Journal Club
Bernard Zinman, Stewart B Harris, Jan Neuman, Hertzel C Gerstein, Ravi R Retnakaran, Janet
Raboud, Ying Qi, Anthony J G Hanley
Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus
(CANOE trial): a double-blind randomised controlled study
Lancet. June 3, 2010 DOI:10.1016/S0140-6736(10)60746-5
Tanenao Eto, Genjiro Kimura, Tsutomu Imaizumi, Shuichi Takishita, Hirotsugu Shimamoto,
Kazuyuki Shimada, Yutaka Imai, Kenjiro Kikuchi, Sadayoshi Ito, Toshio Ogihara, Takao Saruta,
Hiromi Rakugi, Hiroaki Matsuoka, Kazuaki Ueshima and for the Valsartan in Elderly Isolated
Systolic Hypertension Study Group
Target Blood Pressure for Treatment of Isolated Systolic Hypertension in the Elderly. Valsartan in
Elderly Isolated Systolic Hypertension Study
Hypertension published online Jun 7, 2010 DOI: 10.1161/HYPERTENSIONAHA.109.146035;
2010年６月10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
日本糖尿病学会では
血糖は
plasma glucose (略語 PG)
あるいは
blood glucose (略語 BG)
という用語を用いるべきだとしている。
BS は間違い！
J Neuman MSc, R R Retnakaran MD, Y Qi MSc, A J G Hanley PhD); Samuel Lunenfeld
Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (B Zinman); Centre for
Studies in Family Medicine, University of Western Ontario, London, ON, Canada (Prof S
B Harris MD); Division of Endocrinology and Metabolism and the Population Health
Research Institute, Department of Medicine, McMaster University and Hamilton Health
Sciences, Hamilton, ON, Canada (Prof H C Gerstein MD); Division of Infectious Diseases,
University Health Network, Toronto, ON, Canada (J Raboud PhD); and Dalla Lana School
of Public Health (J Raboud) and Department of Nutrition and Public Health Sciences (A J
G Hanley), University of Toronto, Toronto, ON, Canada
www.thelancet.com Published online June 3, 2010 DOI:10.1016/S0140-6736(10)60746-5
Background
The evolving epidemic of type 2
diabetes has challenged health-care
providers to assess the safety and
efficacy of various diabetes prevention
strategies. The CANOE (CAnadian
Normoglycemia Outcomes Evaluation)
trial investigated whether low-dose
combination therapy would affect
development of type 2 diabetes.
Primary Prevention of Type 2 Diabetes Mellitus
● Life style modification
・Malmö feasibility study
・Malmö Prfevention Trial
・DaQing IGT and Diabetes Study
・Finnish Diabetes Prevnetion Study
・Japan Diabetes Prevention Study
・Stockholm Diabetes Prevention Program
● Drug intervention
・Diabetes Prevention Program
・STOP-NIDDM
・TRIPOD
・EDIT
・NAVIGATOR
・DREAM
・ACT NOW
・ONTARGET
(Eriksson, 1991)
(Eriksson, 1998)
(Pan, 1997)
(Tuomilehto, 2001)
(Kuzuya, on going)
(Bjärås, on going)
(DPP Research Group, 2002)
(Chiasson, 2002)
(Buchanan, 2001)
(Holman, 2003)
(Rury R. Holman, 2010) negative
(Boche, 2006)
(DeFronzo，2008)
(ONTARGET group, 2008)
STOP-NIDDM：Study To Prevent NDDM,
TRIPOD：Troglitazone In Prevention of Diabetes
EDIT：Early Diabetes Intervention Trial,
NAVIGATOR：Natglinide and Valsartan in Impaired Glucose Tolerance Outcome Reaserach
DREAM：Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications
Prevention of Diabetes Mellitus
*ONTARGET 2008
*ONTARGET 2008
*TRANSCEND 2008
*Kyoto Heart 2009
*NAVIGATOR 2010
4.7
4.7
4.7
3.27
6.5
ARB
ARB+ACEI
ARB
ARB+x
ARB
399
323
319
58
1532
8542
8502
2954
1116
3748
10.0
8.1
26.4
51.6
62.9
ACEI
ACEI
placebo
x
placebo
366
366
395
86
1722
8576
8576
2972
998
3725
9.2
9.2
28.8
76.7
71.1
松田昌文：DREAM study 内分泌・糖尿病科 26(1):35-41, 2008.
Prevention of Diabetes Mellitus
*ACTNOW
*CANOE
*VICTORY
*NAVIGATOR
BIP
2008
2010
2009
2010
2004
4.0
3.9
4
6.5
6.2
Pioglitazone
Met+Rosi
Voglibose
Nateglinide
Bezafibrate
10
14
50
1674
66
303
103
897
3726
156
8.3
34.9
13.9
69.1
68.2
Placebo
Placebo
Placebo
Placebo
Placebo
45
41
106
1580
80
299
104
881
3747
147
37.6
101.1
30.0
64.9
87.8
松田昌文：２型糖尿病治療薬選択の考え方 月刊糖尿病 2:16-22, 2010.
Methods
In this double-blind, randomised controlled trial undertaken
in clinics in Canadian centres, 207 patients with impaired
glucose tolerance were randomly assigned to receive
combination rosiglitazone (2 mg) and metformin (500 mg)
twice daily or matching placebo for a median of 3・9 years
(IQR interquartile range 3・0–4・6). Randomisation was
computer-generated in blocks of four, with both
participants and investigators masked to treatment
allocation. The primary outcome was time to development
of diabetes, measured by an oral glucose tolerance test or
two fasting plasma glucose values of 7・0 mmol/L (126
mg/dl) or greater. Analysis was by intention to treat.
This study is registered with ClinicalTrials. gov, number
NCT00116932.
Figure 1: Trial profile
OGTT=oral glucose tolerance test. BMI=body-mass index.
Table 1: Demographic, clinical, and metabolic characteristics at baseline
/0.0259
131mg/dl
112mg/dl
/0.0113
97mg/dl
x18
158mg/dl
Data are median (IQR) or number (%). AHA=American Heart Association. IDF=International Diabetes Federation.
CVD=cardiovascular disease. ACE=angiotensin-converting enzyme. ARB=angiotensin-receptor blockers. BMI=body-mass index.
ALT=alanine aminotransferase. CRP=C-reactive protein. BNP=pro-brain natriuretic peptide. IS=insulin sensitivity. OGTT=oral
glucose tolerance test. HOMA-IR=homoeostasis model of assessment of insulin resistance. ISSI-2=insulin secretion-sensitivity
index-2. HOMA-B=homoeostasis model of assessment of β-cell function. IGT=impaired glucose tolerance. IFG=impaired fasting
glucose. *Defi ned as any history of past smoking but not currently smoking.
66% risk reduction
Figure 2: Time to occurrence of the development of diabetes
HR=hazard ratio.
Matsuda M, DeFronzo R. Insulin sensitivity indices obtained from oral glucose
tolerance testing: comparison with the euglycemic insulin clamp. Diabet Care 1999;
22: 1462–70.
Results
103 participants were assigned to rosiglitazone and metformin, and 104 to
placebo; all were analysed. Vital status was obtained in 198 (96%)
participants, and medication compliance (taking at least 80% of assigned
medication) was 78% (n=77) in the metformin and rosiglitazone group and
81% (n=80) in the placebo group. Incident diabetes occurred in
significantly fewer individuals in the active treatment group (n=14 [14%])
than in the placebo group (n=41 [39%]; p<0・0001). The relative risk
reduction was 66% (95% CI 41–80) and the absolute risk reduction was
26% (14–37), yielding a number needed to treat of 4 (2・70–7・14). 70 (80%)
patients in the treatment group regressed to normal glucose tolerance
compared with 52 (53%) in the placebo group (p=0・0002). Insulin
sensitivity decreased by study end in the placebo group (median –1・24,
IQR –2・38 to –0・08) and remained unchanged with rosiglitazone and
metformin treatment (–0・39, –1・30 to 0・84; p=0・0006 between groups).
The change in β-cell function, as measured by the insulin secretionsensitivity index-2, did not differ between groups (placebo –252・3, –382・2
to –58・0 vs rosiglitazone and metformin –221・8, –330・4 to –87・8; p=0・28).
We recorded an increase in diarrhoea in participants in the active
treatment group compared with the placebo group (16 [16%] vs 6 [6%];
p=0・0253).
Conclusion
Low-dose combination therapy with
rosiglitazone and metformin was
highly effective in prevention of
type 2 diabetes in patients with
impaired glucose tolerance, with
little effect on the clinically relevant
adverse events of these two drugs.
Funding GlaxoSmithKline.
Editorial Comments
Thomas A Buchanan, Anny H Xiang
Preventing type 2 diabetes with low-dose combinations
Lancet June 3, 2010 DOI:10.1016/S0140-6736(10)60900-2
The report included no off-drug testing, so it is not clear that
diabetes prevention represented any real slowing or arrest of
metabolic deterioration. We must halt the progressive β-cell
disease if we are to keep patients at low-risk glucose levels
over the long haul. We need data on more intensive
approaches, including high-dose combination therapy, to
provide clinicians with a full range of evidence-based
approaches to halt or reverse this progressive disease relatively
early in its course.
False-colour transmission electron micrograph
showing cells of islet of Langerhans
At right in green, yellow, and brown are insulin-secreting
β cells; in red at left are α cells, which secrete glucagon.
Message
メトホルミンとロジグリタゾンの低用量併用で
糖尿病発症予防効果がありそう。
膵β細胞を保護するような治療を心がけるべき
である。そのための早期介入について今後デー
タを更に出してゆく必要がある。
the Osaka University Graduate School of Medicine (T.O., H.R.), Osaka, Japan; Keio University School of
Medicine (T.S.), Tokyo, Japan; Dokkyo Medical University (H.M.), Tochigi, Japan; Sapporo Medical University
(K.S.), Sapporo, Japan; Jichi Medical University (K.S.), Shimotsuke, Japan; Tohoku University Graduate School
of Pharmaceutical Sciences and Medicine (Y.I.), Sendai, Japan; Hokkaido Cardiovascular Hospital (K.K.),
Sapporo, Japan; Tohoku University Graduate School of Medicine (S.I.), Sendai, Japan; Faculty of Medicine
(T.E.), University of Miyazaki, Miyazaki, Japan; Nagoya City University Graduate School of Medical Sciences
(G.K.), Nagoya, Japan; Kurume University School of Medicine (T.I.), Kurume, Japan; University of the Ryukyus
School of Medicine (S.T.), Okinawa, Japan; Shiga University of Medical Science (H.U.), Shiga, Japan.
DOI: 10.1161/HYPERTENSIONAHA.109.14603
Background
In this prospective, randomized, openlabel, blinded end point study, we aimed to
establish whether strict blood pressure
control (<140 mm Hg) is superior to
moderate blood pressure control (≧140
mm Hg to <150 mm Hg) in reducing
cardiovascular mortality and morbidity in
elderly patients with isolated systolic
hypertension.
Methods
We divided 3260 patients aged 70 to 84
years with isolated systolic hypertension
(sitting blood pressure 160 to 199 mm Hg)
into 2 groups, according to strict or
moderate blood pressure treatment. A
composite of cardiovascular events was
evaluated for ≧2 years.
Figure 1. Study profile.
Figure 2. Changes in BP during treatment. The BP differences between the 2 groups
were statistically significant during the follow-up period.
Figure 4. Comparisons of hazard ratios and 95% CIs for the primary end point and secondary end point. Hazard ratio was adjusted
for the following covariates: sex, age, BMI, smoking, dyslipidemia, diabetes mellitus, and antihypertensive agents used before
enrollment. 1Data include sudden death, fatal and nonfatal stroke, fatal and nonfatal myocardial infarction, heart failure death, other
cardiovascular death, unplanned hospitalization because of cardiovascular diseases, renal dysfunction (doubling of serum creatinine
and creatinine, to _2.0 mg per 100 mL, or introduction of dialysis). 2Data include cardiovascular death, nonfatal stroke (exclude
transient ischemic attack), and nonfatal myocardial infarction.
Figure 5. Comparisons of hazard ratios and 95% CIs for primary end point in each
prespecified subgroup. Hazard ratio was adjusted for covariates: sex, age, BMI, smoking,
dyslipidemia, diabetes mellitus, and antihypertensive agents used before enrollment.
1Data show the number of events/number of patients.
Results
The strict control (1545 patients) and moderate
control (1534 patients) groups were well matched
(mean age: 76.1 years; mean blood pressure:
169.5/81.5 mm Hg). Median follow-up was 3.07
years. At 3 years, blood pressure reached
136.6/74.8 mm Hg and 142.0/76.5 mm Hg,
respectively. The blood pressure difference
between the 2 groups was 5.4/1.7 mm Hg. The
overall rate of the primary composite end point was
10.6 per 1000 patient-years in the strict control
group and 12.0 per 1000 patient-years in the
moderate control group (hazard ratio: 0.89; [95%
CI: 0.60 to 1.34]; P=0.38).
Conclusion
In summary, blood pressure targets of
<140 mm Hg are safely achievable in
relatively healthy patients ≧70 years
of age with isolated systolic
hypertension, although our trial was
underpowered to definitively
determine whether strict control was
superior to less stringent blood
pressure targets.
Message
高齢（70歳以上）高血圧の患者でも血圧は
140 mmHg未満は可能のようで，結果もよさ
そうだが，有意差はなかった。