close

Вход

Забыли?

вход по аккаунту

?

ep.12.s1.25

код для вставкиСкачать
ACE/AACE Diabetes Recommendations Implementation Conference
ACARBOSE FOR THE PREVENTION OF DIABETES,
HYPERTENSION, AND CARDIOVASCULAR DISEASE
IN SUBJECTS WITH IMPAIRED GLUCOSE TOLERANCE:
THE STUDY TO PREVENT NON-INSULIN-DEPENDENT
DIABETES MELLITUS (STOP-NIDDM) TRIAL
Jean-Louis Chiasson, MD
ABSTRACT
Objective: To evaluate, in subjects with impaired glucose tolerance (IGT), the effect of acarbose on the incidence of diabetes, hypertension, and cardiovascular disease.
Methods: The Study to Prevent Non-InsulinDependent Diabetes Mellitus (STOP-NIDDM) Trial was
an international, multicenter, double-blind, placebo-controlled, randomized investigation, undertaken in 9 participating countries from December 1995 through August
2001. Patients were randomly assigned to receive placebo
(N = 715) or acarbose, 100 mg three times a day (N =
714), and underwent follow-up for a mean of 3.3 years.
Sixty-one subjects (4%) were excluded from the study
because they did not have IGT or had no postrandomization data; thus, 1,368 subjects remained for intent-to-treat
analysis. The outcome measures were the development of
diabetes based on a single oral glucose tolerance test, the
development of hypertension (≥140/90 mm Hg), and the
development of major cardiovascular events, including
coronary heart disease, cardiovascular death, stroke, and
peripheral vascular disease.
Results: Two hundred eleven subjects in the acarbose-treated group and 130 in the placebo group discontinued treatment prematurely; however, they underwent
follow-up for assessment of end points. Acarbose treatment resulted in a 25% relative risk reduction in the development of type 2 diabetes (hazards ratio [HR], 0.75; 95%
confidence interval [CI], 0.63 to 0.90; P = 0.0015), in a
34% risk reduction in the development of new cases of
hypertension (HR, 0.66; 95% CI, 0.49 to 0.89; P =
0.0059), and in a 49% risk reduction in the development
of cardiovascular events (HR, 0.51; 95% CI, 0.28 to 0.95;
P = 0.03). A post hoc cost-effectiveness analysis done
from the Swedish perspective showed that acarbose treatFrom the Department of Medicine, Université de Montréal and Research
Center, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec,
Canada.
Presented at the American College of Endocrinology and the American
Association of Clinical Endocrinologists Diabetes Recommendations
Implementation Conference, Washington, DC, January 31 and February 1,
2005.
© 2006 AACE.
ment was likely to be cost-effective in the management of
subjects with IGT.
Conclusion: The STOP-NIDDM Trial demonstrated
that, in subjects with IGT, acarbose treatment was effective in reducing the risk of type 2 diabetes. It also suggested that it was associated with a reduction in hypertension and cardiovascular disease. (Endocr Pract.
2006;12[Suppl 1]:25-30)
Abbreviations:
CI = confidence interval; CV = cardiovascular; HR =
hazards ratio; IGT = impaired glucose tolerance;
OGTT = oral glucose tolerance test; STOP-NIDDM =
Study to Prevent Non-Insulin-Dependent Diabetes
Mellitus
INTRODUCTION
The prevalence of type 2 diabetes mellitus is increasing worldwide at an epidemic rate (1). Furthermore, it is
associated with high morbidity and excess mortality, particularly from cardiovascular (CV) disease, and as such is
exerting tremendous pressure on health-care costs (2,3).
For all these reasons, type 2 diabetes is now recognized as
one of the major challenges of the 21st century (4). With
a better understanding of the pathophysiology of type 2
diabetes and its CV complications, the concept of prevention was tested.
It is generally accepted that insulin resistance and a
decreased capacity for insulin secretion are major factors
involved in the development of type 2 diabetes (5).
Whether insulin resistance or decreased insulin secretion
is the first defect to appear in time is still under debate.
Clearly, however, as long as the beta cells can compensate
for the insulin resistance, glucose tolerance will remain
normal. Only when the beta cells fail to compensate fully
for the insulin resistance or the insulin action will
impaired glucose tolerance (IGT) appear (6). All subjects
in whom diabetes develops are thought to go through a
phase of IGT characterized by postprandial hyperglycemia. Even this moderate postprandial hyperglycemia
is sufficient to induce glucose toxicity and contribute to
ENDOCRINE PRACTICE Vol 12 (Suppl 1) January/February 2006 25
26 ACE/AACE Diabetes Conference (Chiasson), Endocr Pract. 2006;12(Suppl 1)
further impairment of insulin secretion and action and,
thus, to accelerate the progression to diabetes (7,8).
Several studies have shown that the higher the 2-hour plasma glucose level after a 75-g glucose challenge within the
IGT range, the higher the incidence of diabetes (9-11).
More than 60% of patients with type 2 diabetes die of
CV disease (12,13). Although diabetes is associated with
a clustering of CV risk factors such as obesity, high blood
pressure, and dyslipidemia, it is now recognized that
hyperglycemia per se is a risk factor for CV disease (1417). Accumulating evidence indicates that postprandial
hyperglycemia is a stronger risk factor than fasting plasma
glucose (18-22) (Fig. 1). In fact, epidemiologic prospective studies have shown that CV diseases manifest years
before the development of diabetes (23). Subjects with
IGT have a twofold increase in the relative risk of coronary heart disease-related mortality (24).
On the basis of those observations, it was postulated
that decreasing postprandial hyperglycemia by administration of acarbose in subjects with IGT would prevent or
delay the progression to diabetes. Similarly, in this highrisk population for CV disease, it was hypothesized that
blunting the postprandial increase in plasma glucose levels would also decrease the risk of CV complications.
These hypotheses were tested in the Study to Prevent NonInsulin-Dependent Diabetes Mellitus (STOP-NIDDM)
Trial.
ACARBOSE FOR PREVENTION OF TYPE 2
DIABETES
The STOP-NIDDM Trial was an international, double-blind, placebo-controlled, randomized investigation
conducted in a population with IGT, undertaken in
Canada, Germany, Austria, Norway, Denmark, Sweden,
Finland, Spain, and Israel from December 1995 through
August 2001 (25,26). The primary objective was to evaluate the effect of acarbose, through its novel mechanism of
action in reducing postprandial hyperglycemia, on the rate
of progression of IGT to type 2 diabetes. Overall, 1,429
subjects with IGT were randomly assigned to receive
placebo (N = 715) or acarbose, 100 mg three times a day
(N = 714). Sixty-one subjects (4%) were excluded from
the study because they did not have IGT (N = 17) or had
no postrandomization data (N = 44); thus, 682 subjects
remained in the acarbose group and 686 in the placebo
group for intent-to-treat analysis. The mean duration of
follow-up was 3.3 years. Two hundred eleven subjects
(31%) in the acarbose group and 130 (19%) in the placebo
group discontinued treatment prematurely; however, follow-up of them was continued for assessment of end
points. All study subjects had a yearly oral glucose tolerance test (OGTT). On the basis of a single OGTT, diabetes
developed in 506 subjects—221 (32%) in the acarbose
group and 285 (42%) in the placebo group.
On Cox proportional hazards analysis, the hazards
ratio (HR) was 0.75 (95% confidence interval [CI], 0.63 to
0.90; P = 0.0015). This 25% relative risk reduction was
independent of age, body mass index, and sex. Furthermore, if two OGTTs are used to confirm the diagnosis of
diabetes, as is now recommended, the number of subjects
with IGT converting to diabetes decreased to 105 (15%) in
the acarbose group versus 165 (24%) in the placebo group.
With use of the same analysis, the HR was 0.64 (95% CI,
0.49 to 0.85), for an absolute reduction of 8.7% and a relative risk reduction of 36% (Fig. 2). Acarbose treatment
was also associated with an increase in the reversion of
IGT to normal glucose tolerance (P<0.0001).
Relative risk
< 7.8
7.8-11
> 11
2.5
2
1
7.0-7.7
> 7.7
Fasting plasma glucose (mmol/L)
pl
6.1-6.9
h
< 6.1
2-
0
a
(m sma
m g
ol lu
/L co
)
s
> 11
7.8-11
< 7.8
0.5
e
1.5
Fig. 1. Risk of cardiovascular mortality according to fasting plasma glucose and 2-hour
plasma glucose levels in the DECODE Study. Adapted from Diabetes Epidemiology:
Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) Study Group and the
European Diabetes Epidemiology Group (22).
Cumulative incidence
of diabetes
ACE/AACE Diabetes Conference (Chiasson), Endocr Pract. 2006;12(Suppl 1) 27
n = 165
200
160
n = 105
120
80
Acarbose
Placebo
Hazard ratio = 0.64 (CI 95%
95% 0.49 - 0.85); p = 0.0018
Relative risk = 36%
Absolute risk = 8.7%
Fig. 2. Effect of acarbose on the cumulative incidence of diabetes in subjects with impaired glucose
tolerance, based on two oral glucose tolerance tests to confirm the diagnosis. CI = confidence interval.
Adapted from Rabasa-Lhoret R, Chiasson JL. In: DeFronzo RA, Ferrannini E, Kee H, Zimmet P, eds.
International Textbook of Diabetes Mellitus. Vol 1. 3rd ed. West Sussex, England: John Wiley & Sons
Ltd., 2004: 901-914.
Therefore, it was concluded that decreasing postprandial hyperglycemia with acarbose was effective in delaying the development of type 2 diabetes in subjects with
IGT.
ACARBOSE FOR PREVENTION OF
HYPERTENSION AND CV DISEASE
Another important objective of the STOP-NIDDM
Trial was to test whether decreasing postprandial hyperglycemia in subjects with IGT would also decrease the risk
of hypertension and CV complications (27). The main outcome measure was the number of subjects in whom hypertension or major CV events developed.
Hypertension was considered present if a blood pressure ≥140/90 mm Hg was reported on 2 separate occasions
or if the treating physician prescribed an antihypertensive
medication. During the study, hypertension developed in
193 subjects—78 in the acarbose group in comparison
with 115 in the placebo group (HR, 0.66; 95% CI, 0.49 to
0.89; P = 0.0059) (Fig. 3).
The CV events included coronary heart disease (acute
myocardial infarction, new angina, revascularization procedures), CV death, stroke, and peripheral vascular disease. All these events were ascertained by an independent
“Cardiovascular Event Adjudicating Committee” composed of 3 independent cardiologists, who were blinded to
treatment. Furthermore, all subjects had an electrocardiogram before randomization and at the end of the study;
these were reviewed and interpreted by 2 independent cardiologists, also blinded to treatment. Overall, 47 subjects
had at least 1 cardiovascular event—32 in the placebo
group compared with 15 in the acarbose group (Fig. 4).
Therefore, decreasing postprandial hyperglycemia was
associated with a 49% relative risk reduction in the incidence of CV events (HR, 0.51; 95% CI, 0.28 to 0.95; P =
0.03). Among the CV events, the major reduction was in
the risk of acute myocardial infarction—12 cases in the
placebo group compared with 1 in the acarbose group
(HR, 0.09; 95% CI, 0.01 to 0.72; P = 0.02). In addition, the
electrocardiograms confirmed 8 silent myocardial infarctions that were not diagnosed clinically; 1 was in the acarbose group and 7 in the placebo group. Thus, a total of 2
myocardial infarctions occurred in the acarbose group versus 19 in those taking placebo (P<0.001 by the Fisher
exact test). These data suggest that acarbose could
decrease the risk of CV disease in subjects with IGT.
The STOP-NIDDM Trial is the first prospective intervention study to show that acarbose treatment was associated with a reduction in the incidence of new cases of
hypertension and CV disease in subjects with IGT. These
observations are compatible with the hypothesis that postprandial hyperglycemia is a risk factor for CV disease.
COST-EFFECTIVENESS OF ACARBOSE IN
MANAGEMENT OF SUBJECTS WITH IGT
Using the STOP-NIDDM Trial population, the costeffectiveness of the use of acarbose in the treatment of
subjects with IGT was assessed in Sweden, one of the
countries that participated in this study (unpublished data).
The cost-effectiveness was based on the effect of acarbose
in reducing the risk of the development of diabetes (25%),
of hypertension (34%), and of CV disease (49%). The cost
28 ACE/AACE Diabetes Conference (Chiasson), Endocr Pract. 2006;12(Suppl 1)
n = 115
No. of subjects
120
110
100
90
n = 78
80
Acarbose
Placebo
Hazard ratio = 0.66 (CI 95%
95% 0.49 - 0.89); p = 0.0059
Fig. 3. Effect of acarbose on the cumulative incidence of hypertension in subjects with impaired
glucose tolerance. CI = confidence interval. From Chiasson et al (27). Reprinted with permission.
was calculated on the basis of Swedish costs for baseline
laboratory tests, for physician visits every 6 months, and
for treatment and follow-up for type 2 diabetes without
complications, hypertension, and CV events (during a 40month period) irrespective of who pays or benefits. When
all the intent-to-treat population was included, the cost for
the 40-month period was similar for both groups, slightly
in favor of placebo (4.310 euro compared with 4.528 euro
for the acarbose group). This analysis does not take into
account the long-term follow-up with the delay in the
appearance of complications, which very likely would
favor acarbose treatment. Furthermore, when subgroups
with a high risk for diabetes or a high risk for CV events
(or both) based on the formula of Stern et al (28) and the
formula of Anderson et al (29), respectively, were analyzed, acarbose treatment was cost saving; the cost of
acarbose was more than fully offset by savings attributable
to reduced probability of clinical events. Although this
study was conducted from a Swedish perspective, because
of the relative homogeneity in terms of clinical practice
and economic development in the 9 countries participating
in the STOP-NIDDM Trial, we predict that the cost-effectiveness results for Sweden are likely to be applicable to
the other participating countries as well.
with IGT was also associated with reduction in the risk of
developing hypertension. Third, the study also suggested
that decreasing postprandial hyperglycemia in subjects
with IGT could also reduce the risk of CV disease. This
result, however, needs to be confirmed in a well-designed
prospective intervention study statistically powered to
yield a definitive answer to this important question.
Finally, it can be predicted that acarbose is likely to be
cost-effective in the management of subjects with IGT.
On the basis of the STOP-NIDDM Trial observations,
as well as those of other trials on the prevention of type 2
diabetes, it can be recommended that intervention should
probably predate the actual diagnosis of diabetes. All these
intervention studies have shown that, in a high-risk population with IGT, diabetes could be prevented or at least
delayed. Consequently, the diabetes-specific complications should be delayed by appropriate management, and
such intervention should theoretically be cost-effective
over time. Of foremost importance, if the risk of CV complications can be decreased in this high-risk population, as
suggested in the STOP-NIDDM Trial, that outcome would
definitely justify early intervention before the development of diabetes.
CONCLUSION
ACKNOWLEDGMENT
On the basis of the STOP-NIDDM Trial experience,
several conclusions can be drawn. First, the study demonstrated that reducing postprandial hyperglycemia with
acarbose in subjects with IGT was associated with a significant reduction in the risk of developing diabetes.
Second, acarbose treatment in this high-risk population
We acknowledge the contribution of the coordinating
nurses and dietitians in all medical centers that participated in this study. We are grateful to Susanne Bordeleau for
preparation of the manuscript and illustrations. The STOPNIDDM Trial was funded by an unrestricted research
grant from Bayer AG.
ACE/AACE Diabetes Conference (Chiasson), Endocr Pract. 2006;12(Suppl 1) 29
n = 32
No. of subjects
n = 47
35
30
25
20
n = 15
15
Acarbose
Placebo
Fig. 4. Effect of acarbose on the number of cardiovascular events in subjects with impaired glucose
tolerance. Adapted from Chiasson et al (27).
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Wild S, Roglic G, Green A, Sicree R, King H. Global
prevalence of diabetes: estimates for the year 2000 and
projections for 2030. Diabetes Care. 2004;27:1047-1053.
Jonsson B. The economic impact of diabetes. Diabetes
Care. 1998;21(Suppl 3):C7-C10.
Skyler JS, Oddo C. Diabetes trends in the USA. Diabetes
Metab Res Rev. 2002;18(Suppl 3):S21-S26.
Zimmet P, Alberti KG, Shaw J. Global and societal
implications of the diabetes epidemic. Nature. 2001;414:
782-787.
Kahn SE. The relative contributions of insulin resistance
and beta-cell dysfunction to the pathophysiology of type 2
diabetes. Diabetologia. 2003;46:3-19.
Ferrannini E, Gastaldelli A, Miyazaki Y, et al.
Predominant role of reduced beta-cell sensitivity to glucose
over insulin resistance in impaired glucose tolerance.
Diabetologia. 2003;46:1211-1219.
Leahy JL, Bonner-Weir S, Weir GC. Beta-cell dysfunction induced by chronic hyperglycemia: current ideas on
mechanism of impaired glucose-induced insulin secretion
3. Diabetes Care. 1992;15:442-455.
Rossetti L. Glucose toxicity: the implications of hyperglycemia in the pathophysiology of diabetes mellitus. Clin
Invest Med. 1995;18:255-260.
Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott
DM, Bennett PH. The natural history of impaired glucose
tolerance in the Pima Indians. N Engl J Med. 1988;319:
1500-1506.
Harris MI. Impaired glucose tolerance—prevalence and
conversion to NIDDM. Diabet Med. 1996;13(3 Suppl 2):
S9-S11.
Heine RJ, Nijpels G, Mooy JM. New data on the rate of
progression of impaired glucose tolerance to NIDDM and
predicting factors. Diabet Med. 1996;13(3 Suppl 2):S12S14.
Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso
M. Mortality from coronary heart disease in subjects with
type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:
229-234.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of maturity-onset diabetes mellitus and risk of
coronary heart disease and stroke in women. Arch Intern
Med. 1991;151:1141-1147.
Haffner S, Cassells HB. Metabolic syndrome—a new risk
factor of coronary heart disease? Diabetes Obes Metab.
2003;5:359-370.
Wei M, Gaskill SP, Haffner SM, Stern MP. Effects of
diabetes and level of glycemia on all-cause and cardiovascular mortality: the San Antonio Heart Study. Diabetes
Care. 1998;21:1167-1172.
Haffner SM, Cassells H. Hyperglycemia as a cardiovascular risk factor. Am J Med. 2003;115(Suppl 8A):6S-11S.
Patane G, Piro S, Rabuazzo AM, Anello M, Vigneri R,
Purrello F. Metformin restores insulin secretion altered by
chronic exposure to free fatty acids or high glucose: a
direct metformin effect on pancreatic beta-cells. Diabetes.
2000;49:735-740.
Donahue RP, Abbott RD, Reed DM, Yano K. Postchallenge glucose concentration and coronary heart disease
in men of Japanese ancestry: Honolulu Heart Program.
Diabetes. 1987;36:689-692.
Fontbonne A, Eschwège E, Cambien F, et al. Hypertriglyceridaemia as a risk factor of coronary heart disease
mortality in subjects with impaired glucose tolerance or
diabetes: results from the 11-year follow-up of the Paris
Prospective Study. Diabetologia. 1989;32:300-304.
Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato
T, Sekikawa A. Impaired glucose tolerance is a risk factor
for cardiovascular disease, but not impaired fasting glucose: the Funagata Diabetes Study. Diabetes Care. 1999;
22:920-924.
Barzilay JI, Spiekerman CF, Wahl PW, et al. Cardiovascular disease in older adults with glucose disorders:
comparison of American Diabetes Association criteria for
diabetes mellitus with WHO criteria. Lancet. 1999;354:
622-625.
Diabetes Epidemiology: Collaborative Analysis of
Diagnostic Criteria in Europe (DECODE) Study Group
and the European Diabetes Epidemiology Group.
Glucose tolerance and mortality: comparison of WHO and
American Diabetes Association diagnostic criteria. Lancet.
1999;354:617-621.
30 ACE/AACE Diabetes Conference (Chiasson), Endocr Pract. 2006;12(Suppl 1)
23.
24.
25.
Hu FB, Stampfer MJ, Haffner SM, Solomon CG,
Willett WC, Manson JE. Elevated risk of cardiovascular
disease prior to clinical diagnosis of type 2 diabetes.
Diabetes Care. 2002;25:1129-1134.
Eschwege E, Richard JL, Thibult N, et al. Coronary
heart disease mortality in relation with diabetes, blood glucose and plasma insulin levels: the Paris Prospective Study,
ten years later. Horm Metab Res Suppl. 1985;15:41-46.
Chiasson JL, Gomis R, Hanefeld M, Josse RG, Karasik
A, Laakso M. The STOP-NIDDM Trial: an international
study on the efficacy of an alpha-glucosidase inhibitor to
prevent type 2 diabetes in a population with impaired glucose tolerance; rationale, design, and preliminary screening
data; Study to Prevent Non-Insulin-Dependent Diabetes
Mellitus. Diabetes Care. 1998;21:1720-1725.
26.
27.
28.
29.
Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik
A, Laakso M (STOP-NIDDM Trial Research Group).
Acarbose for prevention of type 2 diabetes mellitus: the
STOP-NIDDM randomised trial. Lancet. 2002;359:20722077.
Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik
A, Laakso M (STOP-NIDDM Trial Research Group).
Acarbose treatment and the risk of cardiovascular disease
and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM Trial. JAMA. 2003;290:486-494.
Stern MP, Williams K, Haffner SM. Identification of
persons at high risk for type 2 diabetes mellitus: do we
need the oral glucose tolerance test? Ann Intern Med. 2002;
136:575-581.
Anderson KM, Odell PM, Wilson PW, Kannel WB.
Cardiovascular disease risk profiles. Am Heart J. 1991;
121(1 Pt 2):293-298.
Документ
Категория
Без категории
Просмотров
0
Размер файла
119 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа