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 10 月 23 日 8:30-8:55 ８階 医局 Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, Wasserman SM, Stein EA; for the TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2014 Oct 1. pii: S0140-6736(14)61374-X. doi: 10.1016/S0140-6736(14)61374-X. Zhao D, Cho J, Kim MH, Friedman DS, Guallar E. Diabetes, Fasting Glucose, and the Risk of Glaucoma: A Meta-analysis. Ophthalmology. 2014 Oct 2. pii: S0161-6420(14)00697-6. doi: 10.1016/j.ophtha.2014.07.051.
KYNAMROTM (mipomersen sodium) KYNAMRO TM is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis Lancet 2010; 375: 998–1006
Lomitapide (INN, marketed as Juxtapid) is a drug for the treatment of familial hypercholesterolemia, developed by Aegerion Pharmaceuticals. It has been tested in clinical trials as single treatment and in combinations with atorvastatin, ezetimibe and fenofibrate. The US Food and Drug Administration (FDA) approved lomitapide on 21 December 2012, as an orphan drug to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non-high-density lipoprotein (non-HDL) cholesterol in patients with homozygous familial hypercholesterolemia (HoFH). http://en.wikipedia.org/wiki/Lomitapide Lomitapide inhibits the microsomal triglyceride transfer protein (MTP or MTTP) which is necessary for very low-density lipoprotein (VLDL) assembly and secretion in the liver.
PCSK9 (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. http://caltagmedsystems.blogspot.jp/2012/04/pcsk9-attractive-drug-target-for.html 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). Proprotein convertase subtilisin/kexin type 9
N Engl J Med 2012;366:1108-18. single ascending-dose studies of REGN727 抗体治療！！ Alirocumab SAR236553 (REGN727)
N Engl J Med 2012;367:1891-900. DOI: 10.1056/NEJMoa1201832 抗体治療 + スタチン Alirocumab SAR236553 (REGN727) primary hypercholesterolemia
Lancet. 2014 Jan 4;383(9911):60-8.Effect of ALN-PCS treatment on serum LDL cholesterol ALN-PCS:a small interfering RNA that inhibits PCSK9 synthesis
www.thelancet.com Published online October 2, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61374-X Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (Prof F J Raal PhD); Amgen Inc, One Amgen Center Drive, Thousand Oaks, CA, USA (N Honarpour MD, F Xu MS, R Scott MD, S M Wasserman MD); Division of Lipidology, Department of Medicine, University of Cape Town, UCT Faculty Health Sciences, Cape Town, South Africa (D J Blom MD); Vascular Medicine, Academic Medical Centre, Amsterdam, Netherlands (G Kees Hovingh MD); and Metabolic and Atherosclerosis Research Center, Cincinnati, OH, USA (Prof E A Stein PhD) Evolocumab (AMG 145)
Background Homozygous familial hypercholesterolaemia is a rare, serious disorder caused by very low or absent plasma clearance of LDL, substantially raised LDL cholesterol, and accelerated development of cardiovascular disease. Conventional lipid-lowering treatments are modestly effective. Evolocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), reduced LDL cholesterol by 16% in a pilot study. We now report results with evolocumab in a randomised, double-blind, placebo-controlled phase 3 trial.
Methods This randomised, double-blind, placebo-controlled phase 3 trial was undertaken at 17 sites in ten countries in North America, Europe, the Middle East, and South Africa. 50 eligible patients (aged ≥12 years) with homozygous familial hypercholesterolaemia, on stable lipid- regulating therapy for at least 4 weeks, and not receiving lipoprotein apheresis, were randomly allocated by a computer-generated randomisation sequence in a 2:1 ratio to receive subcutaneous evolocumab 420 mg or placebo every 4 weeks for 12 weeks. Randomisation was stratified by LDL cholesterol at screening (<11 mmol/L or ≥11 mmol/L) and implemented by a computerised interactive voice-response system. Patients, study personnel, and the funder were masked to treatment and to the efficacy results by the central laboratory not returning LDL cholesterol or any lipid results to the clinical sites after the baseline visit. The primary endpoint was percentage change in ultracentrifugation LDL cholesterol from baseline at week 12 compared with placebo, analysed by intention- to-treat. This trial is registered with ClinicalTrials.gov, number NCT01588496.
Data are mean (SD), range, n (%), or median (IQR). PCSK9=proprotein convertase subtilisin/kexin type 9.*Ethnicity was self-reported and some patients did not answer this question. Table 1: Baseline characteristics LDL-C 8.7mmol/L=336mg/dL LDL-C 9.2mmol/L=355mg/dL LDL-C 9.0mmol/L=347mg/dL HDL-C 1.0mmol/L=38.6mg/dL TG 1.3mmol/L=115mg/dL 0.0259 for Cholesterol 0.0113 for TG
Data are least- squares mean (95% CI) except for hsCRP data, which are median (IQR). Least-squares mean is from the repeated measures model, which includes treatment group, stratifi cation factor, scheduled visit, and interaction of treatment with scheduled visits as covariates for all endpoints. PCSK9=proprotei n convertase subtilisin/kexin type 9. hsCRP=high- sensitivity C- reactive protein. NA=not applicable. *Multiplicity adjustments following the Hochberg procedure were used to control for overall signifi cance at the 0·05 level of signifi cance for the primary and secondary endpoints. Table 2: Efficacy outcomes
Table 4: Adverse events ALT=alanine aminotransferase. AST=aspartate aminotransferase. ULN=upper limit of normal. *Reported in at least one patient in either or both treatment groups. †Searched with use of high-level term grouping, which includes injection-site rash, infl ammation, pruritus, reaction, or urticaria. ‡Searched with use of high-level grouping, which includes deliria (including confusion), cognitive and attention disorders and disturbances, dementia and amnestic disorders, disturbances in thinking and perception, and mental impairment disorders. §Excludes one patient who had a positive binding antibody test at baseline and negative antibody testing at all other study assessments.
Findings Of the 50 eligible patients randomly assigned to the two treatment groups, 49 actually received the study drug and completed the study (16 in the placebo group and 33 in the evolocumab group). Compared with placebo, evolocumab significantly reduced ultracentrifugation LDL cholesterol at 12 weeks by 30·9% (95% CI −43·9% to −18·0%; p<0·0001). Treatment-emergent adverse events occurred in ten (63%) of 16 patients in the placebo group and 12 (36%) of 33 in the evolocumab group. No serious clinical or laboratory adverse events occurred, and no anti-evolocumab antibody development was detected during the study.
Interpretation In patients with homozygous familial hypercholesterolaemia receiving stable background lipid-lowering treatment and not on apheresis, evolocumab 420 mg administered every 4 weeks was well tolerated and significantly reduced LDL cholesterol compared with placebo. Funding Amgen Inc.
Message ホモ接合体家族性高コレステロール血症（ FH ）患者 50 人を対象に、前駆たんぱく質転換酵素サブチリシン / ケ キシン 9 型（ PCSK9 ）に対するモノクローナル抗体 evolocumab の LDL コレステロール低下効果を第 3 相試 験で検討（ TESLA Part B 試験）。 12 週後、プラセボ に比べて evolocumab が LDL コレステロールを 30.9% 低下させた ( Ｐ＜ 0.0001) 。 大規模臨床治験中 ( 心血管障害リスク者 ) ODYSSEY (NCT01663402) with alirocumab, FOURIER (NCT01764633) with evolocumab, and SPIRE-1 (NCT01975389) and SPIRE-2 (NCT01975376) with bococizumab,
Department of Epidemiology and Welch Center for Prevention, Epidemiology, and Clinical Research, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. 2 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea. 3 Biostatistics and Clinical Epidemiology Center, Research Institute for Future Medicine, School of Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea. 4 Saevit Eye Hospital, Goyang, Gyeonggi-do, Korea. 5 Department of Epidemiology, Graduate School of Public Health, Seoul National University, Seoul, Korea. 6 Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland.
Topic: We performed a systematic review to summarize the association of diabetes and blood glucose levels with glaucoma, intraocular pressure (IOP), and ocular hypertension in the general population. Clinical Relevance: Diabetes has been proposed as a risk factor for glaucoma, but epidemiologic studies have been inconsistent, and the association is still controversial. Furthermore, no systematic reviews evaluated other metabolic abnormalities, such as the metabolic syndrome, with the risk of glaucoma.
Methods: We identified the studies by searching the PubMed and EMBASE databases. We used inversevariance weighted random-effects models to summarize relative risks across studies.
Results: We identified 47 studies including 2 981 342 individuals from 16 countries. The quality of evidence generally was higher in the cohort compared with case- control or cross-sectional studies. The pooled relative risk for glaucoma comparing patients with diabetes with those without diabetes was 1.48 (95% confidence interval [CI], 1.29-1.71), with significant heterogeneity across studies (I 2 = 82.3%; P < 0.001). The risk of glaucoma increased by 5% (95% CI, 1%-9%) for each year since diabetes diagnosis. The pooled average difference in IOP comparing patients with diabetes with those without diabetes was 0.18 mmHg (95% CI, 0.09-0.27; I 2 = 73.2%), whereas the pooled average increase in IOP associated with an increase in 10 mg/dl in fasting glucose was 0.09 mmHg (95% CI, 0.05-0.12; I 2 = 34.8 %)
Conclusions: Diabetes, diabetes duration, and fasting glucose levels were associated with a significantly increased risk of glaucoma, and diabetes and fasting glucose levels were associated with slightly higher IOP.