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
Elisa De Franco, Sarah E Flanagan, Jayne AL Houghton, Hana Lango Allen, Deborah JG Mackay, I
Karen Temple, Sian Ellard, Andrew T Hattersley
The effect of early, comprehensive genomic testing on clinical care in
neonatal diabetes: an international cohort study
Lancet, July 29, 2015 .
Melanie J. Davies, MD; Richard Bergenstal, MD; Bruce Bode, MD; Robert F. Kushner, MD; Andrew
Lewin, MD; Trine Vang Skjøth, MD; Arne Haahr Andreasen, MSc; Christine Bjørn Jensen, MD; Ralph
A. DeFronzo, MD
Efficacy of Liraglutide for Weight Loss Among Patients With Type 2
Diabetes The SCALE Diabetes Randomized Clinical Trial
JAMA. 2015;314(7):687-699. doi:10.1001/jama.2015.9676
2015年9月03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
Sellami Mnif Houda
文昌帝君
龍山寺（1738年創建）
MODY
http://www.diabetesgenes.org/content/mody-probability-calculator
HNF1A Glucokinase HNF4A Renal Cysts & Diabetes (HNF1B)
Neonatal Diabetes
KIR6.2/SUR1 (KCNJ11 ABCC8) Sulfonylurea therapy!
２型糖尿病の病態に関連する遺伝子
Nat Genet. 2012 Sep;44(9):981-90.
Article
The effect of early, comprehensive genomic
testing on clinical care in neonatal
diabetes: an international cohort study
Elisa De Franco, Sarah E Flanagan, Jayne AL Houghton, Hana Lango Allen,
Deborah JG Mackay, I Karen Temple, Sian Ellard, Andrew T Hattersley
Institute of Biomedical and Clinical Science, University of Exeter Medical School,
Exeter, UK (E De Franco PhD, S E Flanagan PhD, J A L Houghton PhD, H Lango
Allen PhD, Prof S Ellard PhD, Prof A T Hattersley DM) ; Wessex Regional Genetics
Laboratory, Salisbury Foundation Trust, Salisbury, UK (D J G Mackay PhD, Prof I K
Temple MD) ; University Hospital Southampton NHS Trust, Southampton, UK (D J G
Mackay, Prof I K Temple) ; and Human Genetics and Genomic Medicine, Faculty of
Medicine, University of Southampton, Southampton, UK (D J G Mackay)
Lancet. July 29, 2015
Traditional genetic testing (analysis of one or a few genes) is
changing
Improved sequencing methods enable simultaneous
analysis of several genes.
. Genetic subtype (Neonatal diabetes) defines treatment, with
improved glycaemic control on sulfonylurea treatment for most
patients with potassium channel mutations.
TARGET
To investigated the effect of early, comprehensive testing of all
known genetic causes of neonatal diabetes.
Methods
-Large, international, cohort study,
- patients with neonatal diabetes diagnosed with diabetes
before 6 months of age
-From 79 countries.
- Mutations were identified by comprehensive genetic testing
including Sanger sequencing, 6q24 methylation analysis, and
targeted next-generation sequencing of all known neonatal
diabetes genes.
Supplementary Table 2. Number and references for 253 patients included in the cohort who have been included in previous publications by the Exeter team.
PLAGL1 ?
Supplementary Table 3. Genetic causes of neonatal diabetes identified in 840 neonatal diabetes patients.
RESULTS:
- Recessive causes were common (158 [81%] of
195 patients) in the off spring of consanguineous
parents but unusual (81 [13%] of 645 patients)
when the parents were not consanguineous (p<0・
0001; df=1).
-The major genetic cause differed depending on
whether the parents were related
- Mutations in the INS gene were present at a
similar proportion in the two group
- In non-consanguineous group, most INS gene
mutations were heterozygous
46%
p<0·0001
12%
The pancreatic phenotypes include:
- Transient neonatal diabetes (6q24, ABCC8, KCNJ11,
INS, HNF1B, SLC2A2, ZFP57 subtypes), in which the
diabetes resolves
-Permanent diabetes responding to sulfonylurea
treatment (KCNJ11 and ABCC8)
- Permanent insulin-treated diabetes (INS, GCK,
EIF2AK3, FOXP3, GLIS3, NEUROD1, NEUROG3,
NKX2-2, MNX1, IER3IP1, RFX6, and some cases with
GATA6, GATA4 and PDX1 mutations)
- Developmental disorders of the exocrine pancreas
(GATA6, PTF1A, PDX1 and GATA4) requiring pancreatic
enzyme replacement in addition to insulin treatment
- Diabetes caused by SLC19A2 gene mutations can
sometimes be successfully treated with thiamine.
the identification of the genetic cause defines
the treatment requirements for the endocrine and
exocrine pancreatic function
Specific extra-pancreatic features (neurological features) are
being the most common (n=184). Mutations in nine genes
(ABCC8 [22% of cases], KCNJ11 [29% of cases], EIF2AK3,
SLC19A2, IER3IP1, PTF1A, NEUROD1, MNX1, and NKX22) cause neonatal diabetes with neurological abnormalities.
generally become evident in infancy, after diagnosis of
neonatal diabetes; therefore, early genetic diagnosis in these
patients predicts future development of neurological
complications.
The different genetic causes of neonatal diabetes identified so far
have a range of both pancreatic and extra-pancreatic phenotypes
The median time from the diagnosis of diabetes to referral for genetic
testing showed a marked decrease from more than 4 years (240
weeks, IQR 218–4099) in 2004, to less than 3 months (10 weeks,
IQR 3–23) since 2012
The number of referrals per year was steady during the past 10 years
at 80–100 per year
Patients with a genetic diagnosis of transient neonatal diabetes caused
by 6q24 methylation defects or potassium channel gene
mutations :Patient’s diabetes had remitted before referral was
dependent on the time from diagnosis to genetic testing; only 10 (10%)
of 101 patients tested early (48 months after diagnosis) had entered
remission when genetic testing was done (p <0·0001 )
(A) Effect of early
genetic diagnosis in
transient neonatal
diabetes caused by
6q24 methylation
defects or potassium
channel gene mutations.
Bar chart representing
clinical features at the
time of genetic testing
for neonatal diabetes.
Orange=diabetes,
purple=diabetes
remitted.
Wolcott-Rallison syndrome is caused by biallelic mutations in EIF2AK3, a gene known to be important
for regulation of endoplasmic reticulum stress (DG: the presence of insulin-dependent diabetes and
skeletal dysplasia or liver dysfunction)
(B) The effect of age at genetic testing on
whether patients have non-diabetes features of
Wolcott-Rallison Syndrome at the time of referral
for genetic testing.
Diabetes diagnosed in the first 6
months of life : skeletal dysplasia is
not evident until the infant is 1 or 2
years of age and liver dysfunction
generally manifests during
intercurrent illness as recurrent
episodes of acute liver failure
which can present at any time after
the neonatal diabetes
The non-diabetes features were
present only in 3 (12%) of 26
patients with early referral (48
months from diagnosis of diabetes;
p <0·0001
Bar chart representing clinical features at the
time of genetic testing for neonatal diabetes.
Orange=diabetes only, light blue=diabetes and
either skeletal abnormalities or liver dysfunction,
dark blue=diabetes, skeletal abnormalities, and
liver dysfunction.
Specific mutations in KCNJ11 and ABCC8 cause a syndromic form of neonatal diabetes
characterised by severe development delay and neurological features (DEND
[Developmental delay, Epilepsy and Neonatal Diabetes] and iDEND syndrome)
Neurological features were not present in any of the patients with early referral (0 of 7
referred 48 months from diagnosis of diabetes, p<0·0001 )
(C) The effect of age at genetic testing on whether patients with a KCNJ11
p.Val59Met mutation have neurological features at the time of referral for
genetic testing.
Bar chart representing clinical features at the time of genetic testing for
neonatal diabetes. Orange=diabetes only, green=diabetes and neurological
features
CONCLUSION
This study describes the transformation that can occur in clinical practice once
genetic testing becomes the initial investigation.
Traditionally, genetic testing was used to confirm a clinical diagnosis based on
disease course or a cluster of clinical features.
Now, early comprehensive genetic testing gives a diagnosis before the
development of specific features
The future of care in neonatal diabetes will increasingly rely on the results of
genetic testing with the genetic diagnosis, not only informing a clinician of the
likely course and best treatment for the diabetes, but also predicting
development of additional clinical features.
This model represents a new framework in which genetic testing defi nes,
rather than just confirms, the clinical diagnosis.
Message
2000-2013年に遺伝子検査を実施した新生児糖
尿病患者1020人を対象に、包括的早期遺伝子
検査の診療への影響をコホート研究で検討。新
生児糖尿病の発現から遺伝子検査を受けるまで
の期間が短くなっていた（2004年以前は4年、
2012年以降は3カ月）。3カ月以内の早期検査を
受けた患者で合併症率が少なく、寛解率が高
かった。
http://www.m3.com/clinical/journal/15734
Reviewed on 20091029
Astrup A, Rössner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, Madsen J, Rasmussen MF,
Lean ME; NN8022-1807 Study Group.: Effects of liraglutide in the treatment of obesity: a
randomised, double-blind, placebo-controlled study. Lancet. 2009 Nov 7;374(9701):1606-16. doi:
10.1016/S0140-6736(09)61375-1.
SCALE Obesity and Prediabetes
N Engl J Med. 2015 Jul 2;373(1):11-22. doi:
10.1056/NEJMoa1411892.
Figure 1. Liraglutide and Body Weight.
Panel A shows the mean body weight for patients in the fullanalysis set who completed each scheduled visit, according to
presence or absence of prediabetes at screening. I bars
indicate standard error, and the separate symbols above the
curves represent the 56- week weight change using lastobservation-carried-forward (LOCF) imputation. The fullanalysis set comprised patients who underwent randomization,
were exposed to at least one treatment dose, and had at least
one assessment after baseline (69 patients were excluded
from the full-analysis set: 61 owing to lack of an assessment
and 8 owing to no exposure). Panel B shows the proportions
of patients who lost at least 5%, more than 10%, and more
than 15% of their baseline body weight. Data shown are the
observed means for the full-analysis set (with LOCF). Findings
from logistic- regression analysis showed an odds ratio of 4.8
(95% confidence interval [CI], 4.1 to 5.6) for at least 5% weight
loss and an odds ratio of 4.3 (95% CI, 3.5 to 5.3) for more
than 10% weight loss; the analysis of more than 15% weight
loss was performed post hoc (odds ratio, 4.9 [95% CI, 3.5 to
6.7]). Panel C shows the cumulative percentage of patients
with those changes in body weight after 56 weeks of treatment.
Article
Efficacy of Liraglutide for Weight Loss
Among Patients With Type 2 Diabetes The
SCALE Diabetes Randomized Clinical Trial
Melanie J. Davies, MD; Richard Bergenstal, MD; Bruce Bode, MD; Robert
F. Kushner, MD; Andrew Lewin, MD; Trine Vang Skjøth, MD; Arne Haahr
Andreasen, MSc; Christine Bjørn Jensen, MD; Ralph A. DeFronzo, MD;
1Diabetes
Research Centre, University of Leicester, Leicester, United Kingdom
Diabetes Center, Park Nicollet Health Services, Minneapolis, Minnesota
3Atlanta Diabetes Associates, Atlanta, Georgia
4Northwestern University, Chicago, Illinois
5National Research Institute, Los Angeles, California
6Novo Nordisk A/S, Søborg, Denmark
7Texas Diabetes Institute, San Antonio
2International
JAMA. 2015;314(7):687-699. doi:10.1001/jama.2015.9676
- Weight loss is recommended for patients with type 2 diabetes.
-Moderate weight loss (5%-10%) can improve glycemic control and other
cardiometabolic risk factors and comorbidities .
- Liraglutide : analog of the incretin hormone (GLP-1),
a unique therapeutic potential for both obesity and type 2 diabetes
owing to its dual benefits on body weight and glycemic control.
TARGET:
To study the efficacy and safety of liraglutide (3.0mg), as an adjunct to diet and
exercise, for weight management in participants who :
1- were overweight or obese
2- had type 2 diabetes
METHODS:
56–week randomized double-blind, placebo controlled,
parallel-group trial with 12-week observational off-drug
follow-up period.
Study conducted at 126 sites in 9 countries between June
2011 and January 2013.
1361 Elligible patients
846 were randomized.
Inclusion criteria:
1-Body mass index of 27.0 or greater
2-Age 18 years or older
3-Taking 0 to 3 oral hypoglycemic agents (metformin,
thiazolidinedione, sulfonylurea)
4-Stable body weight, and glycated hemoglobin level 7-10%
Participants were randomly assigned (in a blinded
fashion; week0) to
Group liraglutide (3.0mg);
Or Group liraglutide (1.8mg);
or placebo in a 2:1:1 ratio.
Three coprimary end points at week 56:
(1)relative change in bodyweight;
(2)the proportion of participants losing 5% or more of
baseline body weight;
(3)proportion losing more than 10% of baseline
bodyweight.
Secondary efficacy end points included changes at
week 56 in waist circumference, BMI, HbA1c level,
prandial plasma glucose increment
RESULTS
No cases of acute pancreatitis were reported
In the present trial,
Few severe hypoglycemic episodes were reported (5 with liraglutide [3.0
mg], 3 with liraglutide [1.8 mg]), all in participants receiving concomitant
sulfonylurea therapy.
Measures of weight-related quality of life were significantly improved with
liraglutide (3.0 mg) but not liraglutide (1.8 mg), primarily driven by a
significant improvement in participants’ physical function.
Exploratory comparisons between the 2 doses of liraglutide showed that
liraglutide (3.0 mg) was statistically significantly better than liraglutide
(1.8 mg) on all weight- and glycemic-related end points; the difference
between the 3.0-mg dose and the 1.8-mg dose in reduction of HbA1c
level, while statistically significant, was small (0.19%), but the 3.0-mg
dose did lead to a larger reduction in participants’ use of oral
hypoglycemic agents compared with liraglutide (1.8 mg) .
The present study had several limitations. It was not powered to enable
conclusions about safety
Conclusion:
Among overweight and obese participants with type
2 diabetes, use of subcutaneous liraglutide (3.0
mg) daily, compared with placebo, resulted in
weight loss over 56 weeks. Further studies are
needed to evaluate longer-term efficacy and safety.
Message
過体重／肥満の2型糖尿病患者846人を対象に、リラグ
ルチド1日1回皮下注射の減量効果を無作為化試験で
検証（SCALE Diabetes試験）。56週後、プラセボ群に
比べリラグルチド3.0mg群および1.8mg群で体重減少
が大きく（差の推定値－4.00％［95％CI,－5.10％-－
2.90％］、－2.71％［95％CI,－4.00％-－1.42％］；いず
れもP＜0.001）、5％以上および 10％超の減量達成率
が高かった。
http://www.m3.com/clinical/journal/15787

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