Presentation on theme: "Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi."— Presentation transcript:
Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2014 年 4 月 10 日 8:30-8:55 ８階 医局 Blom DJ1, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, Ceska R, Roth E, Koren MJ, Ballantyne CM, Monsalvo ML, Tsirtsonis K, Kim JB, Scott R, Wasserman SM, Stein EA; the DESCARTES Investigators. A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia. N Engl J Med Mar 29. doi: /NEJMoa Lincoff AM1, Tardif JC2, Schwartz GG3, Nicholls SJ4, Rydén L5, Neal B6, Malmberg K7, Wedel H8, Buse JB9, Henry RR10, Weichert A11, Cannata R1, Svensson A11, Volz D11, Grobbee DE12; for the AleCardio Investigators. Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus: The AleCardio Randomized Clinical Trial. JAMA Mar 30. doi: /jama
PCSK9 (Proprotein convertase subtilisin/kexin type 9, neural apoptosis-regulated convertase, NARC-1) is a 692-residue extracellular protein representing the 9th member of the secretory subtilase family expressed primarily in the kidneys, liver and intestines. Genetic studies mapped PCSK9 along with LDLR and APOB to cause autosomal dominant hypercholesterolemia (ADH). Gain-of-function mutations increased plasma levels of low-density lipoprotein cholesterol (LDL-C), whereas nonsense or missense (loss-of-function) mutations, which interfere with folding or secretion of PCSK9, led to a reduction of plasma levels of LDL-C and an 88% decrease in the risk of coronary heart disease (CHD). see Nature Genetics 34, (2003)
Cuchel M et al.Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study.Lancet 2013;381: Stein EA et al.Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol.N Engl J Med 2012; 366: Koren MJ et al.Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL).The Lancet, Early Online Publication, 6 November Giugliano RP et al.Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57).The Lancet, Early Online Publication, 6 November Roth EM et al.Atorvastatin with or without an Antibody to PCSK9 in Primary Hypercholesterolemia.N Engl J Med 2012; 367: Dirk J. B,et al.A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia.N Engl J Med Mar 29. [Epub ahead of print] Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, Hutabarat RM, Clausen VA, Karsten V, Cehelsky J, Nochur SV, Kotelianski V, Horton J, Mant T, Chiesa J, Ritter J, Munisamy M, Vaishnaw AK, Gollob JA, Simon A. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet Oct 1. pii: S (13) doi: /S (13)
N Engl J Med 2012;366: single ascending-dose studies of REGN727 抗体治療！！
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Figure 3 Lancet Oct 1. pii: S (13) doi: /S (13) Effect of ALN-PCS treatment on plasma PCSK9 concentration a small interfering RNA that inhibits PCSK9 synthesis
Figure 4Effect of ALN-PCS treatment on serum LDL cholesterol a small interfering RNA that inhibits PCSK9 synthesis Lancet Oct 1. pii: S (13) doi: /S (13)
the Division of Lipidology, Department of Medicine, University of Cape Town, Cape Town (D.J.B.), and TREAD Research, Cardiology Unit, Department of Internal Medicine, Tygerberg Hospital and Stellenbosch University, Parow (L.B.) — both in South Africa; Center for Clinical and Basic Research, Pardubice (T.H.), and Center of Preventive Cardiology, Third Department of Internal Medicine, Charles University, Prague (R.C.) — both in the Czech Republic; Bethesda Health Research Center, Bethesda, MD (M.B.); Lillestol Research, Fargo, ND (M.J.L.); Midwest Institute for Clinical Research, Indianapolis (P.D.T.); Sterling Research Group (E.R.) and Metabolic and Atherosclerosis Research Center (E.A.S.) — both in Cincinnati; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); Baylor College of Medicine and the Houston Methodist DeBakey Heart and Vascular Center, Houston (C.M.B.); Amgen, Thousand Oaks, CA (M.L.M., J.B.K., R.S., S.M.W.); and Amgen, Uxbridge, United Kingdom (K.T.). March 29, 2014 DOI: /NEJMoa
Background Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab.
Methods We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52.
Mean (SE) PCSK9 Concentration Over Time in AMG 145 First-in-Human Study
Figure 1. Enrollment and Outcomes. Patients were included in the safety and efficacy analyses if they had the required data available for the result of interest. For example, for the primary end point, patients needed to have data for low-density lipoprotein cholesterol levels at baseline and at 52 weeks. Reasons for screening exclusions before the run-in period are not available.
Figure 2. Percent Reduction from Baseline in Low-Density Lipoprotein (LDL) Cholesterol Levels in the Evolocumab Group, as Compared with the Placebo Group, at Weeks 12 and 52, According to Background Lipid-Lowering Therapy. Values are means with lower 95% confidence limits (as indicated by T bars) in the active-treatment groups after taking into account the values in the placebo group. LDL cholesterol was measured by means of ultracentrifugation separation.
Results Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non–high- density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain.
Conclusions At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high- dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT )
Ribbon diagram and close-up view of the ligand binding pockets derived from co- crystal structures of aleglitazar in a ternary complex with a) the PPARα ligand binding domain and a 13-residue fragment of SRC1 motif 3 (KDHQLLRYLLDKD) (PDB: 3G8I), and b) the PPARγ ligand binding domain and a 13-residue fragment of SRC1 motif 1 (QTSHKLVQLLTTT) (PDB: 3G9E). The SRC1 fragments are shown in green and aleglitazar is shown in space- filling model. Protein–ligand hydrogen bonds are shown as red, dashed lines. For comparison, models of fenofibrate in PPARα (based on the X-ray complex with GW735, PDB: 2P54) and pioglitazone in PPARγ (based on the X-ray complex with rosiglitazone, PDB: 1FM6) are overlaid onto aleglitazar in the right panels. The dotted ellipses show additional hydrophobic interaction atoms present in aleglitazar that are not present in pioglitazone. PPARα ligand binding domain the PPARγ ligand binding domain
Department of Cardiovascular Medicine, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio (Lincoff, Cannata); Montreal Heart Institute Coordinating Center, Universite de Montreal, Montreal, Canada (Tardif); Veterans Affairs Medical Center and University of Colorado School of Medicine, Denver (Schwartz); South Australian Health and Medical Research Institute, University of Adelaide, Adelaide (Nicholls); Department of Medicine, Karolinska Institutet, Stockholm, Sweden (Ryden, Malmberg); George Institute for Global Health, University of Sydney, Sydney, Australia (Neal); F. Hoffman-La Roche Ltd, Basel, Switzerland (Malmberg,Weichert, Svensson, Volz); Nordic School of Public Health, Frolunda, Sweden (Wedel); University of North Carolina School of Medicine, Chapel Hill (Buse); University of California San Diego, San Diego (Henry); Julius Center for Health Sciences and Primary Care and Julius Clinical, University Medical Center Utrecht, Utrecht, the Netherlands (Grobbee). JAMA. doi: /jama
Importance No therapy directed against diabetes has been shown to unequivocally reduce the excess risk of cardiovascular complications. Aleglitazar is a dual agonist of peroxisome proliferator–activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles. Objective To determine whether the addition of aleglitazar to standard medical therapy reduces cardiovascular morbidity and mortality among patients with type 2 diabetes mellitus and a recent acute coronary syndrome (ACS).
Design, Setting, and Participants AleCardio was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted in 720 hospitals in 26 countries throughout North America, Latin America, Europe, and Asia-Pacific regions. The enrollment of 7226 patients hospitalized for ACS (myocardial infarction or unstable angina) with type 2 diabetes occurred between February 2010 and May 2012; treatment was planned to continue until patients were followed-up for at least 2.5 years and 950 primary end point events were positively adjudicated. Interventions Randomized in a 1:1 ratio to receive aleglitazar 150 µg or placebo daily. Main Outcomes and Measures The primary efficacy end point was time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Principal safety end points were hospitalization due to heart failure and changes in renal function.
Hazard Ratios for Primary Endpoint in Subgroups
Gastrointestinal Hemorrhages Cumulative Kaplan-Meier Estimates of Time to First Occurrence of Gastrointestinal Hemorrhage Includes only patients who received at least one dose of study drug and according to drug actually received. The increase in gastrointestinal bleeding seen in patients randomized to aleglitazar was an unexpected finding and has not been observed in prior studies of PPAR agonists. The mechanism is unknown, as safety and clinical studies showed no gastrointestinal toxicity or hemostatic abnormalities with aleglitazar, and there are no known pharmacodynamic interactions with aspirin or thienopyridines.
Results The trial was terminated on July 2, 2013, after a median follow-up of 104 weeks, upon recommendation of the data and safety monitoring board due to futility for efficacy at an unplanned interim analysis and increased rates of safety end points. A total of 3.1% of patients were lost to follow-up and 3.2% of patients withdrew consent. The primary end point occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo group (hazard ratio, 0.96 [95% CI, ]; P =.57). Rates of serious adverse events, including heart failure (3.4% for aleglitazar vs 2.8% for placebo, P =.14), gastrointestinal hemorrhages (2.4% for aleglitazar vs 1.7% for placebo, P =.03), and renal dysfunction (7.4% for aleglitazar vs 2.7% for placebo, P <.001) were increased.
Conclusions and Relevance Among patients with type 2 diabetes and recent ACS, use of aleglitazar did not reduce the risk of cardiovascular outcomes. These findings do not support the use of aleglitazar in this setting with a goal of reducing cardiovascular risk. Trial Registration clinicaltrials.gov Identifier:NCT