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
Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Leccesi L,
Nanni G, Pomp A, Castagneto M, Ghirlanda G, Rubino F.
Bariatric Surgery versus Conventional Medical Therapy for Type 2 Diabetes.
N Engl J Med. 2012 Mar 26. [Epub ahead of print]
Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S; for the
Dapagliflozin 006 Study Group.
Long-Term Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus
Receiving High Doses of Insulin: A Randomized Trial.
Ann Intern Med. 2012 Mar 20;156(6):405-415.
2012年4月5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 authors evaluated
the efficacy of intensive
medical therapy alone
versus medical therapy
plus Roux-en-Y gastric
bypass or sleeve
gastrectomy in 150 (50
each) obese patients
with uncontrolled type 2
diabetes. The mean
(±SD) age of the
patients was 49±8
years, and 66% were
women. The average
glycated hemoglobin
level was 9.2±1.5%.
Figure 1. Changes in Measures of Diabetes Control from Baseline. Values for change in glycated hemoglobin (Panel A), change in
fasting plasma glucose (Panel B), the average number of diabetes medications (Panel C), and change in body-mass index (BMI) (Panel
D) were plotted at 3, 6, 9, and 12 months. Least-square means and standard errors from a repeated measures model are plotted for
glycated hemoglobin, average number of medications, and BMI; medians and interquartile ranges are plotted for fasting plasma
glucose. P values are for the comparison between each surgical group and the medical-therapy group and were calculated from a
repeated-measures model that considers data over time.
10.1056/nejmoa1200225 nejm.org
the Departments of Internal Medicine (G.M., C.G., A.I., L.L., G.G.) and
Surgery (G.N., M.C., F.R.), Università Cattolica S. Cuore; and National
Research Council of Italy–Institute of Systems Analysis and Computer
Science (IASI), BioMatLab (S.P., A.D.G.)
10.1056/nejmoa1200111 nejm.org
Background
Roux-en-Y gastric bypass and
biliopancreatic diversion can
markedly ameliorate diabetes in
morbidly obese patients, often
resulting in disease remission.
Prospective, randomized trials
comparing these procedures with
medical therapy for the treatment of
diabetes are needed.
Methods
In this single-center, nonblinded, randomized,
controlled trial, 60 patients between the ages of 30
and 60 years with a body-mass index (BMI, the
weight in kilograms divided by the square of the
height in meters) of 35 or more, a history of at least 5
years of diabetes, and a glycated hemoglobin level
of 7.0% or more were randomly assigned to receive
conventional medical therapy or undergo either
gastric bypass or biliopancreatic diversion. The
primary end point was the rate of diabetes remission
at 2 years (defined as a fasting glucose level of <100
mg per deciliter [5.6 mmol per liter] and a glycated
hemoglobin level of <6.5% in the absence of
pharmacologic therapy).
Medical Therapy
Patients in the medical-therapy group were assessed
and treated by a multidisciplinary team that included a
diabetologist, a dietitian, and a nurse, with planned visits
at baseline and at 1, 3, 6, 9, 12, and 24 months after
study entry. Oral hypoglycemic agents and insulin doses
were optimized on an individual basis with the aim of
reaching a glycated hemoglobin level of less than 7%.
Programs for diet and lifestyle modification, including
reduced overall energy and fat intake (<30% total fat,
<10% saturated fat, and high fiber content) and
increased physical exercise (≥30 minutes of brisk
walking every day, possibly associated with moderateintensity aerobic activity twice a week), were designed
by an experienced diabetologist with assistance from a
dietitian.
Bariatric Surgery
Patients who were assigned to undergo either gastric
bypass or biliopancreatic diversion were evaluated by a
multidisciplinary team (including a diabetologist, a
dietitian, and a nurse) at baseline and at 1, 3, 6, 9, 12, and
24 months after surgery. (A detailed description of the
surgical procedures is provided in the Supplementary
Appendix, available at NEJM.org.) Medical therapy was
adjusted according to the seven-point glycemic profile
during the first 3 months and according to glycated
hemoglobin levels thereafter. Discontinuation of medical
therapy was considered in cases of normalization of the
glycemic profile, glycated hemoglobin levels, or both.
Daily multivitamin and mineral supplementation was
prescribed to the surgical groups; patients undergoing
biliopancreatic diversion received additional vitamin D
and calcium supplementation.
Figure: RYGB. Copyright is retained by
Cine-Med and has been kindly granted
for publication.
Figure: BPD. Copyright is retained by
Cine-Med and has been kindly granted
for publication.
* Plus–minus values
are means ±SD.
† P values for the
overall comparisons
were calculated with
the use of analysis
of variance. P values
for the comparisons
between each of the
two surgical
procedures and
medical therapy and
for the comparison
between the two
types of surgery
were calculated with
the use of the
Bonferroni method in
post hoc analyses.
There were no operative deaths among patients undergoing either gastric
bypass or biliopancreatic diversion. An incisional hernia requiring reoperation 9
months after surgery developed in a patient undergoing biliopancreatic diversion,
and one patient undergoing gastric bypass had an intestinal obstruction
requiring reoperation 6 months after surgery.
Two patients who were receiving medical therapy had persistent diarrhea
associated with metformin, a condition that resolved when the drug was
discontinued and another oral hypoglycemic agent was substituted.
Results
At 2 years, diabetes remission had occurred in no
patients in the medical-therapy group versus 75% in the
gastric-bypass group and 95% in the biliopancreaticdiversion group (P<0.001 for both comparisons). Age,
sex, baseline BMI, duration of diabetes, and weight
changes were not significant predictors of diabetes
remission at 2 years or of improvement in glycemia at 1
and 3 months. At 2 years, the average baseline glycated
hemoglobin level (8.65±1.45%) had decreased in all
groups, but patients in the two surgical groups had the
greatest degree of improvement (average glycated
hemoglobin levels, 7.69±0.57% in the medical-therapy
group, 6.35±1.42% in the gastric-bypass group, and
4.95±0.49% in the biliopancreatic-diversion group).
Conclusions
In severely obese patients with type
2 diabetes, bariatric surgery
resulted in better glucose control
than did medical therapy.
Preoperative BMI and weight loss
did not predict the improvement in
hyperglycemia after these
procedures. (Funded by Catholic University of
Rome; ClinicalTrials.gov number, NCT00888836.)
Message
手術による治療が肥満患者にはよさそうなのだ
が．．．
The success of various types of bariatric surgery
suggests that they should not be seen as a last resort.
Such procedures might well be considered earlier in the
treatment of obese patients with type 2 diabetes.
Message
体格指数35以上の高度肥満の2型糖尿病患者60人
を対象に、薬物療法と減量手術の血糖コント
ロール改善効果を無作為化試験で比較。2年後の
糖尿病寛解率（空腹時血糖値＜100mg/dLおよび
HbA1c＜6.5％）は薬物療法群の0％に対し、胃バ
イパス術群で75％、胆膵路転換手術群で95％
だった（それぞれP＜0.001）。
New hypoglycemic drugs
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Amylin
The 53rd Annual Meeting of the Japan
Diabetes Society 27 May, 2010 Okayama
Hydroxychloroquine
Inhaled insulin
SGLT-2 (sodium glucose transportor-2) inhibitors
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Glucokinase activators
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Prof. McGuill JB
GPR 40 (G-protein coupled receptor 40) agonists
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Dr. Eiki J
PPARx
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Prof. Ferrannini E
Dr. Takeuchi K
Bromocriptine
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Prof. Matsuda
糖毒性の概念形成にフロリジンは重要な役割を果たした！
Dapagliflozin
Dapagliflozin (rINN/USAN) is an experimental drug being studied by BristolMyers Squibb in partnership with AstraZeneca as a potential treatment for type 1
and 2 diabetes. Although dapagliflozin's method of action would operate on
either type of diabetes or other conditions resulting in hyperglycemia, the
current clinical trials specifically exclude participants with Type 1 diabetes.
In July 2011 an FDA committee recommended against approval until more data
was available. The Prescription Drug User Fee Act (PDUFA) date for dapagliflozin
for the treatment of Type 2 diabetes was extended three months by the FDA to
January 28, 2012. (Dapagliflozin Declined by FDA)
SGLT2 inhibitors: Canagliflozin Dapagliflozin Remogliflozin Sergliflozin
http://en.wikipedia.org/wiki/Dapagliflozin
Nonselective SGLT inhibitors
block adenosine triphosphate–
dependent, sodium-linked
facilitated transport of glucose
across the brush border cells of
the small intestine (isoform
SGLT1) and renal tubular
epithelium (dominantly isoform
SGLT2), leading to decreased
intestinal absorption and renal
tubular resorption of glucose
http://img.medscape.com/fullsize/migrated/editorial/conferences/2008/15780/wilding.fig1.gif
Austria: Hoppichler F, Luger A, Prager R, Roden M, Kotter T, and Schernthaner G. Bulgaria: Borisova A, Daskalova I, Hristozov K, Lazarova G, Orbetzova M, Petkova M,
Slavcheva A, Stoykova Y, Tankova C, Veleva N, and Zaharieva S. Canada: Ardilouze J, Aronson R, Boucher P, Carthy J, Dzongowski P, Gaudet D, Godsell S, Goldenberg R,
Hart R, Houlden R, Kaiser S, Khandwala H, Landry D, Lau D, O’Keefe D, Sigalas J, Tellier G, Twum-Barima Y, and Woo V. Finland: Alanko J, Kurl S, Ma¨kela¨ J, Niskanen L,
Paul R, Perhonen M, Pihlman S, Rissanen A, Strand J, Valle T; Germany: Bieler T, Fuchs F, Go¨tze D, Hanefeld M, Mo¨lle A, Paschen B, Rose L, Schumacher M, Semmler S,
Sehnert W, Tillenburg B, Wendisch U, and Winkelmann B. Great Britain: Bain S, Farmer I, Jassel GS, Owen D, Reed R, Simpson H, Strang C, and Wilding J. Hungary: Dea´k L,
Gurzo´ M, Hegyi I, Kere´nyi Z, La´szlo´czky A´ , Pa´ll K, Pe´nzes J, Reiber I, Re´ve´sz K, Somogyi A, Tama´s G, and Va´ndorfi G. The Netherlands: Castro Cabezas M, de
Koning E, Timmerman R, and van de Wiel A. Romania: Crisan C, Ferariu I, and Vlaiculescu M. Russian Federation: Arutyunov G, Dreval A, Grineva E, Karpova I, Kobalava Z,
Krasilnikova E, Kukharchuk V, Lantseva O, Pavlova M, Privalov D, Strongin L, Tereschenko S, Vorokhobina N, and Zhelninova T. Slovakia: Belesova K, Fabry J, Kupcova T,
Macko M, Paulovic V, Tomasova L, Truban J, and Vargova A. Spain: Calle Pascual A, De Teresa Parren˜o L, Dura´n Garcı´a S, Freixenet N, Gomis de Barbara´ R, Gonza´lez
Albarra´n O, and Gonza´lez Clemente JM. United States: Bernstein R, Brusco O, Graf R, Freeman J, Hoekstra J, Khairi R, Lubin B, Norwood P, Reed J, Rosenstock J, Soler N,
Sugimoto D, and Wahl T.
Dr. Wilding: Diabetes and Endocrinology Research Group, Department of Obesity and
Endocrinology, Clinical Sciences Center, University Hospital Aintree, Longmoor Lane,
Liverpool L9 7AL, United Kingdom. Dr. Woo: Section of Endocrinology, Health Sciences
Center, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada. Dr. Soler: Springfield
Diabetes and Endocrine Center, Hospital Sisters Health System Medical Group, 2501
Chatham Road, Suite 300, Springfield, IL 62704.
Drs. Pahor and Rohwedder: AstraZeneca, Tinsdaler Weg 183, D-22880 Wedel, Germany.
Ms. Sugg and Dr. Parikh: AstraZeneca, 1800 Concord Pike, Box 15437, Wilmington, DE
19850-5437.
Ann Intern Med. 2012;156:405-415.
Background: Dapagliflozin, a selective
inhibitor of sodium–glucose cotransporter 2,
may improve glycemic control with a lower
dose of insulin and attenuate the associated
weight gain in patients with inadequate
control despite high doses of insulin.
Objective: To evaluate the efficacy and
safety of adding dapagliflozin therapy in
patients whose type 2 diabetes mellitus is
inadequately controlled with insulin with or
without oral antidiabetic drugs.
Design: A 24-week, randomized, placebo-controlled, multicenter
trial followed by a 24-week extension period. An additional 56week extension period is ongoing. (ClinicalTrials.gov registration
number: NCT00673231)
Setting: 126 centers in Europe and North America from 30 April
2008 to 19 November 2009.
Patients: 808 patients with inadequately controlled type 2
diabetes mellitus receiving at least 30 U of insulin daily, with or
without up to 2 oral antidiabetic drugs.
Intervention: Patients were randomly assigned in a 1:1:1:1 ratio
and allocated with a computer-generated scheme to receive
placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily, for 48
weeks.
Measurements: The primary outcome was change in hemoglobin
A1c from baseline to 24 weeks. Secondary outcomes included
changes in body weight, insulin dose, and fasting plasma glucose
level at 24 weeks and during the 24-week extension period.
Adverse events were evaluated throughout both 24-week periods.
Figure 1. Study flow diagram.
DAPA dapagliflozin; INS insulin;
OAD oral antidiabetic drug; PLA placebo.
* This patient received no study
medication or postbaseline assessments.
Table 1. Major Demographic and Baseline Characteristics
BMI body mass index; HbA1c hemoglobin A1c; OAD oral antidiabetic drug.
Appendix Figure 1. Adjusted mean changes in daily insulin dose over time.
Appendix Figure 1. Adjusted mean changes in daily insulin dose at 48 weeks.
Samples are patients in the full analysis set with nonmissing baseline values and
nonmissing values for a given time point. Sample sizes at time 0 are 191, 200, 209, and
194 for the PLA, 2.5-mg DAPA, 5-mg DAPA, and 10-mg DAPA groups, respectively.
Treatment group symbols are shifted horizontally to prevent the error bars from
overlapping. DAPA = dapagliflozin; INS = insulin; PLA = placebo.
Appendix Figure 2. Probability of insulin up-titration due to not achieving
prespecified glycemic targets or of discontinuation due to poor glycemic control
over time.
Symbols represent censored observations. “Week” is the actual number of days from the first dose
of double-blind study medication divided by 7, not the scheduled visit week. Values for patients at
risk are for the beginning of the period. DAPA = dapagliflozin; INS = insulin; PLA = placebo.
Figure 2. Adjusted mean changes in HbA1c level over time.
Figure 2. Adjusted mean changes in HbA1c level at 48 weeks.
Samples are patients in the full analysis set with nonmissing baseline values and
nonmissing values for a given time point. Sample sizes at time 0 are 193, 202, 211, and
193 for the PLA, 2.5-mg DAPA, 5-mg DAPA, and 10-mg DAPA groups, respectively.
Treatment group symbols are shifted horizontally to prevent the error bars from
overlapping. DAPA = dapagliflozin; HbA1c = hemoglobin A1c; INS = insulin; PLA =
placebo.
Appendix Figure 4. Change in mean HbA1c level over time
calculated by using the placebo group to impute missing data
in the safety analysis set and analyzed by treatment group
and discontinuation status.
DAPA = dapagliflozin; INS = insulin; PLA = placebo.
Figure 3. Adjusted mean changes in total body weight over.
Figure 3. Adjusted mean changes in total body weight at 48 weeks.
Samples are patients in the full analysis set with nonmissing baseline values and
nonmissing values for a given time point. Sample sizes at time 0 are 193, 202, 211, and
193 for the PLA, 2.5-mg DAPA, 5-mg DAPA, and 10-mg DAPA groups, respectively.
Treatment group symbols are shifted horizontally to prevent the error bars from
overlapping. DAPA = dapagliflozin; INS = insulin; PLA = placebo.
UTI = urinary tract infection.
* From patients in the safety analysis set. Includes data from after insulin up-titration.
† Based on definitive preferred terms from Medical Dictionary for Regulatory Activities, version 12.1.
‡ A major episode was defined as a symptomatic episode in which the patient required external assistance due to
severe impairment in consciousness or behavior, had a capillary or plasma glucose level <3 mmol/L (<54 mg/dL),
and promptly recovered after receiving glucose or glucagon. A minor episode was defined as a symptomatic
episode in which the patient had a capillary or plasma glucose level <3.5 mmol/L (<63 mg/dL), regardless of the
need for external assistance, or an asymptomatic capillary or plasma glucose level <3.5 mmol/L (<63 mg/dL) that
did not qualify as a major episode. Other episodes were defined as reported suggestive episodes that did not
meet the criteria for a major or minor episode. No episodes of hypoglycemia led to study discontinuation.
§ Identified in the database by using prespecified lists of preferred terms. These events included signs,
symptoms, and other reports suggesting genital infection or UTI as well as definitive terms for genital infection
obtained from spontaneous reporting and active questioning at each study visit.
¶ Identified in the database by using prespecified lists of preferred terms but also by other indicators, such as
serum creatinine level.
Appendix Figure 3. Patients with events suggesting genital infection (top) or urinary tract infection
(bottom) at 24 and 48 weeks.
DAPA = dapagliflozin;
INS = insulin;
PLA = placebo.
Most missing data in longitudinal clinical trials result from patients discontinuing therapy
at a particular time point and subsequent data being unavailable; this is known as
monotone missing data.
A small amount of missing data may result from patients who skip a visit but return for
subsequent visits, known as nonmonotone missing data.
Results: 800 patients were analyzed. After 24 weeks, mean
hemoglobin A1c decreased by 0.79% to 0.96% with dapagliflozin
compared with 0.39% with placebo (mean difference, －0.40% [95%
CI, －0.54% to －0.25%] in the 2.5-mg group, －0.49% [CI, －0.65%
to －0.34%] in the 5-mg group, and －0.57% [CI, －0.72% to －
0.42%] in the 10-mg group). Daily insulin dose decreased by 0.63 to
1.95 U with dapagliflozin and increased by 5.65 U with placebo
(mean difference, －7.60 U [CI, －10.32 to －4.87 U] in the 2.5-mg
group, －6.28 U [CI, －8.99 to －3.58 U] in the 5-mg group, and －
6.82 U [CI, －9.56 to －4.09 U] in the 10-mg group). Body weight
decreased by 0.92 to 1.61 kg with dapagliflozin and increased by
0.43 kg with placebo (mean differences, －1.35 kg [CI, －1.90 to －
0.80 kg] in the 2.5-mg group, －1.42 kg [CI, －1.97 to －0.88 kg] in
the 5-mg group, and －2.04 kg [CI, －2.59 to －1.48 kg] in the 10-mg
group). These effects were maintained at 48 weeks. Compared with
the placebo group, patients in the pooled dapagliflozin groups had a
higher rate of hypoglycemic episodes (56.6% vs. 51.8%), events
suggesting genital infection (9.0% vs. 2.5%), and events suggesting
urinary tract infection (9.7% vs. 5.1%).
Limitation: Insulin doses were not
titrated to target, and the study was not
designed to evaluate long-term safety.
Conclusion: Dapagliflozin improves
glycemic control, stabilizes insulin
dosing, and reduces weight without
increasing major hypoglycemic
episodes in patients with inadequately
controlled type 2 diabetes mellitus.
Primary Funding Source:
AstraZeneca and Bristol-Myers Squibb.
Steven A. Smith, MD, Mayo College of Medicine, 200 First Street SE,
Rochester, MN 55905; e-mail, smith [email protected].
In a recent commentary, Ferrannini stated that the SGLT2 story was
closed and that “reduced SGLT2 activity— whether genetically or
experimentally induced—is efficacious and relatively safe in lowering
hyperglycemia and its toxicity with the added benefits of a degree of
weight control and some natriuresis.” In truth, after 2 centuries of study,
we remain uncertain of the appropriate use and long-term safety of
SGLT2 inhibition in persons with diabetes.
Ann Intern Med. 2012;156:466-467.
Gastrointestinal side effects are more commonly reported with dapagliflozin
than with metformin
Clinical trials suggested that genitourinary infections were more prevalent in
the first 24 weeks, but because of the risk for asymptomatic urinary tract
infections in diabetes, repetitive surveillance will probably be important.
Although no significant increases in pyelonephritis or other potentially lifethreatening renal infections have been shown in dapagliflozin clinical trials,
continued postmarketing surveillance will be necessary.
Dapagliflozin seems to be less effective in patients with renal disease. In
contrast to plausible concerns about renal glycosuria induced by SGLT2
inhibition in diabetic patients, preventing sodium and glucose resorption in
diabetes may prevent proximal tubular epithelial growth, increased
glomerular filtration, and accelerated protein glycation
Wilding and colleagues comment that dapagliflozin is highly selective for the
SGLT2 receptor, which is not expressed in bladder or breast tissue; however,
the potential influence of its metabolites or its expression in tissue known to
have functional receptors, such as brain, liver, thyroid, muscle, or heart
tissue, or in metastatic carcinoma is currently unknown.
Message
高用量インスリン治療中で血糖コントロール不十分
な2型糖尿病患者800人を対象に、SGLT2選択的阻害薬
dapagliflozin併用の有効性を無作為化プラセボ対照試
験で検討。24週後、HbA1c値の低下率は併用群（用量
2.5、5.0、10.0mg/日の3群）で0.79-0.96％、プラセボ
群で0.39％だった。
Ferrannini先生はこのクラスの薬物が臨床応用に供
され一段落としている。長期的な使用で問題があるか
は今後の課題。
で、FDAが2011年7月の諮問委員会の膀胱癌と乳癌の
発癌性の可能性から認可していない。（．．．）