Journal Club
Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, Lawson
FC, Ping L, Wei X, Lewis EF, Maggioni AP, McMurray JJ, Probstfield JL,
Riddle MC, Solomon SD, Tardif JC; ELIXA Investigators.
Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome.
N Engl J Med. 2015 Dec 3;373(23):2247-57. doi: 10.1056/NEJMoa1509225.
Zaccardi F, Htike ZZ, Webb DR, Khunti K, Davies MJ.
Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist
Treatments: A Systematic Review and Network Meta-analysis.
Ann Intern Med. 2015 Dec 8:1-12. doi: 10.7326/M15-1432. [Epub ahead of
print]
2016年1月7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
DPP4阻害薬、GLP-1受容体作動薬、SGLT2阻害薬の心血管障害への影響
1
1.
2.
2
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD,
Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; SAVORTIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2
diabetes mellitus. N Engl J Med 2013;369:1317–1326.
White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR,
Kupfer S, Wilson C, Cushman WC, Zannad F; EXAMINE Investigators. Alogliptin after acute coronary
syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–1335.
European Heart Journal doi:10.1093/eurheartj/ehv239
From the Cardiovascular Division, Brigham and Women’s Hospital, and Harvard Medical School —
both in Boston (M.A.P., B.C., E.F.L., S.D.S.); Estudios Clínicos Latinoamérica, Rosario, Argentina
(R.D.); University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); McMaster
University, Hamilton, ON, Canada (H.C.G.); Rigshospitalet Copenhagen University Hospital,
Copenhagen (L.V.K.); Sanofi U.S., Bridgewater, NJ (F.C.L., L.P., X.W.); Research Center of the
Italian Association of Hospital Cardiologists, Florence (A.P.M.); British Heart Foundation
Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.);
University of Washington Medical Center, Seattle (J.L.P.); Oregon Health and Science University,
Portland (M.C.R.); and Montreal Heart Institute, Université de Montréal, Montreal (J.C.T.).
N Engl J Med 2015;373:2247-57. DOI: 10.1056/NEJMoa1509225
Background
Cardiovascular morbidity and mortality are higher
among patients with type 2 diabetes, particularly
those with concomitant cardiovascular diseases,
than in most other populations. We assessed the
effects of lixisenatide, a glucagon-like peptide 1–
receptor agonist, on cardiovascular outcomes in
patients with type 2 diabetes who had had a
recent acute coronary event.
Methods
We randomly assigned patients with type 2 diabetes
who had had a myocardial infarction or who had
been hospitalized for unstable angina within the
previous 180 days to receive lixisenatide or placebo
in addition to locally determined standards of care.
The trial was designed with adequate statistical
power to assess whether lixisenatide was noninferior
as well as superior to placebo, as defined by an
upper boundary of the 95% confidence interval for
the hazard ratio of less than 1.3 and 1.0, respectively,
for the primary composite end point of cardiovascular
death, myocardial infarction, stroke, or
hospitalization for unstable angina.
* Plus–minus values are means ±SD. There were
no significant between-group differences at
baseline, except with respect to age (P = 0.005),
estimated glomerular filtration rate (eGFR; P =
0.006), glycated hemoglobin level (P = 0.02), and
prior stroke (P = 0.01). To convert the values for
cholesterol to millimoles per liter, multiply by
0.02586. ACS denotes acute coronary syndrome,
HDL high-density lipoprotein, LDL low-density
lipoprotein, NSTEMI non–ST-segment elevation
myocardial infarction, and STEMI ST-segment
elevation myocardial infarction.
† The body-mass index is the weight in kilograms
divided by the square of the height in meters.
‡ Race and ethnic group were self-reported.
§ Peripheral arterial disease included amputation
due to a cause other than trauma.
. Albumin was measured in milligrams and
creatinine in grams.
N Engl J Med 2015;373:2247-57.
* Events were assessed with the use of
the classifications in the Medical
Dictionary for Regulatory Activities
(MedDRA), version 15.0.
† Adjudicated cardiovascular events were
not required to be submitted as serious
adverse events unless they were
considered by the investigator to be
possibly drug-related.
‡ Investigations included abnormal
results on laboratory tests or physical
examination. The most common
MedDRA preferred terms used were
“alanine aminotransferase increased”
(in seven patients in the placebo group
and in two in the lixisenatide group)
and “blood glucose increased” (in four
in the placebo group and in one in the
lixisenatide group).
N Engl J Med 2015;373:2247-57.
Results
The 6068 patients who underwent randomization were
followed for a median of 25 months. A primary end-point
event occurred in 406 patients (13.4%) in the lixisenatide
group and in 399 (13.2%) in the placebo group (hazard ratio,
1.02; 95% confidence interval [CI], 0.89 to 1.17), which
showed the noninferiority of lixisenatide to placebo (P<0.001)
but did not show superiority (P=0.81). There were no
significant between-group differences in the rate of
hospitalization for heart failure (hazard ratio in the
lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of
death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide
was not associated with a higher rate of serious adverse
events or severe hypoglycemia, pancreatitis, pancreatic
neoplasms, or allergic reactions than was placebo.
Conclusions
In patients with type 2 diabetes and a recent
acute coronary syndrome, the addition of
lixisenatide to usual care did not significantly alter
the rate of major cardiovascular events or other
serious adverse events.
(Funded by Sanofi; ELIXA ClinicalTrials.gov number,
NCT01147250.)
Message
急性冠症候群（ACS）を最近発症した2型糖尿病
患者6068例を対象に、通常治療＋リキシセナチ
ド併用による心血管転帰を無作為化試験で検証
（ELIXA試験）。主要複合評価項目（心血管死、
心筋梗塞、脳卒中、不安定狭心症による入院）
発生率で、リキシセナチドはプラセボに対し非
劣性ではあったが（13.4％対13.2％、ハザード
比1.02；95％CI, 0.89 - 1.17、P＜0.001）、優
越性は示されなかった（P＝0.81）。
https://www.m3.com/clinical/journal/16068
Dipeptidyl peptidase-4 阻害薬／GLP-1受容体作動薬
taspoglutide
albiglutide
Exenatide
Lixisenatide
Liraglutide
Dulaglutide
sitagliptin
alogliptin
Semaglutide
omarigliptin
trelagliptin
vildagliptin
linagliptin
anagliptin
teneligliptin
saxagliptin
演者編集
Drs. Zaccardi, Htike, Webb, Khunti, and Davies: Diabetes
Research Centre, Leicester General Hospital, Gwendolen
Road, Leicester LE5 4PW, United Kingdom.
Ann Intern Med. Published online 8 December 2015 doi:10.7326/M15-1432
Background:
Once-weekly glucagon-like peptide-1
receptor agonists (GLP-1RAs) are new
drugs for the treatment of type 2 diabetes.
Purpose:
To summarize evidence for the
cardiometabolic efficacy and adverse
effects of once-weekly GLP-1RAs in adults
with type 2 diabetes.
Data Sources:
Electronic databases (PubMed, Web of Science, Cochrane
Central Register of Controlled Trials, U.S. Food and Drug
Administration, European Medicines Agency, ClinicalTrials.gov)
and congress abstracts from inception through 26 September
2015.
Study Selection:
Randomized, controlled trials (≥24 weeks of follow-up) studying
albiglutide, dulaglutide, once-weekly exenatide, semaglutide,
and taspoglutide and reporting a cardiometabolic (primary
outcome, hemoglobin A1c [HbA1c]) or safety outcome.
Data Extraction:
Extraction was done in duplicate, and risk of bias was assessed.
No language restriction was applied.
Nodes represent the treatments being compared;
their size is proportional to the number of
participants. Edges represent the available direct
comparisons between pairs of treatments, and their
width is proportional to the number of trials
comparing every pair. ALB = albiglutide; BASAL =
basal insulin; dGLP1 = daily glucagon-like peptide1 receptor agonists; DUL 0.75 = dulaglutide, 0.75
mg; DUL 1.5 = dulaglutide, 1.5 mg; EOW =
exenatide once-weekly; GLIM = glimepiride; HbA1c
= hemoglobin A1c; HDL = high-density lipoprotein;
LDL = low-density lipoprotein; MET = metformin;
PIO = pioglitazone; PLA = placebo; RAPID = rapid
insulin; SITA = sitagliptin; TAS 10 = taspoglutide, 10
mg; TAS 20 = taspoglutide, 20 mg.
Ann Intern Med. Published online 8 December 2015 doi:10.7326/M15-1432
Data are reported as mean
differences (95% CIs) and
indicate differences versus the
reference drug (for example,
compared with dulaglutide, 1.5
mg, albiglutide increases HbA1c
by 0.40% [CI, 0.17% to 0.63%]).
ALB = albiglutide; DUL 0.75 =
dulaglutide, 0.75 mg; DUL 1.5 =
dulaglutide, 1.5 mg; EOW =
exenatide once-weekly; HbA1c =
hemoglobin A1c; HDL = highdensity lipoprotein; LDL = lowdensity lipoprotein; TAS 10 =
taspoglutide, 10 mg; TAS 20 =
taspoglutide, 20 mg.
* To convert values to mg/dL,
divide by 0.0555.
† To convert values to mg/dL,
divide by 0.0259.
‡ To convert values to mg/dL,
divide by 0.0113.
Zaccardi and colleagues (5) conducted a network meta-analysis of
randomized trials that could yield, directly or indirectly, estimates of
comparative efficacy between once-weekly glucagon-like peptide-1
receptor agonists. They found these trials to have inadequate blinding
(which could affect co-interventions that may affect hemoglobin A1c level
and weight outcomes) and substantial loss to follow-up. The estimates
for each direct, indirect, and network comparison and their quality
ratings were not reported separately and hindered appraisal. Data on
outcomes of importance to patients, including quality of life, treatment
burden, and morbidity and mortality, were sparse or nonexistent.
Network inspection shows that the 2 leading options, once-weekly
exenatide and 1.5 mg-dulaglutide, were compared mostly to daily
exenatide and 0.75 mg-dulaglutide (both products are from the same
company). Because of the low reliability of the evidence summarized (7),
claims of differences between agents should be met with skepticism,
including rankings that suggest that, within the once-weekly
preparations, exenatide and dulaglutide are associated with the biggest
reduction in hemoglobin A1c level and weight while being well-tolerated.
Ann Intern Med. Published online 8 December 2015 doi:10.7326/M15-2610
Data Synthesis:
34 trials (21 126 participants) were included. Compared with
placebo, all once-weekly GLP-1RAs reduced HbA1c and
fasting plasma glucose; taspoglutide, 20 mg, once-weekly
exenatide, and dulaglutide, 1.5 mg, reduced body weight.
Among once-weekly GLP-1RAs, the greatest differences were
found between dulaglutide, 1.5 mg, and taspoglutide, 10 mg,
for HbA1c (-0.4% [95% CI, -0.7% to -0.2%]), once-weekly
exenatide and albiglutide for fasting plasma glucose (-0.7
mmol/L [CI, -1.1 to -0.2 mmol/L]; -12.6 mg/dL [CI, -19.8 to -3.6
mg/dL]), and taspoglutide, 20 mg, and dulaglutide, 0.75 mg, for
body weight (-1.5 kg [CI, -2.2 to -0.8]). Clinically marginal or no
differences were found for blood pressure, blood lipid levels,
and C-reactive protein levels. Once-weekly exenatide increased
heart rate compared with albiglutide and dulaglutide (1.4 to 3.2
beats/min). Among once-weekly GLP-1RAs, the risk for
hypoglycemia was similar, whereas taspoglutide, 20 mg, had
the greatest risk for nausea (odds ratios, 1.9 to 5.9).
Limitation:
Data were unavailable for semaglutide, definitions of outcomes
were heterogeneous, the last-observation-carried-forward
imputation method was used in 73% of trials, and publication
bias is possible.
Conclusion:
Compared with other once-weekly GLP-1RAs, dulaglutide 1.5
mg, once-weekly exenatide, and taspoglutide, 20 mg, showed a
greater reduction of HbA1c, fasting plasma glucose, and body
weight. Taspoglutide, 20 mg, had the highest risk for nausea;
risk for hypoglycemia among once-weekly GLP-1RAs was
similar.
Primary Funding Source:
Sanofi Aventis (grant to the University of Leicester).
semaglutide
dulaglutide
once-weekly exenatide
albiglutide
taspoglutide
スイスRoche社、糖尿病治療薬候補品タスポグ
ルチドの権利を返還、子会社の中外製薬も国内
開発を中止に
April 15, 2014 albiglutide（Tanzeum、GLP-1受容体作動薬）が、米国食品医薬品局（FDA）により承認された。 FDAは、
2011年2月3日 08:27
albiglutideと甲状腺腫瘍の因果関係の可能性や、小児における有効性、および心血管系に対するリスクを評価する承認後試
験をいくつか行うよう求めている。
http://dm-rg.net/news/2014/04/014572.html
日本GSKがAlbiglutideを発売するかどうかは2015年7月現在未定である。なぜなら、GSKのMRリストラが急速な勢
いで進んでいるからである。2015年3月末現在の日本GSKのMR数は前年度から600人規模で減少。同社はノバル
ティスとグローバルで事業スワップを実施しており、日本国内ではGSKのがん事業がノバルティスに譲渡された。こ
れにより、同事業に携わるMRや研究開発部門といったメンバーのほとんどが、3月中にノバルティスファーマへ転籍
した模様だ。GSKは同時にグローバルでMRの個人売上目標をなくすといった営業刷新を行っており、日本でも今年
から実施している。併せて早期退職者を募集したとされている。しかしながら、移転先のノバルティスファーマも
500人以上削減したとみられている。この外資2社がMR削減の2強だ。このあおりを受け、Tanzeumの日本国内発
売も見通しが立たなくなっているのだ。
http://funabashi-tounyou.blogspot.jp/2014/06/gskglp-1-tanzeum-albiglutide.html
Message
2型糖尿病患者への週1回投与のグルカゴン様ペプチド-1受容体作
動薬（GLP-1RA）5剤の効果と安全性を見た無作為化比較試験34件
（対象計2万1126人）のシステマティックレビューとネットワー
クメタ解析で検証。GLP1-RAは5剤すべてでプラセボに比べHbA1c
と空腹時血糖を低下させていた。Taspoglutide 20mg、デュラグ
ルチド1.5mg、週1回エキセナチドは他剤より血糖改善効果が大き
く、体重減少も認められた。ただしTaspoglutide 20mgは嘔気リ
スクが最も高く、低血糖リスクも高かった。
https://www.m3.com/clinical/journal/16074
すでにtaspoglutide, albiglutideは日本では製品化はないよう
である。デバイスで週1回エキセナチドが負けている。そうなる
と週一のGLP1-RAはLillyのデュラグルチド(トルリシティ/アテオ
ス)が独り勝ちになりそう（2015年7月3日製造販売が承認）。長
期処方が可能になるのが今年の夏以降がどうなるのか？