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Journal Club
Blonde L, Jendle J, Gross J, Woo V, Jiang H, Fahrbach JL, Milicevic Z.
Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin
lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority
study.
Lancet. 2015 May 23;385(9982):2057-66. doi: 10.1016/S0140-6736(15)60936-9.
Blum MR, Bauer DC, Collet TH, Fink HA, Cappola AR, da Costa BR, Wirth CD, Peeters RP, Åsvold
BO, den Elzen WP, Luben RN, Imaizumi M, Bremner AP, Gogakos A, Eastell R, Kearney PM,
Strotmeyer ES, Wallace ER, Hoff M, Ceresini G, Rivadeneira F, Uitterlinden AG, Stott DJ,
Westendorp RG, Khaw KT, Langhammer A, Ferrucci L, Gussekloo J, Williams GR, Walsh JP, Jüni P,
Aujesky D, Rodondi N; Thyroid Studies Collaboration.
Subclinical thyroid dysfunction and fracture risk: a meta-analysis.
JAMA. 2015 May 26;313(20):2055-65. doi: 10.1001/jama.2015.5161.
2015年6月18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
The N-terminal amino acid
sequence of native human
GLP-1 is shown in light
green (centre) and the site
of cleavage by DPP4 is
indicated. The panels
show strategies employed
to develop a | exenatide
and lixisenatide; b |
taspoglutide; c | albiglutide
and dulaglutide; d |
liraglutide and e |
exenatide-LAR. Note that
development of
taspoglutide was halted in
2010, owing to an
increased incidence of
adverse gastrointestinal
effects and
hypersensitivity reactions.
Abbreviations: DPP4,
dipeptidyl peptidase 4;
GLP-1, glucagon-like
peptide 1; LAR, longacting release. Image from
the RCSB PDB
(www.pdb.org) of PDB ID
1AO6 ( Sugio, S. et al.
Crystal structure of human
serum albumin at 2.5 Å
resolution. Protein Eng. 12,
439–446 [1999]).
Nature Reviews Endocrinology 8, 728-742
a | Native GLP-1 is secreted from intestinal L
cells and acts directly on the pancreas to
stimulate insulin release and suppress glucagon
secretion. GLP-1 inhibits gastric motility, retards
gastric emptying and, through actions on the
CNS, reduces appetite but can induce nausea.
b | Short-acting GLP-1 receptor agonists inhibit
gastric motility, reducing transpyloric flow (solid
lines). These effects lead to delayed intestinal
glucose absorption and, indirectly, to a reduction
in postprandial insulin secretion, as well as
appetite suppression and induction of nausea
(dashed lines). Short-acting GLP-1 receptor
agonists also seem to have direct effects on the
CNS and on glucagon secretion.
c | Long-acting GLP-1 receptor agonists act
directly on the pancreas to stimulate insulin
secretion, and they suppress glucagon
secretion via paracrine release of somatostatin.
Through actions on the CNS, these agents also
reduce appetite and might induce nausea.
Nature Reviews Endocrinology 8, 728-742
Nature Reviews Endocrinology 8, 728-742
The two previous studies of GLP-1 receptor agonists comparing once-weekly with
once-daily dosing, DURATION-6 and HARMONY-7 (comparing liraglutide with
exenatide once-weekly and with albiglutide, respectively) had non-inferiority
margins of 0·25% and 0·30%, respectively, with sample sizes of 911 and 812
patients, compared with 599 patients in AWARD-6. Findings from these studies
showed between-treatment group differences of 0·21% (95% CI 0·08–0·33) for
DURATION-6 and 0·21% (0·08–0·34) for HARMONY-7, which did not show noninferiority to liraglutide.
JB Buse, M Nauck, T Forst, et al.
Exenatide once weekly versus liraglutide once daily in patients with type 2
diabetes (DURATION-6): a randomised, open-label study
Lancet, 381 (2013), pp. 117–124
RE Pratley, MA Nauck, AH Barnett, for the HARMONY 7 study group, et al.
Once-weekly albiglutide versus once-daily liraglutide in patients with type 2
diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised,
open-label, multicentre, non-inferiority phase 3 study
Lancet Diabetes Endocrinol, 2 (2014), pp. 289–297
AWARD-6 for movie
http://www.medscape.com/viewarticle/826899#2
Dulaglutide Weekly Injection (LY2189265)
a
The Ohio State University, Columbus, OH, USA
b Clínica Juaneda, Endocrinología, Palma de Mallorca, Spain
c Profil Mainz GmbH & Co KG, Mainz, Germany
d Universidad Autónoma de Nuevo León, Monterrey, NL, Mexico
e Lilly Diabetes, Eli Lilly and Company, Indianapolis, IN, USA
Lancet. 2014 Jul 10. pii: S0140-6736(14)60976-4. doi: 10.1016/S0140-6736(14)609764. [Epub ahead of print]
Figure 2: Trial outcome
measures (A) Change in
HbA1c from baseline to
week 26 (MMRM). (B)
HbA1c values from baseline
to week 26 (MMRM). (C)
Percentage of patients
achieving HbA1c targets.
(D) Change in fasting
plasma glucose
concentrations from
baseline to week 26, as
measured by a central
laboratory. (E) Seven-point
self-measured plasma
glucose by time of day. (F)
Bodyweight from baseline to
26 weeks (MMRM).
HbA1c=glycated
haemoglobin.
MMRM=mixed model for
repeated measures.
LSM=least-squares mean.
FSG=fasting serum glucose.
SMPG=seven-point selfmeasured glucose. *p<0·05.
•a Department of Endocrinology, Ochsner Medical Center, New Orleans, LA, USA
•b Endocrine and Diabetes Center, Karlstad Hospital, Örebro University, Örebro, Sweden
•c Federal University of Rio Grande do Sul, Porto Alegre, Brazil
•d Section of Endocrinology and Metabolism, University of Manitoba, Winnipeg, MB, Canada
•e Lilly Diabetes, Eli Lilly and Company, Indianapolis, IN, USA
•f Lilly Research Laboratories, Vienna, Austria
Lancet. 2015 May 23;385(9982):2057-66. doi: 10.1016/S0140-6736(15)60936-9.
Background
For patients with type 2 diabetes who do not
achieve target glycaemic control with
conventional insulin treatment, advancing to a
basal–bolus insulin regimen is often
recommended. We aimed to compare the efficacy
and safety of long-acting glucagon-like peptide-1
receptor agonist dulaglutide with that of insulin
glargine, both combined with prandial insulin
lispro, in patients with type 2 diabetes.
Methods
We did this 52 week, randomised, open-label, phase 3, noninferiority trial at 105 study sites in 15 countries. Patients
(aged ≥18 years) with type 2 diabetes inadequately
controlled with conventional insulin treatment were randomly
assigned (1:1:1), via a computer-generated randomisation
sequence with an interactive voice-response system, to
receive once-weekly dulaglutide 1·5 mg, dulaglutide 0·75 mg,
or daily bedtime glargine. Randomisation was stratified by
country and metformin use. Participants and study
investigators were not masked to treatment allocation, but
were unaware of dulaglutide dose assignment. The primary
outcome was a change in glycated haemoglobin A1c
(HbA1c) from baseline to week 26, with a 0·4% noninferiority margin. Analysis was by intention to treat. This trial
is registered with ClinicalTrials.gov, number NCT01191268.
Figure 1: Trial profile
One patient in the dulaglutide 1・5 mg group and another in the dulaglutide 0・75 mg group died after treatment discontinuation, but
while still in the study not taking the study drug. *19 screened patients at one site, eight of whom were randomised, were excluded
from analysis because of Good Clinical Practice compliance issues.
†Discontinuation of study treatment from week 0 to week 52. One patient in the dulaglutide 1・5 mg group, four patients in the
dulaglutide 0・75 mg, and two patients in the glargine group discontinued treatment because of severe, persistent hyperglycaemia
(prespecified criteria).
Table 1: Baseline characteristics
Figure 2: Efficacy variables
(A) Least-squares mean change in HbA1c from baseline to weeks 26 and 52 weeks and (B) over time. (C)
Proportion of patients achieving HbA1c targets; values above the bars are n (%). (D) Least-squares mean change
in FSG from baseline. (E) Baseline and 26 week 8-point SMPG profiles. (F) Change in weight over time. Error bars
show 95% CIs. HbA1c=glycated haemoglobin A1c. FSG=fasting serum glucose. SMPG=self-monitored plasma
Table 3: Adverse events, changes from
baseline in vital signs, and treatmentemergent dulaglutide antidrug antibodies
from baseline to 52 weeks
Data are n (%), unless otherwise indicated.
p values are for dulaglutide vs insulin
glargine.
Hypersensitivity events were assessed with
specifi c standardised MedDRA queries
(anaphylactic reaction, angioedema, or
severe cutaneous adverse reaction narrow
terms).
Injection-site reaction was based on a Lilly
search category that included specific
MedDRA Preferred Terms subsidiary to the
MedDRA HLT for injection-site reaction.
NA=not applicable.
BP=blood pressure.
GLP-1=glucagon-like peptide-1.
*Reported by at least 0·5% patients across
all treatment groups.
†The study protocol required that severe
hypoglycaemia be reported as a serious
adverse event; this requirement might
have aff ected the incidence of these
categories of reported events.
‡These outcomes were summarised only,
no statistical comparisons were done.
§Results for both dulaglutide groups
combined for all post-baseline
observations including follow-up.
The appendix shows pancreatic enzyme data.
Findings
Between Dec 9, 2010, and Sept 21, 2012, we randomly assigned 884
patients to receive dulaglutide 1·5 mg (n=295), dulaglutide 0·75 mg (n=293),
or glargine (n=296). At 26 weeks, the adjusted mean change in HbA1c was
greater in patients receiving dulaglutide 1·5 mg (−1·64% [95% CI −1·78 to
−1·50], −17·93 mmol/mol [−19·44 to −16·42]) and dulaglutide 0·75 mg
(−1·59% [−1·73 to −1·45], −17·38 mmol/mol [−18·89 to −15·87]) than in
those receiving glargine (−1·41% [−1·55 to −1·27], −15·41 mmol/mol
[−16·92 to −13·90]). The adjusted mean difference versus glargine was
−0·22% (95% CI −0·38 to −0·07, −2·40 mmol/mol [–4·15 to −0·77];
p=0·005) for dulaglutide 1·5 mg and −0·17% (–0·33 to −0·02, −1·86
mmol/mol [–3·61 to −0·22]; p=0·015) for dulaglutide 0·75 mg. Five (<1%)
patients died after randomisation because of septicaemia (n=1 in the
dulaglutide 1·5 mg group); pneumonia (n=1 in the dulaglutide 0·75 mg
group); cardiogenic shock; ventricular fibrillation; and an unknown cause
(n=3 in the glargine group). We recorded serious adverse events in 27 (9%)
patients in the dulaglutide 1·5 mg group, 44 (15%) patients in the
dulaglutide 0·75 mg group, and 54 (18%) patients in the glargine group. The
most frequent adverse events, arising more often with dulaglutide than
glargine, were nausea, diarrhoea, and vomiting.
Interpretation
Dulaglutide in combination with lispro
resulted in a significantly greater
improvement in glycaemic control than did
glargine and represents a new treatment
option for patients unable to achieve
glycaemic targets with conventional insulin
treatment.
Funding
Eli Lilly and Company.
Message
従来治療で管理不十分の2型糖尿病（DM）患者
884人を対象に、インスリンリスプロ併用でのグ
ラルギン1日1回投与に対するGLP-1受容体作動薬
dulaglutide週1回投与の非劣性を評価（AWARD-4
試験）。26週時HbA1c平均変化はdulaglutideの
1.5mgおよび0.75mgの両群で非劣性の基準を満た
http://www.m3.com/clinical/journal/15492
した。
インスリン業界の老舗のLilly社は持効型インスリンの開発では遅れていた。ジェ
ネリックまで出している。しかし、今回の発表で週１回の持効型インスリン相当の
作用がDulaglutideにあることが発表された。ただし、毎日３回の食事用インスリ
ンとの併用が必要？なので実臨床でどれだけ受け入れられるか？
また、SMBGも朝のみは必要なさそう。貼り付けタイプのSMBGが出るとそちら
は解決されそうであるが。
注射回数： GLP1RA+Degludec ２ｘ７ (or 7) ｖｓ今回：１＋３ｘ７／週
1Department
of General Internal Medicine, Inselspital, Bern University Hospital, Bern, Switzerland
of Medicine and Epidemiology and Biostatistics, University of California, San Francisco
3Service of Endocrinology, Diabetes and Metabolism, University Hospital of Lausanne, Lausanne, Switzerland
4Department of Medicine, University of Minnesota School of Medicine, Minneapolis
5Geriatric Research Education and Clinical Center, VA Medical Center, Minneapolis, Minnesota
6University of Pennsylvania School of Medicine, Philadelphia
7Associate Editor, JAMA
8Department of Physical Therapy, Nicole Wertheim College of Nursing and Health Science, Florida International University, Miami
9Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
10Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
11Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway
12Department of Endocrinology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
13Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
14Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
15Radiation Effects Research Foundation, Nagasaki, Japan
16School of Population Health, University of Western Australia, Crawley, WA, Australia
17Department of Medicine, Imperial College London, London, United Kingdom
18Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom
19Department of Epidemiology and Public Health, University College Cork, Cork, Ireland
20Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
21Cardiovascular Health Research Unit, University of Washington, Seattle
22Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
23Department of Clinical and Experimental Medicine, Geriatric Endocrine Unit, University Hospital of Parma, Parma, Italy
24Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom
25Department of Public Health, University of Copenhagen, Copenhagen, Denmark
26National Institute on Aging, National Institutes of Health, Baltimore, Maryland
27School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia
28Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
29Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
2Departments
JAMA. 2015 May 26;313(20):2055-65.
doi: 10.1001/jama.2015.5161.
Importance Associations between subclinical thyroid
dysfunction and fractures are unclear and clinical trials are
lacking.
Objective To assess the association of subclinical thyroid
dysfunction with hip, nonspine, spine, or any fractures.
Data Sources and Study Selection The databases of
MEDLINE and EMBASE (inception to March 26, 2015) were
searched without language restrictions for prospective cohort
studies with thyroid function data and subsequent fractures.
Data Extraction Individual participant data were obtained
from 13 prospective cohorts in the United States, Europe,
Australia, and Japan. Levels of thyroid function were defined
as euthyroidism (thyroid-stimulating hormone [TSH], 0.454.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L),
and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L)
with normal thyroxine concentrations.
Main Outcome and MeasuresThe primary outcome was hip
fracture. Any fractures, nonspine fractures, and clinical spine
fractures were secondary outcomes.
Hazard ratios (HRs) were
adjusted for age and sex.
Data marker sizes are
proportional to the inverse of
the variance of the HRs.
Error bars indicate 95%CIs.
Not every outcome was
available for each study.
Calculations of τ2 were used
to measure heterogeneity in
effect estimates across
cohorts, with a prespecified
τ2 (≦0.04) indicating low
heterogeneity and greater
than 0.04 to 0.36 indicating
moderate heterogeneity.
All hazard ratios (HRs) were
age and sex adjusted. Error
bars indicate 95%CIs. The
multivariable analysis
yielded similar results
(eTable 3 in Supplement 1).
a The PROSPER
(Prospective Study of
Pravastatin in the Elderly
at Risk) Study was not
included because follow-up
data were only available
for any fracture.
b These HRs were adjusted
for sex and age as a
continuous variable to
avoid residual confounding
within age strata.
c The HUNT (NordTrondelag Health Study),
Cardiovascular Health
Study, Sheffield, and
OPUS (Osteoporosis and
Ultrasound Study) studies
were not included because
follow-up data for any
fracture were not available.
d The HUNT, Cardiovascular
Health Study, Leiden 85Plus, and PROSPER
studies were not included
because follow-up data for
nonspine fractures were
not available.
e The HUNT, Cardiovascular
Health Study, Leiden 85Plus, Sheffield, OPUS, and
PROSPER studies were
not included because
Results Among 70 298 participants, 4092 (5.8%) had subclinical hypothyroidism
and 2219 (3.2%) had subclinical hyperthyroidism. During 762 401 person-years of
follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture
in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%;
8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sexadjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs
euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082
participants vs 2534 in 56 471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53;
121 events in 888 participants vs 2203 in 25 901); for nonspine fracture, HR was
1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21 722); and for
spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs
255 in 20 328). Lower TSH was associated with higher fracture rates: for TSH of
less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in
510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in
212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events
in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8
events in 162 participants). Risks were similar after adjustment for other fracture
risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication
users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42
(95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture.
No association was found between subclinical hypothyroidism and fracture risk.
Conclusions and Relevance
Subclinical hyperthyroidism was
associated with an increased risk of hip
and other fractures, particularly among
those with TSH levels of less than 0.10
mIU/L and those with endogenous
subclinical hyperthyroidism. Further
study is needed to determine whether
treating subclinical hyperthyroidism can
prevent fractures.
Message
潜在性甲状腺機能障害と骨折の関連を、前向き
コホート研究13件（参加者約7万人）のメタ解析
で検証。機能正常者に対する潜在性甲状腺機能
亢進症の骨折ハザード比は股関節1.36、全骨折
1.28、非脊椎1.16、脊椎1.51だった。特に甲状
腺刺激ホルモン低値（0.10mIU/L未満）、内因性
潜在性甲状腺亢進症が骨折リスク増加と関連し
た。
TSHが0.1を超えていればまぁよいかな？
http://www.m3.com/clinical/journal/15495

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