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Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data.
Wharton, S, Astrup, A, Endahl, L, Lean, MEJ, Satylganova, A, Skovgaard, D, Wadden, TA, Wilding, JPH
International journal of obesity (2005). 2021;(5):923-933
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Abstract
In the approval process for new weight management therapies, regulators typically require estimates of effect size. Usually, as with other drug evaluations, the placebo-adjusted treatment effect (i.e., the difference between weight losses with pharmacotherapy and placebo, when given as an adjunct to lifestyle intervention) is provided from data in randomized clinical trials (RCTs). At first glance, this may seem appropriate and straightforward. However, weight loss is not a simple direct drug effect, but is also mediated by other factors such as changes in diet and physical activity. Interpreting observed differences between treatment arms in weight management RCTs can be challenging; intercurrent events that occur after treatment initiation may affect the interpretation of results at the end of treatment. Utilizing estimands helps to address these uncertainties and improve transparency in clinical trial reporting by better matching the treatment-effect estimates to the scientific and/or clinical questions of interest. Estimands aim to provide an indication of trial outcomes that might be expected in the same patients under different conditions. This article reviews how intercurrent events during weight management trials can influence placebo-adjusted treatment effects, depending on how they are accounted for and how missing data are handled. The most appropriate method for statistical analysis is also discussed, including assessment of the last observation carried forward approach, and more recent methods, such as multiple imputation and mixed models for repeated measures. The use of each of these approaches, and that of estimands, is discussed in the context of the SCALE phase 3a and 3b RCTs evaluating the effect of liraglutide 3.0 mg for the treatment of obesity.
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Dietary interventions in overweight and obese pregnant women: a systematic review of the content, delivery, and outcomes of randomized controlled trials.
Flynn, AC, Dalrymple, K, Barr, S, Poston, L, Goff, LM, Rogozińska, E, van Poppel, MN, Rayanagoudar, G, Yeo, S, Barakat Carballo, R, et al
Nutrition reviews. 2016;(5):312-28
Abstract
CONTEXT Interventions targeting maternal obesity are a healthcare and public health priority. OBJECTIVE The objective of this review was to evaluate the adequacy and effectiveness of the methodological designs implemented in dietary intervention trials for obesity in pregnancy. DATA SOURCES A systematic review of the literature, consistent with PRISMA guidelines, was performed as part of the International Weight Management in Pregnancy collaboration. STUDY SELECTION Thirteen randomized controlled trials, which aimed to modify diet and physical activity in overweight and obese pregnant women, were identified. DATA SYNTHESIS There was significant variability in the content, delivery, and dietary assessment methods of the dietary interventions examined. A number of studies demonstrated improved dietary behavior in response to diet and/or lifestyle interventions. Nine studies reduced gestational weight gain. CONCLUSION This review reveals large methodological variability in dietary interventions to control gestational weight gain and improve clinical outcomes in overweight and obese pregnant women. This lack of consensus limits the ability to develop clinical guidelines and apply the evidence in clinical practice.
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Potatoes and risk of obesity, type 2 diabetes, and cardiovascular disease in apparently healthy adults: a systematic review of clinical intervention and observational studies.
Borch, D, Juul-Hindsgaul, N, Veller, M, Astrup, A, Jaskolowski, J, Raben, A
The American journal of clinical nutrition. 2016;(2):489-98
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Abstract
BACKGROUND Potatoes have been related to increased risks of obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD) mainly because of their high glycemic index. OBJECTIVE We conducted a systematic review to evaluate the relation between intake of potatoes and risks of obesity, T2D, and CVD in apparently healthy adults. DESIGN MEDLINE, Embase, the Web of Science, and the Cochrane Central Register of Controlled Trials were searched for intervention and prospective observational studies that investigated adults without any known illnesses at baseline, recorded intake of potatoes, and measured adiposity (body weight, body mass index, or waist circumference), cases of T2D, cases of cardiovascular events, or risk markers thereof. RESULTS In total, 13 studies were deemed eligible; 5 studies were related to obesity, 7 studies were related to T2D, and one study was related to CVD. Only observational studies were identified; there were 3 studies with moderate, 9 studies with serious, and one study with critical risk of bias. The association between potatoes (not including french fries) and adiposity was neutral in 2 studies and was positive in 2 studies. French fries were positively associated with adiposity in 3 of 3 studies. For T2D, 2 studies showed a positive association, whereas 5 studies showed no or a negative association with intake of potatoes and T2D. French fries were positively associated with T2D in 3 of 3 studies that distinguished this relation. For CVD, no association was observed. CONCLUSIONS The identified studies do not provide convincing evidence to suggest an association between intake of potatoes and risks of obesity, T2D, or CVD. French fries may be associated with increased risks of obesity and T2D although confounding may be present. In this systematic review, only observational studies were identified. These findings underline the need for long-term randomized controlled trials. This trial was registered at the PROSPERO International prospective register of systematic reviews (www.crd.york.ac.uk/PROSPERO/) as CRD42015026491.
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Personalized weight loss strategies-the role of macronutrient distribution.
Martinez, JA, Navas-Carretero, S, Saris, WH, Astrup, A
Nature reviews. Endocrinology. 2014;(12):749-60
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Abstract
A large number of different dietary approaches have been studied in an attempt to achieve healthy, sustainable weight loss among individuals with overweight and obesity. Restriction of energy intake is the primary method of producing a negative energy balance leading to weight loss. However, owing to the different metabolic roles of proteins, carbohydrates and lipids in energy homeostasis, diets of similar overall energy content but with different macronutrient distribution can differentially affect metabolism, appetite and thermogenesis. Evidence increasingly suggests that the fuel values of calories provided by distinct macronutrients should be considered separately, as metabolism of specific molecular components generates differences in energy yield. The causes of variation in individual responses to various diets are currently under debate, and some evidence suggests that differences are associated with specific genotypes. This Review discusses all available systematic reviews and meta-analyses, and summarizes the results of relevant randomized controlled intervention trials assessing the influence of macronutrient composition on weight management. The initial findings of research into personalized nutrition, based on the interactions of macronutrient intake and genetic background and its potential influence on dietary intervention strategies, are also discussed.
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When, for whom and how to use sibutramine?
Astrup, A, Toubro, S
International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. 2001;:S2-7
Abstract
Sibutramine is the first of a new generation of weight management drugs, and offers long-term control of weight when used as an adjunct to diet and exercise. This paper considers the criteria set down by the European Union's regulatory agency for its use and how this relates to the information now available on its efficacy, side-effect profile and benefits in different patient groups. The data presented relate to 18-65y olds; its use in other age groups has not been established. The EU licence permits continuous treatment for periods of up to 1 y; the STORM study has now led the US Food and Drug Administration to extend clearance to 2 y. The addition of sibutramine to a regimen of diet, exercise and lifestyle modification results in 3-5 times more patients responding to a weight-reduction programme, ie achieving more than 5% weight maintenance. Sibutramine is indicated for use in obese patients (BMI > 30 kg/m2) and also overweight patients with a BMI > 27 kg/m2 who have additional obesity-related risk factors such as type 2 diabetes or dyslipidaemia.
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Lessons from obesity management programmes: greater initial weight loss improves long-term maintenance.
Astrup, A, Rössner, S
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2000;(1):17-9
Abstract
It is a common belief that weight loss achieved at a slow rate is better preserved than if the weight is lost more rapidly. However, the literature shows that initial weight loss is positively, not negatively, related to long-term weight maintenance. There is evidence from randomised intervention trials to support that a greater initial weight loss induced without changes in lifestyle (e.g. liquid formula diets or anorectic drugs) improves long-term weight maintenance, providing it is followed by a 1-2 years integrated weight maintenance programme consisting of lifestyle interventions involving dietary change, nutritional education, behaviour therapy and increased physical activity. In conclusion, we find evidence to suggest that a greater initial weight loss as the first step of a weight management programme may result in improved sustained weight maintenance.
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Thermogenic drugs as a strategy for treatment of obesity.
Astrup, A
Endocrine. 2000;(2):207-12
Abstract
There is accumulating evidence to support the hypothesis that a low-energy-output phenotype is at high risk of weight gain and obesity, irrespective of whether this is owing to a low resting metabolic rate and/or physical inactivity. The low-energy-output phenotype is associated with impaired appetite control, which is improved if energy output is increased. This is the background for pharmacologic stimulation of energy expenditure as a tool to improve the results of obesity management. Targets are the leptin receptors, the sympathetic nervous system and its peripheral beta-adrenoceptors, selective thyroid hormone derivatives, and stimulation of the mitochondrial uncoupling proteins. Currently available compounds such as recombinant leptin, ephedrine/caffeine, and sibutramine possess thermogenic properties owing to their activation of the sympathoadrenal system. Compounds acting selectively on the human beta3-adrenoceptor are still promising tools to achieve a sustained stimulation of lipolysis and energy expenditure, and several are in the pipeline.