Transcript PowerPoint - 埼玉医科大学総合医療センター 内分泌・糖尿病内科

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.
Cuchel M, Meagher EA, du Toit Theron 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 HoFH Lomitapide 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.
2013年1月17日 8:30-8:55
８階 医局
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
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 (Ms Delah-anty); University of Minnesota,
Minneapolis (Dr Ban-tle); Baylor College of Medicine, Houston, Texas
(Dr Pownall); 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
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.
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.
Interventions Participants 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 antihyperglycemic medication).
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 antihyperglycemic medication.
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 antihyperglycemic medication.
Data are prevalence and 95%
CIs for any remission (partial or
complete). Estimates are based
on sample with multiple
imputation (n = 4503). In complete case analysis (year 1: n =
4327; year 2: n = 4191; year 3: n
= 4168; year 4: n = 4098), prevalence 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)
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).
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).
Conclusions In 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 remission rates were modest.
Trial Registration clinicaltrials.gov Identifier: NCT00017953
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!!!
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
Lomitapide has a December 29, 2012, PDUFA date and Mipromersen has a January 29, 2013,
PDUFA date. (The Prescription Drug User Fee Act )
Mipromersenは2010年3月25日の抄読会でとりあげています
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
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
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
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 Toit Theron 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); Ospedale Niguarda, 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 Plessis MMed); and Aegerion Pharmaceuticals,
Cambridge, MA, USA (L T Bloedon, W J Sasiela PhD
Lancet 2013; 381: 40–46
Background Patients with
homozygous familial hypercholesterolaemia respond
inadequately to existing drugs. We
aimed to assess the efficacy and
safety of the microsomal triglyceride
transfer protein inhibitor lomitapide
in adults with this disease.
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.
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).
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.
2
One subject was escalated
against protocol specified rules
to 80 mg for about 1 month.
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 effi
cacy 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.
Interpretation Our study suggests that
treatment with lomitapide could be a
valuable drug in the management of
homozygous familial hypercholesterolaemia.
Funding FDA Office of the Orphan Product
Development, Aegerion Pharmaceuticals.
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