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Journal Club
TODAY Study Group.
A Clinical Trial to Maintain Glycemic Control in Youth with Type 2 Diabetes.
N Engl J Med. 2012 Apr 29. [Epub ahead of print]
O'Neil PM, Smith SR, Weissman NJ, Fidler MC, Sanchez M, Zhang J, Raether
B, Anderson CM, Shanahan WR.
Randomized Placebo-Controlled Clinical Trial of Lorcaserin for Weight Loss in
Type 2 Diabetes Mellitus: The BLOOM-DM Study.
Obesity (Silver Spring). 2012 Mar 16. doi: 10.1038/oby.2012.66. [Epub ahead of
print]
2012年5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
ΔHbA1C
Jadad Score: Oxford quality scoring system (highest quality to lowest)
Was the study described as randomized? yes and good=2, yes but not good=1, no=0
Was the study described as double blind? yes and good=2, yes but not good=1, no=0
Was there a description of withdrawals and dropouts? yes =1, no=0
Phung OJ, Scholle JM, Talwar M, Coleman CI
Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia
in Type 2 Diabetes
JAMA. 2010;303(14):1410-1418 reviewed on April 10, 2010
66% risk reduction
Figure 2: Time to occurrence of the development of diabetes
HR=hazard ratio.
Lancet. 2010 Jul 10;376(9735):103-11.
Phil Zeitler, M.D., Ph.D., University of Colorado Denver, Aurora; Kathryn Hirst,
Ph.D., and Laura Pyle, M.S., George Washington University, Washington, DC;
Barbara Linder, M.D., Ph.D., National Institute of Diabetes and Digestive and
Kidney Diseases, Bethesda, MD; Kenneth Copeland, M.D., University of
Oklahoma Health Sciences Center, Oklahoma City; Silva Arslanian, M.D.,
Children’s Hospital of Pittsburgh, Pittsburgh; Leona Cuttler, M.D., Case Western
Reserve University, Cleveland; David M. Nathan, M.D., Massachusetts General
Hospital, Boston; Sherida Tollefsen, M.D., Saint Louis University, and Denise
Wilfley, Ph.D., Washington University — both in St. Louis; and Francine Kaufman,
M.D., Children’s Hospital Los Angeles, Los Angeles
10.1056/NEJMoa1109333
Background
Despite the increasing prevalence
of type 2 diabetes in youth, there
are few data to guide treatment. We
compared the efficacy of three
treatment regimens to achieve
durable glycemic control in children
and adolescents with recent-onset
type 2 diabetes.
Methods
Eligible patients 10 to 17 years of age were
treated with metformin (at a dose of 1000 mg
twice daily) to attain a glycated hemoglobin level
of less than 8% and were randomly assigned to
continued treatment with metformin alone or to
metformin combined with rosiglitazone (4 mg
twice a day) or a lifestyle-intervention program
focusing on weight loss through eating and
activity behaviors. The primary outcome was loss
of glycemic control, defined as a glycated
hemoglobin level of at least 8% for 6 months or
sustained metabolic decompensation requiring
insulin.
Figure 1. Enrollment,
Randomization, and Retention of
the Study Participants.
All randomly assigned participants
were included in the primary
outcome analysis (i.e., all
participants contributed time in the
study, although data for some
participants were censored before
the end of the study for the reasons
shown in the figure).
Figure 2. Overall Primary Outcome Results. Survival curves for freedom from
glycemic failure are shown. Data are shown for up to 60 months of follow-up
(accounting for 98.4% of cases of glycemic failure), although the rates and
analysis are based on the complete data set.
Figure 3 Primary Outcome Results According to Sex and Race or Ethnic Group.
Survival curves for freedom from glycemic failure are shown. Data are shown for
up to 60 months of followup (accounting for 98.4% of cases of glycemic failures),
although the rates and analysis are based on the complete data set.
APPENDIX E. Figures of Mean A1c Over
Time in Study (all values prior to failure)
APPENDIX D. Reason for Failure and Median Time to Failure by Treatment Group
Results
Of the 699 randomly assigned participants (mean duration of
diagnosed type 2 diabetes, 7.8 months), 319 (45.6%)
reached the primary outcome over an average followup of
3.86 years. Rates of failure were 51.7% (120 of 232
participants), 38.6% (90 of 233), and 46.6% (109 of 234) for
metformin alone, metformin plus rosiglitazone, and
metformin plus lifestyle intervention, respectively. Metformin
plus rosiglitazone was superior to metformin alone (P =
0.006); metformin plus lifestyle intervention was intermediate
but not significantly different from metformin alone or
metformin plus rosiglitazone. Prespecified analyses
according to sex and race or ethnic group showed
differences in sustained effectiveness, with metformin alone
least effective in non-Hispanic black participants and
metformin plus rosiglitazone most effective in girls. Serious
adverse events were reported in 19.2% of participants.
Conclusions
Monotherapy with metformin was
associated with durable glycemic
control in approximately half of children
and adolescents with type 2 diabetes.
The addition of rosiglitazone, but not an
intensive lifestyle intervention, was
superior to metformin alone.
(Funded by the National Institute of Diabetes and
Digestive and Kidney Diseases and others; TODAY
ClinicalTrials.gov number, NCT00081328.)
Message
最近2型糖尿病を発症した若年患者（10-17歳）
699人を対象に、3つの治療法の血糖コントロー
ル持続性を無作為化比較試験で検討。平均3.86
年の追跡の結果、血糖コントロール失敗率はメ
トホルミン単独群で51.7％、＋ライフスタイル
介入群で46.6％、＋インスリン抵抗性改善薬
rosiglitazone群で38.6％だった。
In 2006, the European Medicines Agency approved the
marketing of rimonabant in Europe. In 2007, however, new
contraindications were formulated by the Agency. Also in
2007, the US Food and Drug Administration denied
approval in the USA. Reasons for concern were
neuropsychiatric side effects, including depression and
suicide attempts.
an inverse agonist for the
cannabinoid receptor CB1.
Lancet 2005; 365: 1389–97
On 7 December 2010,
an FDA Advisory
Committee voted 137 for the approval of
Contrave, and voted
11-8 for the conduct
of a post-marketing
cardiovascular
outcomes study.
Contrave's PDUFA
date is 31 January
2011. Subsequently,
on 2 February 2011,
the FDA rejected the
drug and it was
decided that an
extremely large-scale
study of the long-term
cardiovascular effects
of Contrave would be
needed, before
approval could be
considered.[
On March 31st 2010, Orexigen submitted a New
Drug Application (NDA) to the U.S. Food and
Drug Administration (FDA) for Contrave.
www.thelancet.com Published online July 30, 2010 DOI:10.1016/S0140-6736(10)60888-4
Novo Nordisk now plans to re-initiate the global phase 3
programme in the first half of 2011 in clinical trials comprising
approximately 5,000 patients (June 22, 2010)
www.thelancet.com Published online October 23, 2009 DOI:10.1016/S0140-6736(09)61375-1
Phentermine/topiramate (Qnexa)
Phentermine is an appetite suppressant and stimulant of the amphetamine and
phenethylamine class. Topiramate is an anticonvulsant that has weight loss side
effects.
On December 28, 2009 a new drug application (NDA) was submitted to the FDA
for approval and on March 1, 2010, Vivus announced that the agency accepted
the NDA.
FDA approval was declined in October 2010 due to concerns about dangerous
side effects, including suicidal thoughts, heart palpitations, memory lapses and
birth defects.
In January 2011, the Food and Drug Administration expressed concerns about
the potential for Qnexa to cause birth defects and asked Vivus to examine this
possibility before the drug can be approved.
On February 22, 2012, FDA advisors voted 20:2 to recommend that the FDA
adopt phentermine/topiramate as an obesity treatment. Final approval is
expected later in 2012, with recommendations for post-market monitoring for
cardiovascular risk and an indication against use by pregnant women.
http://en.wikipedia.org/wiki/5-HT_receptor
Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter.
The serotonin receptors modulate the release of many
neurotransmitters, including glutamate, GABA, dopamine,
epinephrine / norepinephrine, and acetylcholine, as well as
many hormones, including oxytocin, prolactin, vasopressin,
cortisol, corticotropin, and substance P, among others.
The serotonin receptors influence various biological and
neurological processes such as aggression, anxiety, appetite,
cognition, learning, memory, mood, nausea, sleep, and
thermoregulation. The serotonin receptors are the target of a
variety of pharmaceutical and illicit drugs, including many
antidepressants, antipsychotics, anorectics, antiemetics,
gastroprokinetic agents, antimigraine agents, hallucinogens,
and entactogens.
Note that there is no 5-HT1C receptor since, after the receptor was cloned and
further characterized, it was found to have more in common with the 5-HT2
family of receptors and was redesignated as the 5-HT2C receptor. Note that
there is also no 5-HT5B receptor, as it exists only in mice and rats and not in
humans or monkeys.
Very nonselective agonists of 5-HT receptor subtypes include ergotamine (an
antimigraine), which activates 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine
receptors. LSD (a psychedelic) is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6
agonist.
lorcaserin
Lorcaserin is a selective 5-HT2C receptor agonist, and in vitro
testing of the drug showed reasonable selectivity for 5-HT2C
over other related targets. 5-HT2C receptors are located almost
exclusively in the brain, and can be found in the choroid plexus,
cortex, hippocampus, cerebellum, amygdala, thalamus, and
hypothalamus. The activation of 5-HT2C receptors in the
hypothalamus is supposed to activate proopiomelanocortin
(POMC) production and consequently promote weight loss
through satiety. This hypothesis is supported by clinical trials
and other studies. While it is generally thought that 5-HT2C
receptors help to regulate appetite as well as mood, and
endocrine secretion, the exact mechanism of appetite
regulation is not yet known. Lorcaserin has shown 100:1
affinity for 5-HT2C versus other receptors.
Dexfenfluramine was for some years in the mid-1990s
approved by the United States Food and Drug Administration
for the purposes of weight loss. However, following multiple
concerns about the cardiovascular side-effects of the drug,
such approval was withdrawn and it was retired from the
dexfenfluramine market in 1997.
Dexfenfluramine is believed to be solely responsible for the
appetite suppressant properties of fenfluramine, of which it has
been demonstrated to mediate predominantly via activation of
postsynaptic 5-HT1B and 5-HT2C receptors through a
combination of indirect serotonin releasing agent and direct
serotonin receptor agonist activities (the latter of which are
mediated fully by its active metabolite dexnorfenfluramine).
Levonorfenfluramine, an active metabolite of levofenfluramine,
is also a fairly potent serotonin releasing agent (with a potency
of approximately 1/2 that of norfenfluramine and 1/6th that of
dexfenfluramine) and, similarly to dexnorfenfluramine, 5-HT2B
and 5-HT2C receptor agonist, as well as a somewhat less potent
norepinephrine reuptake inhibitor (about 1/2 that of its efficacy
as a serotonin releaser).
Norfenfluramine, or 3-trifluoromethylamphetamine, is a drug of
the amphetamine family which behaves as a serotonin and
norepinephrine releasing agent and potent 5-HT2A, 5-HT2B, and 5HT2C agonist.
fenfluramine
Fenfluramine was introduced on the U.S. market in 1973. It is
the racemic mixture of two enantiomers, dextrofenfluramine
and levofenfluramine. It increases the level of the
neurotransmitter serotonin, a chemical that regulates mood,
appetite and other functions. Fenfluramine causes the release
of serotonin by disrupting vesicular storage of the
neurotransmitter, and reversing serotonin transporter function.
The result is a feeling of fullness and loss of appetite.
The drug was withdrawn from the U.S. market in 1997 after
reports of heart valve disease, and pulmonary hypertension,
including a condition known as cardiac fibrosis.
Since fenfluramine and its active metabolite norfenfluramine
stimulate serotonin receptors, this may have led to the valvular
abnormalities found in patients using fenfluramine. In
particular norfenfluramine is a potent agonist of 5-HT2B
receptors, which are plentiful in human cardiac valves.
Both fenfluramine and benfluorex form norfenfluramine as a
metabolite. This side effect led to the withdrawal of
fenfluramine as an anorectic drug worldwide, and later to the
withdrawal of benfluorex in Europe.
benfluorex
Lorcaserin (APD-356, trade name Lorqess) is a weight-loss
drug developed by Arena Pharmaceuticals. It has
serotonergic properties and acts as an anorectic. On 22
December 2009 a New Drug Application (NDA) was submitted
to the Food and Drug Administration (FDA) in the United
States. On 16 September 2010, an FDA advisory panel voted
to recommend against approval of the drug based on
concerns over both safety and efficacy. In October 2010, the
FDA stated that it that it could not approve the application for
lorcaserin in its present form.
On 10 May 2012, after a new round of studies submitted by
Arena, an FDA panel voted to recommend lorcaserin with
certain restrictions and patient monitoring. The restrictions
include patients with a BMI of over 30, or with a BMI over 27
and a comorbidity like high blood pressure or type 2 diabetes.
1Weight
Management Center, Department of Psychiatry and Behavioral Sciences,
Medical University of South Carolina, Charleston, South Carolina, USA;
2Translational Research Institute for Metabolism and Diabetes, Florida Hospital
and the Sanford-Burnham Medical Research Institute, Orlando, Florida, USA;
3MedStar Health Research Institute at Washington Hospital Center and
Georgetown University, Washington, DC, USA;
4Arena Pharmaceuticals, San Diego, California, USA.
obesity
doi:10.1038/oby.2012.66
AIM
The BLOOM-DM (Behavioral Modification
and Lorcaserin for Obesity and
Overweight Management in Diabetes
Mellitus) study evaluated efficacy and
safety of lorcaserin for weight loss in
patients with type 2 diabetes.
Secondary objectives included
evaluations of glycemic control, lipids,
blood pressure, and quality of life.
METHOD
This 1-year, randomized, placebocontrolled trial enrolled 604 patients
1:1:1 to placebo, lorcaserin 10 mg once
daily (QD) or lorcaserin 10 mg twice daily
(BID).
Figure 2 Analyses of body weight change. (a) Proportion of patients who lost ≥5% or ≥10% of body weight from baseline to week 52
using the modified intent to treat (MITT) population (left panel) or the completers population (right panel). Lorcaserin 10 mg BID, solid
bars; lorcaserin 10 mg QD, hatched bars; placebo, open bars. Values are proportion ± 95% confidence interval. *P < 0.001 as compared
to placebo. (b) Percent change in body weight from baseline to each study visit, using the MITT population (left panel) or the completers
population (right panel). Lorcaserin 10 mg BID, closed circles with solid line; lorcaserin 10 mg QD, open diamonds with dotted line;
placebo, open triangles with dashed line. Values are mean ± SEM. BID, twice daily; QD, once daily
Figure 4
Shifts in echocardiographic
valvular regurgitant scores from
baseline to week 52. Negative
numbers indicate decreased
regurgitant score, positive
numbers are increased
regurgitant scores.
Numerals above bars indicate
numbers of patients. Lorcaserin
10 mg BID, solid bars;
lorcaserin 10 mg QD, hatched
bars; placebo, open bars. BID,
twice daily; QD, once daily.
RESULTS
Patients were treated with metformin, a sulfonylurea (SFU) or both;
had glycated hemoglobin (HbA1c) 7–10%; were 18–65 years old; and
had BMI 27–45 kg/m2. Patients received diet and exercise counseling.
Safety monitoring included serial echocardiograms. Mean (± SD) age
was 52.7 ± 8.7; 54.2% were women; 60.5% were white, 20.9% were
African American, and 13.8% were Hispanic. Mean (± SD) weight was
103.6 ± 17.8 kg; BMI was 36.0 ± 4.5 kg/m2. Most patients (91.7%) took
metformin; 50.2% took a SFU. More patients lost ≥5% body weight
with lorcaserin BID (37.5%; P < 0.001) or lorcaserin QD (44.7%; P <
0.001) vs. placebo (16.1%; modified intent to treat (MITT)/last
observation carried forward (LOCF)). Least square mean (± SEM)
weight change was −4.5 ± 0.35% with lorcaserin BID and −5.0 ± 0.5%
with lorcaserin QD vs. −1.5 ± 0.36% with placebo (P < 0.001 for each).
HbA1c decreased 0.9 ± 0.06 with lorcaserin BID, 1.0 ± 0.09 with
lorcaserin QD, and 0.4 ± 0.06 with placebo (P < 0.001 for each);
fasting glucose decreased 27.4 ± 2.5 mg/dl, −28.4 ± 3.8 mg/dl, and
11.9 ± 2.5 mg/dl, respectively (P < 0.001 for each). Symptomatic
hypoglycemia occurred in 7.4% of patients on lorcaserin BID, 10.5%
on lorcaserin QD, and 6.3% on placebo. Common adverse events were
headache, back pain, nasopharyngitis, and nausea.
CONCLUSION
Lorcaserin was associated with
significant weight loss and
improvement in glycemic control in
patients with type 2 diabetes.
Message
 2012年5月10日、FDAの内分泌・代謝性医薬品諮問委員会（Endocrinological
and Metabolic Drugs Advisory Committee）が開催され、エーザイ社の米国
子会社が米国における独占的販売供給契約を締結している、Arena社の抗肥満
薬 ロルカセリン（lorcaserin、商品名：LORQESS）の安全性と有用性について
の審議が行われた。
http://www.fda.gov/AdvisoryCommittees/Calendar/ucm296516.htm
 ロルカセリンはセロトニン2C(5-HT2C)受容体選択的アゴニストで、食欲や代謝を
調整することで作用を発現し、BMI30以上または合併症を有するBMI27以上の
過体重の患者が対象となっている。
 ダイエット薬ロルカセリン(Lorcaserin)は、セロトニン5-HT2c受容体アゴニストで、
動物試験による発がんリスクについては問題なしとされたものの、心臓弁膜症の
リスクについてはまだ懸念があるとして、エコーによる定期的なチェックが必要で
はないかとの意見も出された.
 しかし、最終的にはベネフィットがリスクを上回るとして、諮問委員会として18対4
（棄権1）で承認を支持する評決が行われた。
http://www.eisai.co.jp/news/news201222pdf.pdf
 FDAが6月27日の期日までに正式承認をすれば、久しぶりの大型新薬となる。
（先の諮問委員会でQnexaも承認支持の評決が行われているが、こちらの承認
の最終決定の期日は7月17日なので、ロルカセリンの方が先となる）