What is the relationship between risk factor * Luc F. Van Gaal

European Heart Journal Supplements (2005) 7 (Supplement L), L21–L26
doi:10.1093/eurheartj/sui082
What is the relationship between risk factor
reduction and degree of weight loss?
Luc F. Van Gaal*, Ilse L. Mertens, and Dominique Ballaux
KEYWORDS
Cardiovascular disease;
Cholesterol;
Diabetes prevention;
Lifestyle intervention;
Obesity;
Weight loss
Moderate weight loss achieved through lifestyle interventions positively impacts on a
number of metabolic and cardiovascular risk factors. Clinical studies have shown that
sustained moderate weight loss lowers blood pressure, improves glucose control, and
improves dyslipidaemia as well as inflammatory, haemostatic, and fibrinolytic factors.
In addition, it is associated with the prevention of progression to Type 2 diabetes in atrisk subjects. Furthermore, increasing physical fitness is associated with increases in
HDL cholesterol and reductions in all-cause mortality. However, there is, as yet,
only indirect evidence that modification of risk factors through weight loss will
reduce mortality.
The INTERHEART study has shown that abnormal lipids,
smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, consumption of fruit, vegetables, and
alcohol, and regular physical activity account for most
of the risk for first myocardial infarction in both sexes
and at all ages in all regions worldwide. Seven of these
nine risk factors are closely linked to overweight and
obesity and may be positively influenced by weight management.1 As an epidemiological study, INTERHEART provides little evidence on the effect of modifying these risk
factors. Nevertheless, there is a considerable body of evidence to suggest that lifestyle modification can have an
important impact on risk factor reduction and perhaps
even on mortality.
Many previous studies have shown that dietary patterns
and lifestyle factors are associated with mortality from
all causes, coronary heart disease, cardiovascular diseases, and cancer. The Healthy Ageing: A Longitudinal
Study in Europe (HALE) is one of the few studies that
has investigated the effects on mortality from all
causes, coronary heart disease, cardiovascular diseases,
and cancer from modifying these factors both singly
and in combination.2 It included 1507 apparently
healthy men and 832 women, aged 70–90, in 11
European countries and showed that over a period of
10 years, there was a lower risk of all-cause mortality
* Corresponding author.
E-mail address: [email protected]
[hazard ratios (HRs) controlled for age, sex, years of education, body mass index, study, and other factors] by:
.
.
.
.
adherence to a Mediterranean diet (HR 0.77; 95% confidence interval [CI], 0.68–0.88)
moderate alcohol use (HR 0.78; 95%CI, 0.67–0.91)
being physically active (HR 0.63; 95%CI, 0.55–0.72)
not smoking (HR 0.65; 95%CI, 0.57–0.75).
Similar results were observed for mortality from coronary heart disease, cardiovascular diseases, and cancer
(Figure 1). The combination of all four low-risk factors
lowered the all-cause mortality rate to 0.35 (95%CI
0.28–0.44). In contrast, lack of adherence to this lowrisk pattern was associated with a population attributable risk of 60% of all deaths, 64% of deaths from
coronary heart disease, 61% from cardiovascular diseases,
and 60% from cancer.
Although the study did not look at weight loss, per se,
it does confirm that lifestyle intervention is an important
aspect of approaches directed at the prevention of cardiovascular disease.
Clinical studies have shown that sustained moderate
weight loss achieved through lifestyle intervention lowers
blood pressure, improves glucose control, prevents diabetes, and improves dyslipidaemia, as well as haemostatic and fibrinolytic factors.3
However, much depends on the individual physician’s
target for intervention in any given obese patient and
what can be negotiated with that patient.
& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: [email protected]
Downloaded from http://eurheartjsupp.oxfordjournals.org/ by guest on September 30, 2014
Department of Diabetology, Metabolism and Nutrition, Antwerp University Hospital, Faculty of Medicine (UA), Belgium
L22
Figure 2 Mean change in diastolic and systolic blood pressures according
to quintiles of weight change achieved in the Trials of Hypertension
Prevention. (Adapted from Stevens et al.15)
To improve a patient’s cardiovascular risk profile, a
maintained weight loss of up to 5% appears to show clinical benefit.4 A weight loss of 5–10% is required to prevent
diabetes5–7 and to improve quality of life8 and symptoms
such as shortness of breath, sweating, and osteoarthritic
abnormalities.9 However, it might be important to consider larger weight loss (.10%) in patients with more
serious complications associated with the obese state,
such as sleep apnoea<sup10 or improved lung function
in asthma.11 Also, modest intentional weight loss seems
to reduce mortality.12,13
6 months, 0.78 (95%CI 0.62–1.00) at 18 months, and
0.81 (95%CI 0.70–0.95) at 36 months.
Analysis of the data adjusted for age, ethnicity, and sex
according to quintiles of weight change at 36 months
(weight loss and usual care combined) shows that
patients who lost the most weight had the largest
reductions in blood pressure (Figure 2).
A recent systematic review found that weight loss of
10 kg was associated with a fall in diastolic blood
pressure of 3.6 mmHg. A weight loss of 10% was
associated with a fall in systolic blood pressure of
6.1 mmHg.16,17
Impact of weight loss on blood pressure
Impact of weight loss on diabetes
prevention
The effect of interventions to promote weight loss
together with dietary sodium restriction on both systolic
and diastolic blood pressures was tested in the Trials of
Hypertension Prevention.14,15 In Phase I of this study,
weight loss intervention included a 3-year programme
of group meetings and individual counselling focused on
dietary change, physical activity, and social support.
Mean weight reduction of 3.9 kg was achieved at 18
months in 564 overweight participants with high normal
blood pressure and resulted in significant decreases in
both systolic and diastolic blood pressures when compared with a usual care control group.14
In Phase II of the study, men and women aged 30–54
with untreated diastolic blood pressure of 83–89 mmHg
and systolic blood pressure of ,140 mmHg, who were
110–165% of their ideal body weight at baseline,
were assigned to weight loss (n ¼ 595) or usual care
(n ¼ 596).15 Weight change from baseline in the lifestyle
intervention group at 6, 18, and 36 months was 24.4,
22.0, and 20.2 kg, respectively, while in the control
group weight increased by 0.1, 0.7, and 1.8 kg.
However, despite this decline over time in the success
rate in terms of weight loss, only a moderate change in
weight at 36 months was associated with a beneficial
effect on blood pressure. The risk ratio for hypertension
in the intervention group was 0.58 (95%CI 0.36–0.94) at
The benefit of modest weight loss achieved by lifestyle
intervention over 2 years on diabetes prevention was
demonstrated in a study by Wing et al., which included
154 overweight individuals with a parental history of
diabetes.18 Irrespective of whether weight change was
achieved by diet (decreasing calories and fat intake), exercise (goal of 1500 kcal/week of moderate activity), or the
combination of diet and exercise, modest weight loss of
4.5 kg reduced the risk of Type 2 diabetes by 30% when
compared with the no-treatment control group.
Similarly, the Finnish Diabetes Prevention Study randomized 522 middle-aged, overweight subjects (172
men and 350 women; mean age, 55 years; mean BMI,
31 kg/m2 with impaired glucose tolerance) to either lifestyle intervention (which consisted of individualized
counselling aimed at reducing weight, total intake of
fat, and intake of saturated fat and increasing intake of
fibre and physical activity) or control.5 After a mean duration of follow-up of 3.2 years, lifestyle intervention
achieved a mean weight loss of 4.2 kg in the intervention
group and 0.8 kg in the control group. The cumulative
incidence of diabetes after 4 years was 11% (95%CI
6–15%) in the intervention group and 23% (95%CI
17–29%) in the control group. Therefore, during the
trial, the risk of diabetes was reduced by 58%
Downloaded from http://eurheartjsupp.oxfordjournals.org/ by guest on September 30, 2014
Figure 1 The impact of dietary pattern and three lifestyle factors for
10 year all-cause and cause-specific mortality in elderly Europeans.
(Adapted from Knoops et al. 2)
L.F. Van Gaal et al.
Relationship between risk factor reduction and degree of weight loss
L23
Figure 3 In the Finnish Diabetes Prevention Study, modest, sustained weight reduction reduced progression to diabetes by 58% in subjects with impaired
glucose tolerance. (Adapted from Tuomilehto et al.5)
Impact of weight loss on diabetes control
Weight treatment is fundamental to the management of
patients with Type 2 diabetes, but frequently presents a
major challenge. However, Wing et al. have shown that
achievement of modest weight loss of 10 kg in 1 year
through a behavioural weight loss programme is associated with reductions in HbA1c of 1.1%, fasting blood
glucose of 1.6 mmol/L, triglycerides of 0.5 mmol/L and
with an increase in HDL of 0.1 mmol/L.19 As has been
shown in the United Kingdom Prospective Diabetes
Study,20 a 1% reduction in HbA1c is associated with 21%
reduction in risk for all diabetes-related complications,
25% reduction in diabetes mortality, 17% reduction in
total mortality, 18% reduction in acute myocardial
infarction,
and
35%
reduction
in
risk
for
microangiopathy.
In addition, patients in this study benefited from a
reduction in triglycerides and a 10% improvement in
HDL cholesterol. In comparison, in the VA-HIT study, a
6% improvement in HDL cholesterol with a fibrate such
as gemfibrozil was associated with an important
reduction in cardiovascular outcome.21
Impact of weight loss on dyslipidaemia
Weight management can positively improve the lipid
profile of obese subjects. In general, a 5–10% weight
loss can produce a reduction in LDL cholesterol of 15%
and triglycerides of 20–30% with an increase in HDL
cholesterol of 8–10%.3
In a prospective study, Wood et al.22 investigated the
effects of weight loss on lipid levels in subjects treated
with a hypocaloric low-saturated fat and low-cholesterol
diet with and without increased physical activity. After
1 year, a 5% weight loss achieved by diet alone resulted
in modest effects on LDL cholesterol and important
effects on triglyceride levels, but only a small nonsignificant effect on HDL-cholesterol levels when compared with the control group. However, when combined
with exercise, there was a significant reduction in triglycerides and a significant increase in HDL cholesterol of
up to 15% (Figure 4). In addition, combination therapy
improved the apolipoprotein B/AI ratio, mainly in men.
A recent meta-analysis has shown that for every 10 kg
weight loss, a fall of 0.23 mmol/L in cholesterol may be
expected for a person suffering from obesity or gross
overweight.23
The value of physical fitness
Encouraging unfit patients to improve their fitness by
starting a physical activity programme can have an
important benefit. Indeed, increasing physical fitness is
an important element of cardiovascular risk reduction
and should be considered to be as important as weight
reduction per se.
In one recently published large prospective trial of
9777 patients, physical fitness was assessed by maximal
exercise tests and evaluation of health status in a group
of men on two occasions 5 years apart.24 The highest
age-adjusted all-cause death rate was observed in men
who were unfit at both examinations; the lowest death
rate was in men who were physically fit at both
Downloaded from http://eurheartjsupp.oxfordjournals.org/ by guest on September 30, 2014
(P , 0.001) in the intervention group (Figure 3). In
addition, weight loss was accompanied by an important
reduction in the waist circumference, reduction in
triglycerides, and an elevation in HDL-cholesterol concentration, all of which were statistically significant
provided the moderate weight loss was maintained.
These results were echoed by the US-based Diabetes
Prevention Program, in which subjects were randomized
to placebo, metformin (850 mg twice daily), or a lifestyle-modification programme with the goals of at
least an initial 7% weight loss and at least 150 min of
physical activity per week.6 Lifestyle intervention
reduced the incidence of diabetes by 58% (95%CI
48–66%) and metformin reduced the incidence by 31%
(95%CI 17–43%) when compared with placebo. A
similar finding was reported in the Chinese Da Qing
IGT and Diabetes Study.7
L24
Figure 4 Effect of moderate (5%) weight loss on triglyceride and
LDL- and HDL- cholesterol levels in men. (Adapted from Wood et al.22)
Other risk factors
Several haemostatic factors that are included within the
metabolic syndrome or associated with obesity are known
to have an important role in the development of cardiovascular disease.25,26 Prospective epidemiological data
have shown elevated fibrinogen levels to be associated
with cardiovascular disease.27 Factor VII and the von
Willebrand factor are also considered to be strong predictors of ischaemic heart disease.28 In addition, levels of
plasminogen activator inhibitor-1 (PAI-1), an inhibitor of
fibrinolysis, are elevated in obese subjects.29,30 PAI-1
has been considered to be an independent predictor
not only for cardiovascular disease but also for the
development of Type 2 diabetes.
Several of these haemostatic and fibrinolytic factors
have been shown to respond favourably to moderate
weight loss. In a randomized trial of weight loss in
moderately overweight men and women, elevated
levels of Factor VII and von Willebrand factor (which
are common in obesity and are a possible reflection of
endothelial dysfunction) were reduced by a 5–10%
weight loss.31 However, more substantial weight loss, as
observed with surgery, is required to achieve any significant change in fibrinogen levels; modest weight loss has
no net change on levels of fibrinogen.
In addition, a 10-week programme of moderate (20%)
energy restriction in non-obese middle-aged men that
resulted in 5–10% weight loss was found to be associated
with a significant decrease in PAI-1 activity, mainly in subjects with high baseline PAI-1 levels. There was also a concomitant increase in tissue-plasminogen activator (t-PA)
activity, suggesting an increase in fibrinolytic capacity.32
Improvement in each of these haemostatic variables
correlated with the amount of weight loss and the degree
to which plasma triglycerides declined. In addition,
changes in PAl-1 and t-PA were related, in a sex-specific
way, to changes in waist circumference, waist-to-hip
ratio, and systolic blood pressure. Overall, these findings
suggest that even moderate weight loss can improve
abnormalities in haemostatic and fibrinolytic factors.
Modest weight reduction achieved by means of a lowenergy Mediterranean style diet has been shown to
induce a reduction in markers of vascular inflammation,
such as C-reactive protein and interleukins 6, 7, and
18.33 Several pro-inflammatory molecules have been
associated with thrombotic cardiovascular events, and
substantial reduction of such markers may potentially
contribute to a decreased cardiovascular risk.
Effects of weight loss on mortality
The question of whether the observed reductions in risk
factors achieved with weight reduction, a healthy lifestyle, and physical fitness can be translated into clinical
outcome and mortality is contentious. At present, there
is only limited, indirect evidence in this respect, largely
from studies that were not specifically designed to
show this effect.
Analysis of prospective data from a questionnairebased study of 43 457 overweight, never-smoking US
white women aged 40–64 suggests that intentional
weight loss among women with obesity-related conditions is associated with decreased premature mortality.12 Among these women (n ¼ 15 069), intentional
weight loss of any amount was associated with a 20%
reduction in all-cause mortality, primarily due to a
40–50% reduction in mortality from obesity-related
cancers; diabetes-associated mortality was also reduced
by 30–40% in those who intentionally lost weight.
However, among women with no pre-existing illness
(n ¼ 28 388), the association was somewhat more
equivocal.
Randomized trial evidence is limited. However, in the
Malmo Preventive Trial, men with impaired glucose tolerance at 48 years of age were assigned to an intervention
group (n ¼ 288) or a routine care group (n ¼ 135) for
6 years.34 At the end of 6 years, the intervention group
showed a change in body weight of 22.3% to 23.7%
compared with increases of 0.5–1.7% in the control
group. At 12-year follow-up, mortality from all causes
was significantly reduced in the intervention group
when compared with the control group (P , 0.05).
Death due to cardiovascular diseases, which included
ischaemic heart disease, cerebrovascular disease, and
other heart diseases, was lower in the intervention
group but did not achieve statistical significance.34 The
study suggests that a long-term intervention programme
with an emphasis on lifestyle changes, including dietary
Downloaded from http://eurheartjsupp.oxfordjournals.org/ by guest on September 30, 2014
examinations. Men who improved from unfit to fit
between the first and subsequent examinations had an
age-adjusted death rate of 67.7/10 000 man-years. This
is a reduction in mortality risk of 44% (95%CI 25–59%)
relative to men who remained unfit at both examinations. Improvement in fitness was associated with
lower death rates after adjusting for age, health status,
and other risk factors of premature mortality. It was estimated that for each minute increase in maximal treadmill time between examinations, there was a
corresponding 7.9% (P ¼ 0.001) decrease in risk of
mortality.
L.F. Van Gaal et al.
Relationship between risk factor reduction and degree of weight loss
Conclusion
Moderate weight loss has a positive impact on a large
number of metabolic and cardiovascular risk factors. A
sustained moderate weight loss of 4 kg is associated
with prevention of the progression to Type 2 diabetes
for at-risk patients. Increasing physical fitness is associated with increases in HDL cholesterol and a reduction
in all-cause mortality. Comprehensive lifestyle modification appears to be able to bring about significant
regression of coronary atherosclerosis after only 1 year,
whereas weight loss appears to be associated with a
further improvement in cardiac endpoints and perhaps
mortality, although this needs to be confirmed in adequately powered studies.
There may be no universally accepted single approach
to achieving and maintaining weight reduction. However,
a successful weight management programme is likely to
include a focus on establishing a healthy diet and increasing physical activity, combined with behavioural support.
Such intervention provides a sound basis for tackling
seven of the known nine risk factors implicated in the
development of myocardial infarction.
Key points
.
.
.
Sustained moderate weight loss of 5–10% has a positive impact on a large number of metabolic and cardiovascular risk factors, particularly blood pressure,
glucose control, and dyslipidaemia, as well as haemostatic and fibrinolytic factors.
Sustained moderate weight loss of 4 kg is associated with a prevention of the progression to Type
2 diabetes in at-risk patients.
To date, there is no accepted direct evidence that
weight management per se is associated with a
reduction in hard clinical endpoints or mortality.
Conflict of interest: The author has consulted for Abbott and
sanofi-aventis, and lectured at sponsored symposia.
References
1. Yusuf S, Hawken S, Ounpuu S et al.; INTERHEART Study Investigators.
Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case–control
study. Lancet 2004;364:937–952.
2. Knoops KT, de Groot LC, Kromhout D et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and
women: the HALE project. JAMA 2004;292:1433–1439.
3. Van Gaal LF, Wauters MA, De Leeuw IH. The beneficial effects of
modest weight loss on cardiovascular risk factors. Int J Obes Relat
Metab Disord 1997;21(Suppl. 1):S5–S9.
4. Wilson PW, Kannel WB, Silbershatz H et al. Clustering of metabolic
factors and coronary heart disease. Arch Intern Med 1999;159:
1104–1109.
5. Tuomilehto J, Lindstrom J, Eriksson JG et al.; Finnish Diabetes
Prevention Study Group. Prevention of Type 2 diabetes mellitus by
changes in lifestyle among subjects with impaired glucose tolerance.
N Engl J Med 2001;344:1343–1350.
6. Knowler WC, Barrett-Connor E, Fowler SE et al.; Diabetes Prevention
Program Research Group. Reduction in the incidence of Type 2
diabetes with lifestyle intervention or metformin. N Engl J Med
2002;346:393–403.
7. Pan XR, Li GW, Hu YH et al. Effects of diet and exercise in preventing
NIDDM in people with impaired glucose tolerance. The Da Qing IGT
and Diabetes Study. Diabetes Care 1997;20:537–544.
8. Kolotkin RL, Crosby RD, Williams GR et al. The relationship between
health-related quality of life and weight loss. Obes Res 2001;9:
564–571.
9. Felson DT, Zhang Y, Anthony JM et al. Weight loss reduces the risk for
symptomatic knee osteoarthritis in women. The Framingham Study.
Ann Intern Med 1992;116:535–539.
Downloaded from http://eurheartjsupp.oxfordjournals.org/ by guest on September 30, 2014
counselling and physical exercise, will reduce mortality
in subjects with impaired glucose tolerance, who are at
an increased risk of developing Type 2 diabetes and of
premature death due to ischaemic heart disease and
other causes.
The Lifestyle Heart Trial suggested that comprehensive
lifestyle changes may be able to bring about regression of
even severe coronary atherosclerosis after only 1 year,
without the use of lipid-lowering drugs.35 In this prospective, randomized, controlled study, 20 patients were
assigned to a usual-care control group and 28 patients
were assigned to an experimental group and adopted a
10% fat wholefood diet, took regular aerobic exercise,
received stress-management training, stopped smoking,
and enrolled in a psychosocial support group. Coronary
angiography after 1 year revealed regression of stenosis
diameter in the experimental group, but progression in
the control group. The degree of stenosis regression
was greater among those patients with the greater
adherence to the lifestyle intervention. Five-year
follow-up of the patients in this study has demonstrated
continued regression of coronary atherosclerosis with
worsening disease progression in patients who made
only moderate lifestyle changes.36 Importantly, angina
frequency was reduced by 91% after 1 year and by 72%
after 5 years in patients who radically changed their lifestyle. In controls, angina frequency increased by 186% in
the first year of the trial, but had decreased by 36% after
5 years, mainly because three patients had coronary
angioplasty after the first year.
A further indication that weight loss together with a
healthy lifestyle may lead to some beneficial effects is
provided by a randomized, controlled trial conducted in
patients with suspected recent acute myocardial infarction. Patients were assigned to diet A(n ¼ 204) or diet
B(n ¼ 202) within 24–48 h of infarction; both groups
were advised to follow a fat-reduced diet, although
diet A also included more fruit, vegetables, nuts, and
grain products. Blood lipoprotein concentrations and
body weight fell significantly in patients following diet
A when compared with those following diet B, as did
the incidence of cardiac events at 1 year (P , 0.001)
and total mortality (P , 0.01).13 Patients assigned to
the cardioprotective diet, who achieved weight loss of
7 kg, had significantly reduced rates of cardiac events,
total cardiac mortality, and total mortality when compared with those patients who lost only 3 kg on the
same diet, indicating more benefit from additional
weight loss.
L25
L26
23. Poobalan A, Aucott L, Smith WC et al. Effects of weight loss in overweight/obese individuals and long-term lipid outcomes—a systematic
review. Obes Rev 2004;5:43–50.
24. Blair SN, Kohl HW III, Barlow CE et al. Changes in physical fitness and
all-cause mortality. A prospective study of healthy and unhealthy
men. JAMA 1995;273:1093–1098.
25. Mertens I, Van Gaal LF. Visceral fat as a determinant of fibrinolysis
and hemostasis. Semin Vasc Med 2005;5:48–55.
26. Mertens I, Van Gaal LF. Obesity, haemostasis and the fibrinolytic
system. Obes Rev 2002;3:85–101.
27. Kannel WB, Wolf PA, Castelli WP et al. Fibrinogen and risk of
cardiovascular disease. The Framingham Study. JAMA 1987;258:
1183–1186.
28. Meade TW, Mellows S, Brozovic M et al. Haemostatic function and
ischaemic heart disease: principal results of the Northwick Park
Heart Study. Lancet 1986;2:533–537.
29. Hamsten A, Wiman B, de Faire U et al. Increased plasma levels of a
rapid inhibitor of tissue plasminogen activator in young survivors of
myocardial infarction. N Engl J Med 1985;313:1557–1563.
30. Vague P, Juhan-Vague I, Aillaud MF et al. Correlation between blood
fibrinolytic activity, plasminogen activator inhibitor level, plasma
insulin level, and relative body weight in normal and obese subjects.
Metabolism 1986;35:250–253.
31. Folsom AR, Qamhieh HT, Wing RR et al. Impact of weight loss on
plasminogen activator inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately overweight adults. Arterioscler Thromb
1993;13:162–169.
32. Velthuis-te Wierik EJ, Westerterp KR, van den Berg H. Impact of a
moderately energy-restricted diet on energy metabolism and body
composition in non-obese men. Int J Obes Relat Metab Disord
1995;19:318–324.
33. Esposito K, Pontillo A, Di Palo C et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a
randomized trial. JAMA 2003;289:1799–1804.
34. Eriksson KF, Lindgarde F. No excess 12-year mortality in men with
impaired glucose tolerance who participated in the Malmo
Preventive Trial with diet and exercise. Diabetologia 1998;
41:1010–1016.
35. Ornish D, Brown SE, Scherwitz LW et al. Can lifestyle changes reverse
coronary heart disease? The Lifestyle Heart Trial. Lancet 1990;
336:129–133.
36. Ornish D, Scherwitz LW, Billings JH et al. Intensive lifestyle
changes for reversal of coronary heart disease. JAMA 1998;
280:2001–2007.
Downloaded from http://eurheartjsupp.oxfordjournals.org/ by guest on September 30, 2014
10. Stenius-Aarniala B, Poussa T, Kvarnstrom J et al. Immediate and long
term effects of weight reduction in obese people with asthma:
randomised controlled study. BMJ 2000;320:827–832.
11. Largerstrand L, Rossner S. Effects of weight loss on pulmonary function in obese men with obstructive sleep apnoea syndrome.
J Intern Med 1993;234:245–247.
12. Williamson DF, Pamuk E, Thun M et al. Prospective study of intentional
weight loss and mortality in never-smoking overweight US white
women aged 40–64 years. Am J Epidemiol 1995;141:1128–1141.
13. Singh RB, Rastogi SS, Verma R et al. Randomised controlled trial
of cardioprotective diet in patients with recent acute
myocardial infarction: results of one year follow up. BMJ 1992;304:
1015–1019.
14. Stevens VJ, Corrigan SA, Obarzanek E et al. Weight loss intervention
in phase 1 of the Trials of Hypertension Prevention. The TOHP
Collaborative Research Group. Arch Intern Med 1993;153:849–858.
15. Stevens VJ, Obarzanek E, Cook NR et al.; Trials for the Hypertension
Prevention Research Group. Long-term weight loss and changes in
blood pressure: results of the Trials of Hypertension Prevention,
Phase II. Ann Intern Med 2001;134:1–11.
16. Avenell A, Broom J, Brown TJ et al. Systematic review of the longterm effects and economic consequences of treatments for obesity
and implications for health improvement. Health Technol Assess
2004;8:iii–iv, 1–182.
17. Mertens IL, Van Gaal LF. Overweight, obesity, and blood pressure: the
effects of modest weight reduction. Obes Res 2000;8:270–278.
18. Wing RR, Venditti E, Jakicic JM et al. Lifestyle intervention in overweight individuals with a family history of diabetes. Diabetes Care
1998;21:350–359.
19. Wing RR, Koeske R, Epstein LH et al. Long-term effects of modest
weight loss in Type II diabetic patients. Arch Intern Med 1987;147:
1749–1753.
20. Turner R, Cull C, Holman R. United Kingdom Prospective Diabetes
Study 17: a 9-year update of a randomized, controlled trial on
the effect of improved metabolic control on complications in
non-insulin-dependent diabetes mellitus. Ann Intern Med 1996;124:
136–145.
21. Rubins HB, Robins SJ, Collins D et al. Gemfibrozil for the secondary
prevention of coronary heart disease in men with low levels of
high-density lipoprotein cholesterol. Veterans Affairs High-Density
Lipoprotein Cholesterol Intervention Trial Study Group. N Engl
J Med 1999;341:410–418.
22. Wood PD, Stefanick ML, Williams PT et al. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise,
in overweight men and women. N Engl J Med 1991;325:461–466.
L.F. Van Gaal et al.