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Journal Club

Journal Club. Gregg EW, Chen H, Wagenknecht LE, Clark JM, Delahanty LM, Bantle J, Pownall HJ, Johnson KC, Safford MM, Kitabchi AE, Pi- Sunyer FX, Wing RR, Bertoni AG; for the Look AHEAD Research Group .

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Journal Club

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  1. Journal Club Gregg EW, Chen H, Wagenknecht LE, Clark JM, Delahanty LM, Bantle J, Pownall HJ, Johnson KC, Safford MM, Kitabchi AE, Pi-Sunyer FX, Wing RR, Bertoni AG; for the Look AHEAD Research Group. Association of an Intensive Lifestyle Intervention With Remission of Type 2 Diabetes. JAMA. 2012 Dec 19;308(23):2489-2496. CuchelM, Meagher EA, du ToitTheron H, Blom DJ, Marais AD, Hegele RA, Averna MR, Sirtori CR, Shah PK, Gaudet D, Stefanutti C, Vigna GB, Du Plessis AM, Propert KJ, Sasiela WJ, Bloedon LT, Rader DJ; Phase 3 HoFHLomitapide Study investigators. 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 Jan 5;381(9860):40-6. 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 2013年1月17日8:30-8:55 ８階　医局

  2. Centers for Disease Control and Pre-vention, Atlanta, Georgia (Dr Gregg); Wake Forest School of Medicine, Winston-Salem, North Carolina (Drs Chen, Wagenknecht, and Bertoni); The Johns Hopkins Medical Institutions, Baltimore, Maryland (Dr Clark); Massachusetts General Hospital, Boston (MsDelah-anty); University of Minnesota, Minneapolis (Dr Ban-tle); Baylor College of Medicine, Houston, Texas (DrPownall); University of Tennessee Health Science Cen-ter, Memphis (Drs Johnson and Kitabchi); University of Alabama at Birmingham (Dr Safford); St Luke’s– Roosevelt Hospital/Columbia University, New York, New York (Dr Pi-Sunyer); and Miriam Hospital/Brown Medi-cal School, Providence, Rhode Island (Dr Wing) The Look AHEAD (Action for Health for Diabetes) study is perhaps the largest randomized controlled trial of an intensive lifestyle intervention among adults with type 2 diabetes to date. JAMA. 2012;308(23):2489-2496

  3. Context The frequency of remission of type 2 diabetes achievable with lifestyle intervention is unclear. Objective To examine the association of a long-term intensive weight-loss intervention with the frequency of remission from type 2 diabetes to prediabetes or normoglycemia.

  4. Design, Setting, and Participants Ancillary observational analysis of a 4-year randomized controlled trial (baseline visit, August 2001–April 2004; last follow-up, April 2008) comparing an intensive lifestyle intervention (ILI) with a diabetes support and education control condition (DSE) among 4503 US adults with body mass index of 25 or higher and type 2 diabetes. InterventionsParticipants were randomly assigned to receive the ILI, which included weekly group and individual counseling in the first 6 months followed by 3 sessions per month for the second 6 months and twice-monthly contact and regular refresher group series and campaigns in years 2 to 4 (n=2241) or the DSE, which was an offer of 3 group sessions per year on diet, physical activity, and social support (n=2262). Main Outcome Measures Partial or complete remission of diabetes, defined as transition from meeting diabetes criteria to a prediabetes or nondiabetic level of glycemia(fasting plasma glucose 126 mg/dL and hemoglobin A1c 6.5% with no an-tihyperglycemic medication).

  5. Partial remission of diabetes was defined as a transition from meeting diabetes criteria to a prediabetes level of glycemia (ie, fasting plasma glucose level of 100-126 mg/dL and HbA 1c of 5.7%-6.5%) with no antihyperglycemicmedication. Complete remission was defined as transition from diabetes criteria to full normalization of glucose (fasting plasma glucose level100 mg/dL and HbA1c5.7%) with no antihyperglycemicmedication.

  6. Data are prevalence and 95% CIs for any remission (partial or complete). Estimates are based on sample with multiple imputation (n = 4503). In com-plete case analysis (year 1: n = 4327; year 2: n = 4191; year 3: n = 4168; year 4: n = 4098), preva-lence estimates with raw cases/denominators were as follows: for intensive lifestyle intervention, year 1: 11.5% (95% CI, 10.1%-12.8%) (247/2157); year 2: 10.4% (95% CI, 9.1%-11.7%) (218/2090); year 3: 8.7% (95% CI, 7.5%-9.9%) (181/2083); and year 4: 7.3% (95% CI, 6.2%-9.4%) (150/ 2056); for diabetes support and education, year 1: 2.0% (95% CI, 1.4%-2.6%) (43/2170); year 2: 2.3% (95% CI, 1.6%-2.9%) (48/2101); year 3: 2.2% (95% CI, 1.6%-2.8%) (46/2085); and year 4: 2.0% (95% CI, 1.5%-2.7%) (41/2042)

  7. Data are estimates and 95% CIs based on sample with multiple imputation (n = 4503). Estimates from complete case analysis of persons with no missing data element at any single year (n = 3713) were as follows: for intensive lifestyle intervention, year 1: 14.6% (95% CI, 13.0%-16.2%) (271/1852); year 2: 8.2% (95% CI, 6.8%-9.2%) (148/1852); year 3: 5.8% (95% CI, 4.7%-6.8%) (107/1852); and year 4: 3.4% (95% CI, 2.6%-4.2%) (63/1852); for dia-betes support and education, year 1: 4.3% (95% CI, 3.4%-5.2%) (80/1861); year 2: 1.6% (95% CI, 1.0%-2.1%) (29/1861); year 3: 1.2% (95% CI, 0.7%-1.7%) (22/1861); and year 4: 0.4% (95% CI, 0.1%-0.7%) (8/1861).

  8. Results Intensive lifestyle intervention participants lost significantly more weight than DSE participants at year 1 (net difference, －7.9%; 95% CI, －8.3% to －7.6%) and at year 4 ( 3.9%; 95% CI, 4.4% to 3.5%) and had greater fitness increases at year 1 (net difference, 15.4%; 95% CI, 13.7%-17.0%) and at year 4 (6.4%; 95% CI, 4.7%-8.1%) (P<.001 for each). The ILI group was significantly more likely to experience any remission (partial or complete), with prevalences of 11.5% (95% CI, 10.1%-12.8%) during the first year and 7.3% (95% CI, 6.2%-8.4%) at year 4, compared with 2.0% for the DSE group at both time points (95% CIs, 1.4%-2.6% at year 1 and 1.5%-2.7% at year 4) (P .001 for each). Among ILI participants, 9.2% (95% CI, 7.9%-10.4%), 6.4% (95% CI, 5.3%-7.4%), and 3.5% (95% CI, 2.7%-4.3%) had continuous, sus-tained remission for at least 2, at least 3, and 4 years, respectively, compared with less than 2% of DSE participants (1.7% [95% CI, 1.2%-2.3%] for at least 2 years; 1.3% [95% CI, 0.8%-1.7%] for at least 3 years; and 0.5% [95% CI, 0.2%-0.8%] for 4 years).

  9. ConclusionsIn these exploratory analyses of overweight adults, an intensive life-style intervention was associated with a greater likelihood of partial remission of type 2 diabetes compared with diabetes support and education. However, the absolute re-mission rates were modest. Trial Registration clinicaltrials.gov Identifier: NCT00017953

  10. Message 体格指数25以上の2型糖尿病（DM）患者4503人を対象に、長期的な減量の強化介入のDM寛解効果を無作為化比較試験で評価。生活習慣への強化介入（ILI）群はDM支援・教育コントロール（DSE）群に比べて、主要評価項目の寛解率が有意に高かった（1年時2.0％対11.5％、4年時2.0％対7.3％、各P＜0.001）。 寛解を薬物療法なしで保つのは無理!!!

  11. The Food and Drug Administration (FDA) Endocrinologic and Metabolic Drugs Advisory Committee tackled another lipid-lowering drug today for the treatment of homozygous familial hypercholesterolemia (FH), voting 9 to 6 in favor of approving mipomersen (Genzyme, Cambridge, MA) as an adjunct to maximally tolerated lipid-lowering medications for the reduction of LDL and total cholesterol levels, as well as the reduction of apolipoprotein B (apoB), apoA, and non-LDL cholesterol. Yesterday, the same panel voted 13 to 2 in favor of recommending approval of lomitapide (Aegerion Pharmaceuticals, Cambridge, MA) as an adjunct to a low-fat diet and other lipid-lowering drugs, with or without LDL apheresis, to reduce LDL-cholesterol levels in patients with homozygous FH. In contrast with lomitapide, an oral agent, mipomersen would be available as a 200-mg once-weekly subcutaneous injection. Mipomersen also differs in its mechanism of action, the drug being a first-in-class antisense oligonucleotide (ASO) inhibitor that targets apoB-100. Today, however, the panel wasn't quite as sold on the benefits of mipomersen, questioning the drug's relatively "modest" reductions in LDL-cholesterol levels, but felt the drug did provide benefit in the extremely rare but difficult-to-treat homozygous-FH population. October 18, 2012 http://www.theheart.org/article/1460651.do

  12. Lomitapide has a December 29, 2012, PDUFA date and Mipromersen has a January 29, 2013, PDUFA date.(The Prescription Drug User Fee Act ) アンチセンスオリゴ核酸阻害剤　mipomersen（ antisense oligonucleotide inhibitor ；Gezyme社製） 世界で第２番目のアンチセンス医薬初めて静脈注射製剤(サイトメガロウイルス網膜炎治療薬のホミビルセン(fomivirsen)が１番目のアンチセンス医薬) Mipomersen (previously ISIS 301012, trade name Kynamro) is a cholesterol-reducing drug candidate. It is an antisense therapeutic that targets the messenger RNA for apolipoprotein B. It is administered as a weekly injection. 2012年12月13日に欧州医薬品庁(EMA）のthe Committee for Medicinal Products for Human Use (CHMP) が、認可拒絶を勧告 Mipromersenは2010年3月25日の抄読会でとりあげています

  13. What is PDUFA? PDUFA, as noted above, stands for the Prescription Drug User Fee Act, originally passed in 1992. In its most simple terms, the legislation authorized the FDA to begin collecting fees from drug sponsors that would be utilized to expand review staff so that new drugs could be reviewed more quickly. The act has been periodically reviewed and expanded upon through reauthorizations and is currently in its fourth iteration. What is a PDUFA date? The new system established set time periods for the FDA to review a new application, usually set at a 10-month period. If a drug, however, gets a priority review designation, then the review time will be set at 6 months. (A priority review is given to drugs that offer a significant new breakthrough in treatment, or offer a treatment where none or few exist, and can be given for a drug which treats a serious condition as well as those that treat less serious conditions). The timing for the clock to tick begins when the company submits the new drug application to the FDA. The date is a target for FDA, but the agency can, and many times does, announce a decision prior to the PDUFA date. http://www.eyeonfda.com/eye_on_fda/2010/07/what-is-pdufa.html

  14. 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). 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. http://en.wikipedia.org/wiki/Lomitapide

  15. Institute for Translational Medicine and Therapeutics, Cardiovascular Institute, and Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA (M Cuchel MD, E A Meagher MD, L T Bloedon MS, Prof K J Propert ScD, Prof D J Rader MD); Netcare Private Hospital, Bloemfontein, South Africa (Prof H du ToitTheron MD); Department of Medicine (D J Blom PhD) and Department of Chemical Pathology (Prof A D Marais MD), University of Cape Town, Cape Town, South Africa; Medical Research Council of South Africa, Cape Heart Group, Cape Town, South Africa (D J Blom, A D Marais); Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada(Prof R A Hegele FRCP); Università di Palermo, Palermo, Italy (Prof M R Averna MD); OspedaleNiguarda, Milano, Italy(Prof C R Sirtori MD); Division of Cardiology and Atherosclerosis Research Center, Cedars-Sinai Heart Institute, Los Angeles, CA, USA (Prof P K Shah MD); Department of Medicine, Université de Montreal, Chicoutimi, Quebec, Canada (D Gaudet MD); Extracorporeal Therapeutic Techniques Unit, Immunohematology and Transfusion Medicine, Department of Molecular Medicine, University of Rome ‘Sapienza’, Italy (C Stefanutti MD); Department of Clinical and Experimental Medicine, Università of Ferrara, Italy(G B Vigna MD); Clinical Research Unit, University of Pretoria, Pretoria, South Africa (A M E Du PlessisMMed); and Aegerion Pharmaceuticals, Cambridge, MA, USA (L T Bloedon, W J Sasiela PhD Lancet2013; 381: 40–46

  16. BackgroundPatients with homozygous familial hyper-cholesterolaemiarespond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapidein adults with this disease.

  17. Methods We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model.

  18. Figure 2: Alanine transaminase and aspartate transaminase levels and percentage of hepatic fat in the liver Data are mean, 95% CI. Laboratory reference ranges for alanine transaminase levels were 10–40 U/L in men and 10–33 U/L in women; reference ranges for aspartate transaminase levels were 10–43 U/L in men and 10–36 U/L in women (A). Percentage of fat in the liver, as measured by nuclear magnetic resonance spectroscopy at baseline and 26, 56, and 78 weeks of lomitapide treatment (n=20; B).

  19. Supplemental Table 4: Treatment-emergent adverse events (TEAE) reported in 10% or more of all Subjects during the study 1 Patients may be counted more than once across lomitapide dose levels as the TEAEs are tabulated by dose at onset and patients were escalated through the dose levels to achieve maximum tolerated dose. The All Patients column includes overall incidence with patients counted only once if they experienced the event. 2One subject was escalated against protocol specified rules to 80 mg for about 1 month.

  20. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI –62 to –39) from baseline (mean 8•7 mmol/L [SD 2•9]) to week 26 (4•3 mmol/L [2•5]; p<0•0001). Levels of LDL cholesterol were lower than 2•6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI –57 to –31; p<0•0001) at week 56 and 38% (–52 to –24; p<0•0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities.

  21. Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hyper-cholesterolaemia. Funding FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.

  22. Message 18歳以上のホモ接合体の家族性高コレステロール血症（FT）患者23人を対象に、ミクロソームトリグリセリド転移タンパク質（MTP）阻害薬lomitapideの有効性を第3相試験で検討。主要評価項目の26週目のベースラインからのLDLコレステロール値の平均変化は50％の低下だった。56週で44％、78週で38％低下した。 LDL-C低下させるのにMTP阻害薬もあり！ ただし動脈硬化病変への効果は今後の課題

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