Published by Oxford University Press on behalf of the International Epidemiological Association International Journal of Epidemiology 2006;35:3–9 Ó The Author 2006; all rights reserved. Advance Access publication 5 January 2006 Treatment and prevention of obesity—arethere critical periods for intervention? whether there is sufficient evidence relating critical/sensitiveperiods of development to the risk of later obesity and its Both professionals and the public view obesity, increasingly associated diseases to warrant trials in humans of such apparent in childhood, and already highly prevalent in adults in the Western world, as one of, if not, the most important publichealth problem of our times. The considerable effort expended onresearching risk factors for obesity (a Medline search for studies examining risk factors for obesity conducted at the time of Ideally, any treatment for obesity should assess long-term writing this editorial (November 2005) resulted in 264 326 hits) impacts on obesity associated cardiovascular risk factors, such as contrasts starkly with the simplicity of the key underlying hypertension, dyslipidaemia, and insulin resistance, as well as problem, that obesity is largely a consequence of over-nutrition disease outcomes such as cardiovascular disease, diabetes, and and under-activity. Despite the clarity of this message, there is osteoporosis. However, to date, few studies of any intervention little evidence-based guidance on successful, viable long-term have been sufficiently powered and sufficiently long-term to go strategies to prevent or treat obesity. We believe there is a need to beyond the assessment of weight loss itself.
develop findings from epidemiological research into coherentdecisions regarding prevention and treatment interventions andultimately appropriate polices for the improvement of public health. Our intention was that a themed issue on obesity in the Several systematic reviews and meta-analyses have examined International Journal of Epidemiology would contribute towards the effect of a variety of dietary interventions on weight reduction in adults with obesity. Very low energy density diets In the first half of this editorial we review the current evidence (,800 kcal/day) resulted in the greatest weight loss, ~15–25% of for the treatment of adult obesity and conclude that to date there initial weight, over a short period, in those who completed the is no strong evidence that such treatments have long-term programme.2,3 However, the authors noted that these pro- benefits in terms of health gain. Clearly, lack of evidence does not grammes were associated with high financial cost, high attrition equate to lack of effect and there is no doubt that most trials to rates and high odds of regaining 50% or more of the lost weight date have not been large enough or had sufficiently long-term over 12–24 months of follow-up. With the exception of weight- follow-up to answer these questions. On the other hand treating watchers (a weekly support group activity in the UK), for which established obesity in adulthood may be ‘shutting the gate after the three randomized controlled trials suggested moderate weight horse has bolted’. Further, epidemiology tells us that obesity is loss (up to 3% of original weight) over 2 years of follow-up, trials socially patterned, varies between countries, but in recent years of self-help programmes and programmes available over the has shown marked increases in all countries, and that what we internet do not suggest benefits in terms of weight loss or other eat and the exercise we take is largely determined by the food industry, transport policy, and the built environment (see for In the long-term only low fat diets have been found to be example the piece by Cummins and Macintyre in this issue1).
beneficial, with a pooled weight loss of À3.55kg (95% CI À4.54 Thus, a population approach to the primary prevention of obesity to À2.55kg) at 36 months compared with control groups.4 There and to the prevention of its associated diseases is more likely to be were also long-term beneficial effects on dyslipidaemia and blood beneficial than an individual or small group level approach such pressure for low fat diets in obese individuals. The long-term effects of other diets, including very low calorie diets were Animal studies suggest that brief interventions during critical unclear, and the authors concluded that large long-term or sensitive periods of development can have lasting effects in randomized trials of different dietary regimes with disease terms of disease prevention. This seems such an exciting prospect outcomes were required to determine the true health benefit of to us that we spend the second half of this editorial considering 1 Department of Social Medicine, University of Bristol, UK.
2 National Heart & Lung Institute, Imperial College at St Mary’s, London, UK.
* Corresponding author. Department of Social Medicine, University of Bristol As well as the numerous fad-diets that are available to the public Canynge Hall, Whiteladies Road, Bristol, BS8 2PR Bristol, UK. E-mail:[email protected] there is a burgeoning market in over-the-counter remedies that make extravagant claims about their weight loss potential. Max (n 5 1507) in humans of a selective cannabinoid-1 receptor Pittler and Edzard Ernst recently undertook a review in order to antagonist (rimonabant) was recently published.10 It found a ‘. . . assess the evidence from rigorous clinical trials, systematic reviews marked reduction in weight and waist circumference and and meta-analyses on the effectiveness of dietary supplements.’5 They improvements in high density lipoprotein cholesterol, triglyc- identified five systematic reviews/meta-analyses and an addi- erides, insulin resistance, and the prevalence of the metabolic tional 25 trials, which were not included in any previous review.
syndrome at 1 year of follow-up when rimonabant was given at a None of these studies provided convincing evidence to support dose of 20 mg per day, but much weaker effects on weight the use of supplements, with one exception. Ephedra sinica (also reduction of a 5 mg dose and no effects on metabolic syndrome known as ma-huang) was associated with modest short-term components at this lower dose.10 Despite the marked weight loss weight loss (in the order of 0.9 kg /month) when compared with with the higher dose there was no effect on blood pressure, total placebo. However, this is an ephedrine-containing supplement cholesterol, or low density lipoprotein cholesterol. Further, there and has been found to be associated with a 2-fold to 4-fold is evidence from animal studies that low dose cannabinoid increase in the odds of psychiatric, autonomic or gastrointestinal therapy reduces progression of atherosclerosis,11 and it has, symptoms, and heart palpitations.5 Unsurprisingly, Pittler and therefore, been suggested that blocking cannabinoid receptors Ernst concluded that none of the reviewed supplements could might actually increase the risk of atherosclerosis.12 There is be recommended for over-the-counter use.5 biological evidence that blocking cannabinoid receptors mightresult in demyelination and one participant treated withrimonabant in this trial developed multiple sclerosis.13 Thismay have been a chance occurrence, but there is clearly a need to aggressively investigate potential side-effects of all new drugs.
Over recent decades there has been increased interest in the useof drug treatment for obesity. Two anti-obesity drugs—orlistatand sibutramine—have been widely assessed in a number of Orlistat, a pancreatic lipase inhibitor that reduces the In most populations surgery is reserved for morbid obesity [Body absorption of dietary fat, is effective both in the short-term mass index (BMI) of 35 kg/m2 together with obesity related and long-term at reducing weight, particularly when combined morbidity or BMI of 40 kg/m2 in the absence of associated with dietary and exercise interventions.6,7 The combination of morbidity] and is considered when other non-surgical treatments orlistat and physical activity advice has been found to have long- have failed, though there is evidence of extensive use of surgery term (18–24 months) beneficial effects on dyslipidaemia and to reduce weight outside of these criteria in privately funded hypertension, though it is unclear whether this effect is primarily health care systems. A systematic review identified 26 studies, of due to the drug or the increase in physical activity.6,7 To date which just 5 (2 randomized controlled trials and 3 cohort studies) there are no results of the long-term effects of orlistat on disease compared surgery with non-surgical management, with the endpoints or disease and disability free survival.6,7 Orlistat is remaining 21 (all randomized controlled trials) comparing associated with a higher incidence of gastrointestinal adverse the effectiveness of different surgical procedures to each events, which have in some trials resulted in poor compliance.
other.14 The quality of the studies was noted to be generally Further, there is some evidence that the effect of orlistat, in terms poor, with just 3 of the 24 trials having adequate allocation of weight loss and improvements in cardiovascular disease risk concealment. The authors concluded that ‘the limited evidence factors, is weaker for obese individuals who are also diabetic than suggests that surgery is more effective than conventional management for weight loss in morbid obesity. The comparative safety and effectiveness of Sibutramine is a centrally acting serotonin–norepinephrine different surgical procedures is unclear.’14 reuptake inhibitor that enhances satiety and promotes energyexpenditure. Short-term trials, and one trial over 2 years offollow-up, demonstrate sustained effects on weight loss.8 Beneficial effects of sibutramine on triglyceride, high-density lipoprotein cholesterol, and glycaemic control have also been reported, but there is no direct evidence that sibutramine reducesobesity-associated morbidity and mortality. Because of its Obesity is no longer a health problem confined to adults. The norepinephrine effect it has been anticipated that sibutramine prevalence of childhood obesity has increased ~3-fold in most could increase blood pressure. This hypothesis is supported by industrialized countries over the last 20 years.15 In the US, often some, though not all trials.8,9 Nevertheless, it is not recom- perceived as an extreme example, around a quarter of all children mended for use in obese individuals with hypertension, which, are overweight or at risk of being overweight.16 The rest of the given the concordance between obesity and hypertension, developed world is, however, not far behind.17 Obese children often become obese adults. Childhood obesity increased the risk Many new pharmacological approaches are under investiga- of adult obesity 4-fold in men and 3.2-fold in women in the tion. These include gut hormones, such as cholecystokinin that British 1958 birth cohort, although child to adult BMI normally signal satiety, other centrally acting serotonin agents, correlations across the range were modest.18 Among contem- the anticonvulsant medications topiramate and zonisamide, porary children and adolescents obesity is associated with cannabinoid receptor antagonists, and drugs that act on other elevated blood pressure, dyslipidaemia, glucose intolerance, peptide neurotransmitters. The first randomized controlled trial hyperinsulinaemia, and greater left ventricular mass,19–23 though the evidence linking childhood overweight/obesity with mortality: the perinatal period; the period of adiposity rebound; adult cardiovascular disease events is weak, perhaps in part because these studies are based on individuals who were bornseveral decades ago at times when childhood obesity was lesscommon.24,25 Increasingly, frank type 2 diabetes is being diagnosed in obese adolescents.26,27 Further, obesity and itsassociated cardiovascular disease risk factors are associated with There is increasing evidence that intrauterine over-nutrition atheroscelorosis in autopsy studies of adolescents and young predicts life long obesity.32,33 According to this hypothesis high adults.28 Thus, there is evidence that obesity in contemporary maternal glucose, free fatty acid, and amino acid plasma children and adolescents has already resulted in metabolic and concentrations result in over-nutrition of the fetus which, vascular abnormalities that may be long-lasting. As a conse- through permanent changes in appetite control, neuroendocrine quence attempts to treat established obesity in adulthood may be functioning, or energy metabolism in the developing fetus, leads too late to have important impacts on disease prevention or to obesity in later life.32,33 Since maternal obesity itself is associated with insulin resistance and glucose intolerance, and,therefore, higher plasma concentrations of glucose and free fattyacids, maternal obesity is seen as the prime factor in fetal over- nutrition. Recent evidence supports this hypothesis, with twostudies demonstrating a relationship between greater weight gain during pregnancy and obesity in the offspring at 2–4 years.34,35 The consequences of these finding are potentially One review of interventions to treat or prevent obesity in formidable: ‘the obesity epidemic could accelerate through successive children found that, as with adult obesity, there was no strong generations independent of further genetic or environmental factors’.36 evidence that interventions to treat obesity in children had long- The mechanisms of such an association between maternal weight term benefits in terms of weight loss or associated morbidity.15 and weight gain during pregnancy and obesity in her offspring The authors asked ‘Why is substantial long-term weight loss so difficult are becoming clearer. Offspring of female rats with diet-induced to obtain?’ 15 They concluded that increasing funds were required obesity have been found to be heavier than the offspring of rats for research into new behavioural, environmental, and phar- with the same genotype, but without the diet-induced maternal macological approaches for the prevention and treatment of obesity.37 In vitro, animal and human studies have demonstrated obesity in children, but emphasized that the epidemic of that fetal pancreatic development and fat stores are influenced by childhood obesity was unlikely to be resolved without concerted the availability of fetal fuels—in particular glucose, lipids, and political action to detoxify the obesogenic environment in which amino-acids—which are in turn determined by maternal insulin secretion and responsiveness, and maternal plasma A recent Cochrane systematic review identified just 22 levels of glucose and free fatty acids.33 These in vitro findings controlled (with or without randomization) trials of interven- are confirmed by studies of women with gestational diabetes tions in childhood and adolescence to prevent obesity.29 Most whose offspring have considerably greater birth weights and were school based and most assessed outcomes over a short time a greater risk of obesity and diabetes in later life.33,38 There period only. Important methodological weaknesses were noted is also evidence that these adverse sequelae are not confined in many studies, and in particular the authors noted that ‘. . .many to maternal diabetes; rather there is a linear trend of of the studies included in this review have unit of allocation errors, since increasing offspring birth weight with increasing maternal allocation was often by institution (e.g. school) but assessment was by individual child. The results of these studies . . .are likely to be misleadingly optimistic.’29 Even with this caveat regarding their The long-term follow-up of the offspring of mothers who have possible exaggeration of true effects, most studies found that been involved in randomized trials of the effectiveness of strict combined promotion of healthy eating and physical activity were glycaemic control during pregnancy will provide particularly not effective at preventing childhood obesity. The impact of these valuable insights into the potential of intervening during this interventions on the adverse sequelae of obesity, such as glucose period to improve outcomes in the offspring. In the short term, intolerance, hypertension, and dyslipidaemia, were rarely improved perinatal outcomes have been observed amongst assessed. While better designed studies of these interventions those women with gestational diabetes randomized to intensive may provide evidence of effectiveness in terms of both weight glycaemic control vs those on standard care.40 There were fewer control and metabolic and disease outcomes we believe there is large for gestational age infants amongst those in the interven- also merit in exploring whether brief interventions during key tion group (13% vs 22%, P , 0.001) and fewer infants with periods of development might have long-term benefits in terms macrosomia (10% vs 21%, P , 0.001). However, these of obesity and obesity related disease prevention.
differences may have been largely driven by the shorter periodof gestation among the intensively treated group, due mainly tothe greater rate of inductions of labour in that group.
Nevertheless, long-term follow-up of these infants to determine whether a brief intervention during the intrauterine period has long-term beneficial effects on the offspring in terms of the Three periods in early life may be particularly important for the development of obesity and its associated diseases is important development of obesity and its associated morbidity and for testing the fetal overnutrition hypothesis and determining whether a brief intervention during the intrauterine period patterns and levels of physical activity are largely formed in among this high-risk group has a lasting effect.
adolescence and persist into adulthood.44 Adolescence may alsobe a critical period for the development of atherosclerosis. Lipidrich deposits (fatty streaks) are found in the aortae of almost all children .3 years of age, irrespective of ethnicity, sex,environment, diet, or later CHD.28 Consequently, while these In normal physiological circumstances, during the first year of life lesions may be the seed for atherosclerosis, their relationship to BMI increases rapidly, but then decreases, reaching a minimum extent of adult atherosclerosis is disputed. Autopsy studies in usually ~5–6 years of age. This point of minimum BMI has been humans show that late adolescence (i.e. from ~15–19 years) is called the adiposity rebound, though would be more accurately the key time when fatty streaks convert to raised atherosclerotic termed BMI rebound. Following this nadir, BMI then starts to lesions.28 Intriguingly, this also corresponds to the age at which increase again. Several studies have found that an earlier BMI and skinfold thickness increase in young adults who go ‘adiposity’ rebound (based on the assessment of BMI) increases on to develop the metabolic syndrome,52 suggesting that the the risk of later obesity.41–43 However, the meaning and development of nascent metabolic syndrome may be linked to usefulness of these findings are unclear. BMI is not a true the generation of raised atherosclerotic plaques. By the age of 30, measure of adiposity and other markers of adiposity do not show raised atherosclerotic lesions are present in arteries of 1 in 3 the same patterns as BMI over early life. Thus, ponderal index adults and are associated with the same risk factors (central (kg/m3) and percentage body fat both decrease to about age adiposity, dyslipidaemia, hypertension, glucose intolerance/ 6 years and remain constant thereafter, whereas triceps skin- insulin resistance, chronic inflammation)28 that predict diabetes fold thickness shows two nadirs (at ages 6–8 and 15–17 years).44 and cardiovascular disease. These data suggest that adolescence It has also been demonstrated that early age at adiposity rebound offers a therapeutic window with a unique opportunity to modify predicts later fatness as it identifies children whose BMI centile is the risk of future obesity, diabetes, and cardiovascular disease high and/or moving upwards across centiles, suggesting that BMI and achieve long-term prevention, perhaps via short-term centile crossing or actual BMI in childhood is a more useful measure for predicting later fatness than is age at adiposityrebound.45 This is consistent with findings from the Bogalusastudy, which, although finding an association between early age at adiposity rebound and adult BMI, also noted that BMI atage 7–8 years was a stronger predictor of adult BMI than age at The role of pregnancy in determining offspring obesity has minimum BMI.46 As age at adiposity rebound can only be already been discussed. But in addition, there is increasing determined in retrospect, prevention per se is difficult to evidence that weight gain during pregnancy, and post-partum implement and assess.44 One could try to identify modifiable weight retention, may be an important predictor of the mothers’ risk factors associated with early adiposity rebound, but in one risk of subsequent obesity and diabetes.53 It has been proposed study that aimed to do just that the only independent predictor of that the antenatal period therefore offers a unique period in the early adiposity rebound was parental obesity, which is a known life course during which women at risk of future diabetes and cardiovascular disease might be identified, at a time when they Several studies have found that breast-feeding is protective might be particularly receptive to health promotion or disease against later adiposity, but a recent systematic review and meta-analysis concluded that while mean BMI in later life waslower among breast-fed subjects, the difference was small andlikely to have been strongly influenced by publication bias and confounding factors.48 These conclusions are supported by findings from a large cluster randomized controlled trial of the The idea that an intervention during a key developmental period promotion of breast-feeding,49 which failed to show marked can persistently modify risk factors is supported by studies in differences in obesity or cardiovascular disease risk factors in later animal models of human disease. Brief treatment with childhood. Thus, evidence to date does not support infancy as a angiotensin-converting enzyme (ACE) inhibitors54 or a selective critical period during which interventions might have long-term angiotensin II receptor antagonist55 in young (prior to their effects on the risk of obesity and its associated diseases.
development of hypertension) genetically spontaneous hyper-tensive rats causes a reduction in blood pressure that persiststhroughout life and is associated with a reduction in target organ damage. In humans, as a result of these findings in animal Puberty is a time of rapid change in size and shape for both studies, there are now two on-going trials investigating whether females and males. In females earlier age at menarche is treatment of ‘pre-hypertension’ with an angiotensin receptor associated with obesity, independently of childhood BMI and antagonist for a brief period only in young adults (average age other potential confounding factors.50 Puberty is associated with ~35 years) may delay or prevent subsequent hypertension: the a physiological increase in insulin resistance51 and is thought to Trial of Prevention of Hypertension (TROPHY) and the Danish contribute to a peak of incidence in type 1 diabetes at that age. In Hypertension Project.56 Similarly, animal models of type 1 relation to these changes in insulin metabolism, post-pubertal fat diabetes indicate that intensive prophylactic treatment from deposition in both females and males tends to be more central weaning to 180 days of life in genetically programmed diabetic rather than general. In addition, behaviours such as dietary mice is effective at reducing the risk of development of diabetes.57 In a non-randomized controlled study of non-diabetic brief interventions aimed at permanent beneficial effects on school children who had islet cell antibodies (and thus increased obesity and cardiovascular risk factors. It is possible that most risk of type 1 diabetes) brief treatment in childhood with investigators feel that the epidemiological evidence is still not nicotinomide reduced the risk of future diabetes.58 Similarly, a sufficiently robust to proceed with such trials. But we feel that small trial of prophylaxis with insulin therapy among non- the animal studies in hypertension and diabetes discussed above diabetic children with relatives who had type 1 diabetes produced and the progress from these to undertaking trials of brief promising results.59 However, larger randomized trials of these interventions in young adults offer exciting prospects for the agents have been negative.60,61 Nevertheless, given the difficulty future. Perhaps if we undertake another themed issue of the of establishing the correct therapeutic window, duration of journal in 10 years time we will be able to report on the benefits therapy, dose, and agent, these disappointing findings should of a brief intervention in a critical period of human development not curtail attempts to pursue this approach in this and other Shah Ebrahim and George Davey Smith provided useful Data on childhood obesity from the developing world are sparse, comments on an earlier draft. D.A.L. is supported by a UK but indicate that not only is obesity on the increase but also that Department of Health Career Scientist Award.
obesity co-exists with the long-standing problem of under-nutrition (see, for example, the paper by Andrew Prentice62 inthis themed issue). The impact of interactions between these conditions is not known and difficult to predict. In Asian Indians,long-term adaptation to scarce food supplies has, in times 1Cummins S, Macintyre S. Food environments and obesity— of abundance, resulted in a classically insulin resistant popula- neighbourhood or nation? Int J Epidemiol 2006;35:100–104.
tion, with central obesity, dyslipidaemia, glucose intolerance, 2 Anderson JW, Luan J, Hoie LH. Structured weight-loss programs: meta- and cardiovascular disease. Yet, perhaps as a consequence of analysis of weight loss at 24 weeks and assessment of effects of persistent maternal malnutrition (both under-provision of critical intervention intensity. Adv Ther 2004;21:61–75.
nutrients, and overprovision of obesogenic foods), Indian Asian Tsai AG, Wadden TA. Systematic review: an evaluation of major babies are both short and thin, and are already more glucose commercial weight loss programs in the United States. Ann Intern Med2005;142:56–66.
intolerant, insulin resistant, dyslipidaemic, and, importantly, have a greater percentage of body fat, than their European Avenell A, Brown TJ, McGee MA, Campbell MK et al. What are the long-term benefits of weight reducing diets in adults? A systematic counterparts.63,64 That this population has, in settings of food review of randomized controlled trials. J Hum Nutr Diet 2004;17: abundance, one of the highest rates of diabetes and cardiovas- cular disease in the world, suggests that the intergenerational 5 Pittler MH, Ernst E. Dietary supplements for body-weight reduction: effect of over-nutrition superimposed on under-nutrition may be a systematic review. Am J Clin Nutr 2004;79:529–36.
particularly toxic. This observation underlines the fact that we 6 O’Meara S, Riemsma R, Shirran L, Mather L, ter RG. A systematic must be cautious when extrapolating findings from studies review of the clinical effectiveness of orlistat used for the management performed largely in Western settings to the developing world, of obesity. Obes Rev 2004;5:51–68.
where triggers for obesity and their outcomes may be very 7 Avenell A, Brown TJ, McGee MA, Campbell MK et al. What different. In addition, in many developing countries, obesity in interventions should we add to weight reducing diets in adults with women is particularly prized as a sign of affluence, and is often obesity? A systematic review of randomized controlled trials of adding achieved at the cost of relative malnutrition for other members of drug therapy, exercise, behaviour therapy or combinations of these the family. Given the suggested vicious spiral between obesity interventions. J Hum Nutr Diet 2004;17:293–316.
during pregnancy and childhood obesity, this has potentially dire Arterburn DE, Crane PK, Veenstra DL. The efficacy and safety of implications for the likely future patterns of obesity in these sibutramine for weight loss: a systematic review. Arch Intern Med2004;164:994–1003.
Standard approaches to obesity prevention in the long term Kim SH, Lee YM, Jee SH, Nam CM. Effect of sibutramine on weight loss and blood pressure: a meta-analysis of controlled trials. Obes Res have been disappointing. Targeting the prevention of obesity during the key periods of development may be of particular 10 Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects relevance in reducing subsequent risks of adult obesity and of the cannabinoid-1 receptor blocker rimonabant on weight reduction associated chronic disease. To our knowledge there are no trials and cardiovascular risk factors in overweight patients: 1-year in humans that have examined the long-term effects of maternal experience from the RIO-Europe study. Lancet 2005;365:1389–97.
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Fact Sheet on Positive Prevention/CRACK (Children Requiring A Caring Kommunity)Prepared by Theryn Kigvamasud’Vashti, Communities Against Rape and Abuse P o s i t i v e Prevention, a population control organization in Seattle, offers a $200.00 cash incentive to people who are addicted to drugs and alcohol to undergo a form of long-term orpermanent

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