Journal Club

1
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
DOI10.1016/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?6?10? 830-855 8? ??

• ?????? ???????? ????????
• Department of Endocrinology and Diabetes,
• Saitama Medical Center, Saitama Medical
  University
• ?? ??
• Matsuda, Masafumi

2
(No Transcript)
3
(No Transcript)
4
????????? ??? plasma glucose (?? PG) ????
blood glucose (?? BG) ?????????????????? BS
????!
5
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
DOI10.1016/S0140-6736(10)60746-5
6
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.
7
Primary Prevention of Type 2 Diabetes Mellitus
? Life style modification Malmö feasibility
study (Eriksson, 1991) Malmö Prfevention
Trial (Eriksson, 1998) DaQing IGT and Diabetes
Study (Pan, 1997) Finnish Diabetes Prevnetion
Study (Tuomilehto, 2001) Japan Diabetes
Prevention Study (Kuzuya, on going) Stockholm
Diabetes Prevention Program (Bjärås, on going) ?
Drug intervention Diabetes Prevention
Program (DPP Research Group, 2002) STOP-NIDDM (C
hiasson, 2002) TRIPOD (Buchanan,
2001) EDIT (Holman, 2003) NAVIGATOR (Rury R.
Holman, 2010) negative DREAM (Boche,
2006) ACT NOW (DeFronzo,2008) ONTARGET (ONTARG
ET group, 2008)
STOP-NIDDMStudy To Prevent NDDM,
TRIPODTroglitazone In Prevention of Diabetes
EDITEarly Diabetes Intervention Trial,
NAVIGATORNatglinide and Valsartan in Impaired
Glucose Tolerance Outcome Reaserach DREAMDiabetes
Reduction Assessment with Ramipril and
Rosiglitazone Medications
8
Prevention of Diabetes Mellitus
ONTARGET 2008 4.7 ARB 399 8542 10.0 ACEI 366 857
6 9.2 ONTARGET 2008 4.7 ARBACEI 323 8502
8.1 ACEI 366 8576 9.2 TRANSCEND
2008 4.7 ARB 319 2954 26.4 placebo 395
2972 28.8 Kyoto Heart 2009 3.27 ARBx 58 1116 51
.6 x 86 998 76.7 NAVIGATOR 2010 6.5 ARB 1532 37
48 62.9 placebo 1722 3725 71.1
????DREAM study ??????? 26(1)35-41, 2008.
9
Prevention of Diabetes Mellitus
ACTNOW 2008 4.0 Pioglitazone 10 303 8.3 Placebo
45 299 37.6 CANOE 2010 3.9 MetRosi 14 103 34.9 P
lacebo 41 104 101.1 VICTORY 2009 4 Voglibose 50 8
97 13.9 Placebo 106 881 30.0 NAVIGATOR 2010 6.5 N
ateglinide 1674 3726 69.1 Placebo 1580 3747 64.9 B
IP 2004 6.2 Bezafibrate 66 156 68.2 Placebo 80 147
87.8
????2????????????? ????? 216-22, 2010.
10
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 39
years (IQR interquartile range 3046).
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 70 mmol/L (126
mg/dl) or greater. Analysis was by intention to
treat. This study is registered with
ClinicalTrials. gov, number NCT00116932.
11
Figure 1 Trial profile OGTToral glucose
tolerance test. BMIbody-mass index.
12
Table 1 Demographic, clinical, and metabolic
characteristics at baseline
13
/0.0259 /0.0113
131mg/dl
112mg/dl
14
x18
97mg/dl
158mg/dl
Data are median (IQR) or number (). AHAAmerican
Heart Association. IDFInternational Diabetes
Federation. CVDcardiovascular disease.
ACEangiotensin-converting enzyme.
ARBangiotensin-receptor blockers. BMIbody-mass
index. ALTalanine aminotransferase.
CRPC-reactive protein. BNPpro-brain natriuretic
peptide. ISinsulin sensitivity. OGTToral
glucose tolerance test. HOMA-IRhomoeostasis
model of assessment of insulin resistance.
ISSI-2insulin secretion-sensitivity index-2.
HOMA-Bhomoeostasis model of assessment of ß-cell
function. IGTimpaired glucose tolerance.
IFGimpaired fasting glucose. Defi ned as any
history of past smoking but not currently
smoking.
15
(No Transcript)
16
66 risk reduction
Figure 2 Time to occurrence of the development
of diabetes HRhazard ratio.
17
(No Transcript)
18
(No Transcript)
19
(No Transcript)
20
(No Transcript)
21
(No Transcript)
22
(No Transcript)
23
(No Transcript)
24
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
(n77) in the metformin and rosiglitazone group
and 81 (n80) in the placebo group. Incident
diabetes occurred in significantly fewer
individuals in the active treatment group (n14
14) than in the placebo group (n41 39
plt00001). The relative risk reduction was 66
(95 CI 4180) and the absolute risk reduction
was 26 (1437), yielding a number needed to
treat of 4 (270714). 70 (80) patients in the
treatment group regressed to normal glucose
tolerance compared with 52 (53) in the placebo
group (p00002). Insulin sensitivity decreased
by study end in the placebo group (median 124,
IQR 238 to 008) and remained unchanged with
rosiglitazone and metformin treatment (039,
130 to 084 p00006 between groups). The
change in ß-cell function, as measured by the
insulin secretion-sensitivity index-2, did not
differ between groups (placebo 2523, 3822 to
580 vs rosiglitazone and metformin 2218,
3304 to 878 p028). We recorded an increase
in diarrhoea in participants in the active
treatment group compared with the placebo group
(16 16 vs 6 6 p00253).
25
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.
26
Editorial Comments
Thomas A Buchanan, Anny H Xiang Preventing type 2
diabetes with low-dose combinationsLancet June
3, 2010 DOI10.1016/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
ß-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 ß
cells in red at left are a cells, which secrete
glucagon.
27
Message
???????????????????????????????????? ?ß??????????
?????????????????????????????????????????????
28
(No Transcript)
29
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
30
Background
In this prospective, randomized, open-label,
blinded end point study, we aimed to establish
whether strict blood pressure control (lt140 mm
Hg) is superior to moderate blood pressure
control (?140 mm Hg to lt150 mm Hg) in reducing
cardiovascular mortality and morbidity in elderly
patients with isolated systolic hypertension.
31
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.
32
Figure 1. Study profile.
33
(No Transcript)
34
(No Transcript)
35
Figure 2. Changes in BP during treatment. The BP
differences between the 2 groups were
statistically significant during the follow-up
period.
36
(No Transcript)
37
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.
38
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.
39
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 P0.38).
40
Conclusion
In summary, blood pressure targets of lt140 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.
41
Message
??(70???)???????????140 mmHg?????????,?????????,??
???????
42
(No Transcript)