Abstract
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 at-risk 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 [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 low-risk 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.
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 apnoea10 or improved lung function in asthma.11 Also, modest intentional weight loss seems to reduce mortality.12,13
Impact of weight loss on blood pressure
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=595) or usual care (n=596).15 Weight change from baseline in the lifestyle intervention group at 6, 18, and 36 months was −4.4, −2.0, and −0.2 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 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 diabetes prevention
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% (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
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 non-significant 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 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=0.001) decrease in risk of mortality.
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 low-energy 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 questionnaire-based 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=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=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=288) or a routine care group (n=135) for 6 years.34 At the end of 6 years, the intervention group showed a change in body weight of −2.3% to −3.7% 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 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=204) or diet B(n=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.
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.
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)
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)
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)
Figure 4 Effect of moderate (5%) weight loss on triglyceride and LDL- and HDL- cholesterol levels in men. (Adapted from Wood et al.22)
References
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.
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.
Van Gaal LF, Wauters MA, De Leeuw IH. The beneficial effects of modest weight loss on cardiovascular risk factors.
Wilson PW, Kannel WB, Silbershatz H et al. Clustering of metabolic factors and coronary heart disease.
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.
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.
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.
Kolotkin RL, Crosby RD, Williams GR et al. The relationship between health-related quality of life and weight loss.
Felson DT, Zhang Y, Anthony JM et al. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The Framingham Study.
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.
Largerstrand L, Rossner S. Effects of weight loss on pulmonary function in obese men with obstructive sleep apnoea syndrome.
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.
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.
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.
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.
Avenell A, Broom J, Brown TJ et al. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.
Mertens IL, Van Gaal LF. Overweight, obesity, and blood pressure: the effects of modest weight reduction.
Wing RR, Venditti E, Jakicic JM et al. Lifestyle intervention in overweight individuals with a family history of diabetes.
Wing RR, Koeske R, Epstein LH et al. Long-term effects of modest weight loss in Type II diabetic patients.
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.
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.
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.
Poobalan A, Aucott L, Smith WC et al. Effects of weight loss in overweight/obese individuals and long-term lipid outcomes—a systematic review.
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.
Mertens I, Van Gaal LF. Visceral fat as a determinant of fibrinolysis and hemostasis.
Kannel WB, Wolf PA, Castelli WP et al. Fibrinogen and risk of cardiovascular disease. The Framingham Study.
Meade TW, Mellows S, Brozovic M et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study.
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.
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.
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.
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.
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.
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.
Ornish D, Brown SE, Scherwitz LW et al. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial.
