein expression of adhesion molecules were also evaluated in THP-1 cells. RESULTS Simvastatin/ezetimibe combination, but not the monotherapies, reduced the mRNA expression of the PSGL-1, LFA-1, and Mac-1 genes in PBMC from hypercholesterolemics. Total and LDL cholesterol in serum correlated with PSGL-1 mRNA expression, whereas HDL cholesterol negatively correlated with mRNA levels of L-selectin and VLA-4 genes (P < 0.05). Plasma hsCRP was also correlated with mRNA levels of VLA-4, LFA-1, and Mac-1 (P < 0.05). Atorvastatin and simvastatin at 10 μM reduced mRNA and protein expression of L-selectin, PSGL-1, and VLA-4 in THP-1 cells (P < 0.05). CONCLUSION Cholesterol-lowering therapy modulates gene expression of adhesion molecules in PBMC from hypercholesterolemics and THP-1 cells. Simvastatin/ezetimibe combination gives more benefits by reducing to a larger extent the expression of adhesion molecules in mononuclear cells.