Transcript PowerPoint プレゼンテーション - 埼玉医科大学総合医療センター 内分泌

Journal Club
Andersson C, Weeke P, Brendorp B, Køber L, Fosbøl EL, Sharma AM, Finer N,
Caterson ID, Rode RA, James PT, Torp-Pedersen C.
Differential changes in serum uric acid concentrations in sibutramine promoted
weight loss in diabetes: results from four weeks of the lead-in period of the SCOUT
trial.
Nutr Metab (Lond). 2009 Oct 14;6:42.
Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, Weissman NJ,
Turco M.
Extended-Release Niacin or Ezetimibe and Carotid Intima-Media Thickness.
N Engl J Med. 2009 Nov 15. [Epub ahead of print]
2009年11月19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
Both uric acid and ascorbic acid are
strong reducing agents (electron donors)
and potent antioxidants. In humans, over
half the antioxidant capacity of blood
plasma comes from uric acid
must be GOOD!
Hyperuricaemia may simply reflect
established cardiovascular risk factors,
such as hypertension and renal
impairment and not act causally.
The principal metabolic effects of deficiency
of glucose-6-phosphatase are:
●hypoglycemia
● lactic acidosis
● hypertriglyceridemia
● hyperuricemia
Hyperuricemia results from a combination of increased generation
and decreased excretion of uric acid, which is generated when
increased amounts of G6P are metabolized via the pentose
phosphate pathway. It is also a byproduct of purine degradation.
Uric acid competes with lactic acid and other organic acids for renal
excretion in the urine.
In GSD I increased availability of G6P for the pentose phosphate
pathway, increased rates of catabolism, and diminished urinary
excretion due to high levels of lactic acid all combine to produce
uric acid levels several times normal. Although hyperuricemia is
asymptomatic for years, kidney and joint damage gradually accrue.
Sibutramine
Fig 3 Placebo subtracted weight reduction (kg) with sibutramine
Copyright ©2007 BMJ Publishing Group Ltd.
Rucker, D. et al. BMJ 2007;335:1194-1199
SLC2A9 or GLUT9 is
a high-capacity urate
transporter in
humans.
Hypothesis: Could
Excessive Fructose
Intake and Uric Acid
Cause Type 2
Diabetes? Endocrine
Reviews 30 (1): 96-116,
2008
Background and Aim
Elevated levels of serum uric acid are
associated with an increased risk of
cardiovascular morbidity and mortality. The
response of uric acid to weight loss therapy
(lifestyle plus sibutramine) in an overweight
and obese cardiovascular high risk
population was studied.
This study is registered with ClinicalTrials.gov, number NCT00234832.
Method
Data from a four week single-blind lead-in period of
the Sibutramine Cardiovascular OUTcomes (SCOUT)
study were analyzed. 2584 patients (24%) had
diabetes mellitus (DM) only, 1748 (16%) had
cardiovascular disease (CVD) only and 6397 (60%)
had both DM + CVD. Uric acid concentrations (mean
± standard deviation) at screening were
significantly higher among patients with CVD
compared to patients without CVD (p < 0.0001): 369
± 86 mmol/ L, 374 ± 98 mmol/L and 342 ± 87 mmol/L
in CVD only, CVD+DM and DM only groups,
respectively.
(UA x 59.5 to convert mcmol/L from mg/dl)
/ 59.5
X 18
/ 0.0259 3->116
/ 0.0113
Diabetes prevented decline in UA.
-0.3mg/dl
Diabetes
No diabetes
Diabetes
Figure 4 Mean change in uric acid concentration for patients with diabetes, according to
four week change in urinary glucose, estimated by dip stick.
The dip stick scale ranged between "negative", "trace", "1+", "2+" and "3+" for glucose content. FSG =
fasting serum glucose. Error bars illustrate 95% confidence interval. Variables in table are presented as
means (± standard deviation). Analysis for patients without diabetes was not performed, since 99% of the
patients had a negative dip stick at screening, and 99% of the patients were found to have no change in
glucose dip stick.
SLC2A9 or GLUT9 is
a high-capacity urate
transporter in
humans.
Hypothesis: Could
Excessive Fructose
Intake and Uric Acid
Cause Type 2
Diabetes? Endocrine
Reviews 30 (1): 96-116,
2008
Results
During treatment uric acid decreased significantly
more in patients without DM (p < 0.0001): -15.0
mmol/L (95% confidence interval -17.7;-12.4), -4.6
mmol/L (-6.2;-3.0), and -6.6 mmol/L (-8.7;-4.5) in CVD
only, CVD+DM, and DM only groups, respectively. In
patients who failed to lose weight, sibutramine
induced lower uric acid levels, but greater weight
loss and diabetes were associated with smaller falls
in blood uric acid levels; decreasing fasting and
urinary glucose concentrations in diabetes were
associated with increases in uric acid levels.
Conclusion
A four week daily intake of sibutramine and
life style changes was associated with
significant reductions in mean uric acid levels.
Changes in renal glucose load in diabetes
seem to counteract a potential uricosuric
effect of sibutramine.
Message
果糖摂取と尿酸値や血糖値についての関係がと
りざたされている。GLUT9（SLC2A9)というブド
ウ糖担体は2008年に同定されたばかりで今後の
研究の進展が期待される。
Sibtramineについては血中尿酸値を低下させる
が、糖尿病があるとその作用が減弱。というか、
糖尿病があると血糖が下がったり、体重が減る
ほど 尿酸は却って上昇！
スタチン介入大規模臨床試験における
LDL-Cと冠動脈疾患イベント発症率の関係
4S DM
(placebo)
Diabetes secondary
Patient with CHD event (mean%)
Secondary prevention
Primary prevention
30
CARE DM
4S DM
(placebo)
(simvastatin)
LIPID DM
(pravastatin)
20
20
CARE DM
(pravastatin)
15
10
CARE
(pravastatin)
5
4S
(simvastatin)
CARE
(placebo)
LIPID
(pravastatin)
LIPID DM
(placebo)
LIPID
(placebo)
1.5
58
2.0
77
2.5
3.0
116
WOSCOPS
(placebo)
WOSCOPS
(pravastatin)
AFCAPS
(lovastatin
)
0
4S
(placebo)
AFCAPS
(placebo)
3.5
4.0
154
4.5
Mean LDL cholesterol ( mmol / l ) (mg/dl)
5.0
193
5.5
Fisher M:Heart,90(3),336-340(2004)
Ezetimibe
• 高脂血症治療剤2007年6月11日新発売
－小腸コレステロールトランスポーター阻害剤－
Ezetimibe
diminishes intestinal
cholesterol
absorption by
inhibiting the
Niemann–Pick C1like 1 (NPC1L1)
enterocyte receptor,
License to eat!
"Take this pill and I can eat as much eggs and cake as I want."
薬価：250.9円
Original Article
Simvastatin with or without Ezetimibe in Familial
Hypercholesterolemia
John J.P. Kastelein, M.D., Ph.D., Fatima Akdim, M.D., Erik S.G. Stroes,
M.D., Ph.D., Aeilko H. Zwinderman, Ph.D., Michiel L. Bots, M.D., Ph.D.,
Anton F.H. Stalenhoef, M.D., Ph.D., F.R.C.P., Frank L.J. Visseren, M.D.,
Ph.D., Eric J.G. Sijbrands, M.D., Ph.D., Mieke D. Trip, M.D., Ph.D., Evan
A. Stein, M.D., Ph.D., Daniel Gaudet, M.D., Ph.D., Raphael
Duivenvoorden, M.D., Enrico P. Veltri, M.D., A. David Marais, M.D., Ph.D.,
Eric de Groot, M.D., Ph.D., for the ENHANCE Investigators
N Engl J Med
Volume 358(14):1431-1443
April 3, 2008
Effects of
Simvastatin and
Combined
Therapy with
Simvastatin
plus Ezetimibe
on Levels of
Cholesterol and
Triglycerides
Mean (±SE) IntimaMedia Thickness of
the Carotid Artery
during 24 Months of
Therapy
Levels of Lipids,
Lipoproteins, Sterols, and
C-Reactive Protein at
Baseline and after 24
Months of Treatment, with
Changes from Baseline
New Engl J Med: Volume 359:1398-1399, 2008
SEAS trial, assignment to ezetimibe was associated with an increase in any new
onset of cancer (101 patients in the active-treatment group vs. 65 in the control
group) from several cancer sites. In SHARP and IMPROVE-IT combined, there was
no overall excess of cancer (313 active-treatment vs. 326 control; risk ratio, 0.96;
95% confidence interval, 0.82 to 1.12; P=0.61) and no significant excess at any
particular site. Among patients assigned to ezetimibe, there were more, albeit not
significantly more, deaths from cancer (97, vs. 72 in the control group; P=0.07),
but there were also fewer, although not significantly fewer, other cases of cancer
(216, vs. 254 in the control group; P=0.08).
The available results from these three trials do not provide credible evidence of
any adverse effect of ezetimibe on rates of cancer. Follow-up of longer duration
will permit the balance of risks and benefits to be determined more reliably.
Extended release of niacin
vitamin B3 or nicotinic acid
From the Cardiology Service, Walter Reed Army Medical Center (A.J.T., T.C.V.,
P.J.D., M.M.); and Medstar Research Institute, Washington Hospital Center
(A.J.T., N.J.W.) — both in Washington, DC; Medco Health Solutions, Franklin
Lakes, NJ (E.J.S.); Cardiac Associates, Rockville, MD (L.G.); University of
Maryland Medical Center, Baltimore (M.M.); and Washington Adventist
Hospital, Takoma Park, MD (M.T.).
The ARBITER 6–HALTS (Arterial Biology for the Investigation of the Treatment
Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies) trial
compared the effects of two combination therapies — either niacin or ezetimibe
added to long-term statin therapy — on carotid intima
N Engl J Med 2009;361.
Background
Treatment added to statin monotherapy to
further modify the lipid profile may include
combination therapy to either raise the highdensity lipoprotein (HDL) cholesterol level or
further lower the low-density lipoprotein (LDL)
cholesterol level.
Trial registration: clinical trials.gov NCT00397657
Method
We enrolled patients who had coronary heart disease or
a coronary heart disease risk equivalent, who were
receiving long-term statin therapy, and in whom an LDL
cholesterol level under 100 mg per deciliter (2.6 mmol
per liter) and an HDL cholesterol level under 50 mg per
deciliter for men or 55 mg per deciliter for women (1.3 or
1.4 mmol per liter, respectively) had been achieved. The
patients were randomly assigned to receive extendedrelease niacin (target dose, 2000 mg per day) or
ezetimibe (10 mg per day). The primary end point was
the between-group difference in the change from
baseline in the mean common carotid intima–media
thickness after 14 months. The trial was terminated early,
on the basis of efficacy, according to a prespecified
analysis conducted after 208 patients had completed the
trial.
Plus–minus values are means
±SD.
To convert values for waist
circumference to centimeters,
multiply by 2.54.
To convert values for cholesterol
to millimoles per liter, multiply by
0.02586.
To convert values for triglycerides
to millimoles per liter, multiply by
0.01129.
To convert values for glucose to
millimoles per liter, multiply by
0.05551.
CRP denotes C-reactive protein,
HDL high-density lipoprotein, and
LDL low-density lipoprotein.
† The body-mass index is the
weight in kilograms divided by the
square of the height in meters.
Figure 1. Mean
Percent Changes
in Cholesterol and
Triglyceride
Levels over the
14-Month Study
Period among the
208 Patients Who
Completed the
Study, According
to Treatment
Group.
P values are given
for the comparison
between the two
treatment groups at
14 months. The
vertical bars
indicate the
standard errors.
HDL denotes highdensity lipoprotein,
and LDL lowdensity lipoprotein.
Results
The mean HDL cholesterol level in the niacin group increased by
18.4% over the 14-month study period, to 50 mg per deciliter
(P<0.001), and the mean LDL cholesterol level in the ezetimibe
group decreased by 19.2%, to 66 mg per deciliter (1.7 mmol per
liter) (P<0.001). Niacin therapy significantly reduced LDL
cholesterol and triglyceride levels; ezetimibe reduced the HDL
cholesterol and triglyceride levels. As compared with ezetimibe,
niacin had greater efficacy regarding the change in mean carotid
intima–media thickness over 14 months (P = 0.003), leading to
significant reduction of both mean (P = 0.001) and maximal carotid
intima–media thickness (P≤0.001 for all comparisons).
Paradoxically, greater reductions in the LDL cholesterol level in
association with ezetimibe were significantly associated with an
increase in the carotid intima–media thickness (R = –0.31, P<0.001).
The incidence of major cardiovascular events was lower in the
niacin group than in the ezetimibe group (1% vs. 5%, P = 0.04 by
the chi-square test).
Conclusion
This comparative-effectiveness trial shows
that the use of extended-release niacin
causes a significant regression of carotid
intima–media thickness when combined
with a statin and that niacin is superior to
ezetimibe.
Message
スタチンで既にLDL-コレステロールが100mg/dl未満に
管理された場合にはEzetimibeでLDL-コレステロール
を低下させる意義は疑問？！
スタチンへの併用効果がある薬物は？
ニコチン酸製剤（ペリシット錠やコレキサミン錠）
はよい可能性がある。