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Effects of anti-obesity drugs, diet, and exercise on weight-loss maintenance after a very-low-calorie diet or low-calorie diet: a systematic review and meta-analysis of randomized controlled trials123

Effects of anti-obesity drugs, diet, and exercise on weight-loss maintenance after a... Effects of anti-obesity drugs, diet, and exercise on weight-loss maintenance after a very-low-calorie diet or low-calorie diet: a systematic review and meta-analysis of randomized 1–3 controlled trials Kari Johansson, Martin Neovius, and Erik Hemmingsson ABSTRACT loss requires substantial behavioral efforts, especially when non- Background: Weight-loss maintenance remains a major challenge bariatric surgical methods are used (3, 4). in obesity treatment. Effects of different maintenance strategies after a VLCD have Objective: The objective was to evaluate the effects of anti-obesity been tested in randomized trials, such as anti-obesity drugs (5–9), drugs, diet, or exercise on weight-loss maintenance after an ini- meal replacements (10, 11), high-protein diets (12–17), low- tial very-low-calorie diet (VLCD)/low-calorie diet (LCD) period glycemic-index diets (15), low-fat diets (18), green tea extracts (,1000 kcal/d). (14, 19), a prolonged refeeding period (20), waist corsets (21), Design: We conducted a systematic review by using MEDLINE, the and exercise (22, 23). The effects of these maintenance strategies Cochrane Controlled Trial Register, and EMBASE from January remain unclear, and previous meta-analyses that investigated 1981 to February 2013. We included randomized controlled trials long-term effects of a VLCD have only compared the effects of that evaluated weight-loss maintenance strategies after a VLCD/ VLCDs with LCDs (1, 24). LCD period. Two authors performed independent data extraction The aim of this systematic review and meta-analysis was to by using a predefined data template. All pooled analyses were based quantify the effects of anti-obesity drugs, diet, and exercise on on random-effects models. weight-loss maintenance after a VLCD or LCD. We included Results: Twenty studies with a total of 27 intervention arms and 3017 randomized controlled trials in which all participants started with participants were included with the following treatment categories: a VLCD or LCD (caloric intake cutoff set at ,1000 kcal/d) and anti-obesity drugs (3 arms; n = 658), meal replacements (4 arms; thereafter were randomly assigned to either a maintenance n = 322), high-protein diets (6 arms; n = 865), dietary supplements strategy or control or placebo. (6 arms; n = 261), other diets (3 arms; n = 564), and exercise (5 arms; n = 347). During the VLCD/LCD period, the pooled mean weight change was 212.3 kg (median duration: 8 wk; range 3–16 wk). MATERIALS AND METHODS Compared with controls, anti-obesity drugs improved weight-loss Data sources and searches maintenance by 3.5 kg [95% CI: 1.5, 5.5 kg; median duration: 18 mo (12–36 mo)], meal replacements by 3.9 kg [95% CI: 2.8, 5.0 kg; A systematic search of 3 bibliographic databases [MEDLINE median duration: 12 mo (10–26 mo)], and high-protein diets by 1.5 kg (http://www.ncbi.nlm.nih.gov/pubmed), EMBASE (http://www. [95% CI: 0.8, 2.1 kg; median duration: 5 mo (3–12 mo)]. Exercise embase.com), and Cochrane Controlled Trials Register (http:// [0.8 kg; 95% CI: 21.2, 2.8 kg; median duration: 10 mo (6–12 mo)] www.thecochranelibrary.com)] from 1981 to February 2013 was and dietary supplements [0.0 kg; 95% CI: 21.4, 1.4 kg; median performed by using 3 search strings: 1)“VLED”or“VLCD” or “very duration: 3 mo (3–14 mo)] did not significantly improve weight-loss low energy diet” or “very low calorie diet,” 2) “LED” or “LCD” or maintenance compared with control. “low energy diet” or “low calorie diet,” and 3) “weight loss main- Conclusion: Anti-obesity drugs, meal replacements, and high- tenance” or “maintained weight loss” or “weight maintenance” or protein diets were associated with improved weight-loss maintenance after a VLCD/LCD period, whereas no significant improvements 1 From the Clinical Epidemiology Unit (KJ and MN) and the Obesity Center were seen for dietary supplements and exercise. Am J Clin (EH), Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Nutr 2014;99:14–23. Supported in part by a grant from Cambridge Manufacturing Ltd, North- ants, United Kingdom (to EH). This is a free access article, distributed under terms (http://www.nutrition.org/publications/guidelines-and-policies/license/) that permit unrestricted noncommercial use, distribution, and reproduction in INTRODUCTION any medium, provided the original work is properly cited. Treatment with a very-low-calorie diet (VLCD; ,800 kcal/d) Address correspondence and reprint requests to K Johansson, Clinical Ep- or low-calorie diet (LCD; ,1200 kcal/d) is associated with idemiology Unit, Department of Medicine, Karolinska Institutet, SE-171 76, substantial initial weight loss, but also greater weight regain Stockholm, Sweden. E-mail: kari.johansson@ki.se. compared with weight loss achieved through a more moderate Received July 9, 2013. Accepted for publication October 10, 2013. restriction in energy intake (1, 2). Maintaining a large weight First published online October 30, 2013; doi: 10.3945/ajcn.113.070052. 14 Am J Clin Nutr 2014;99:14–23. Printed in USA.  2014 American Society for Nutrition WEIGHT-LOSS MAINTENANCE AFTER VLCD/LCD 15 “weight regain.” The search was limited to humans, randomized Data synthesis and analysis controlled trials, English language publications, and adults in Primary outcome the databases where limitations were possible (MEDLINE and The primary outcome was the weighted mean difference in EMBASE). The reference lists of identified articles were also weight change (kg) during the weight-loss maintenance phase searched for additional studies, as were reference lists of previously between the intervention and control groups. The random-effects published reviews. Two reviewers (KJ and EH) separately screened model was used to weight and pool the studies within each the abstracts for inclusion or exclusion. Full text articles were maintenance category (anti-obesity drug, diet, and exercise). The retrieved from all abstracts that were potentially relevant and were diet studies were further subdivided into high-protein diet, meal reviewed independently by the 2 researchers. In case of conflicting replacement, dietary supplements, and macronutrients other than views, a third researcher (MN) was asked to resolve the conflict. protein, including low glycemic index, low fat, and eating ac- cording to the Healthy Eating Pyramid. Heterogeneity between studies was assessed by the I statistic Study selection (27), and if this exceeded 50% or was statistically significant, Studies were included if they were randomized controlled the reasons for heterogeneity were explored by subgroup anal- trials of adults (age $18 y), and consisted of an initial weight- yses or meta-regression. Low, moderate, and high heterogeneity loss period with a VLCD or LCD (,1000 kcal/d) followed by were defined according to cutoffs of 25%, 50%, and 75%, re- randomization to a maintenance strategy (anti-obesity drug, diet, spectively (28). To investigate possible publication bias, a funnel and/or exercise) or control. No restrictions regarding study du- plot of the inverse of the SE was inspected visually, and statistical ration were imposed. Studies were excluded if they evaluated significance was calculated by using Egger’s test (29). anti-obesity drugs that never reached approval by regulatory agencies or if the weight-loss period did not include a VLCD or Secondary outcome LCD. Sibutramine and rimonabant were eligible for inclusion A secondary aim was to illustrate weight change after the because they had been approved and widely used as anti-obesity VLCD or LCD phase and weight-loss maintenance phase within drugs before being withdrawn from the market in 2010 and each treatment arm. The random-effects model was used to weight 2009, respectively. and pool the weight changes within each treatment and control arm during the maintenance period. The mean monthly change was es- Data extraction and quality assessment timated from these 2 measurements. The statistical analyses were Data on participants, interventions, weight loss, and weight- conducted by using Comprehensive Meta Analysis (version 2; Biostat Inc). P values ,0.05 were regarded as statistically significant. loss maintenance were extracted by 2 researchers (KJ and EH) independently by using predefined data templates. Disagree- ments were resolved through discussion. For the meta-analysis, RESULTS data on number of subjects and mean changes with corresponding SDs in the intervention and control arm were extracted. Many Study selection studies did not report these values. In those cases, SDs and mean The systematic search resulted in 20 randomized controlled changes were calculated from other data (see “Supplemental trials that met the inclusion criteria (Figure 1), which included data” in the online issue). 27 intervention arms with 3017 participants. Of these, 3 arms Five studies included .2 arms (14, 15, 18, 25, 26). Weighted evaluated anti-obesity drugs (n = 658), 4 meal replacements mean differences were calculated between the 2 groups that (n = 322), 6 high-protein diets (n = 865), 6 dietary supplements showed the most resemblance to other studies in the treatment (n = 261), 3 other diets (n = 564), and 5 exercise (n = 347). category. Larsen et al (15) reported both the isolated and com- bined effects of a high-protein diet and a low-glycemic-index diet. In the meta-analysis, the isolated main effects of high protein Study characteristics compared with low protein and low glycemic index compared Participants with high glycemic index were included. Due et al (18) reported Participant characteristics were similar, with a greater pro- the effect of 2 interventions (low fat and the Healthy Eating portion of women than men in most of the studies (Table 1). The Pyramid, which is high in MUFAs and has a low glycemic in- mean age ranged between 28 and 48 y and mean BMI (kg/m ) dex), and both treatment arms were included and compared with between 27.9 and 41.6. All studies but one were from Europe; the control group. In the study by Hursel et al (14), the green tea most were from the Netherlands (6, 12, 14, 16, 17, 19, 25, 30) effect was analyzed by comparing the green tea/adequate-protein and Scandinavia (7, 10, 11, 18, 20, 22, 23, 26, 31), and the re- group with the placebo/adequate-protein group, and the high- maining 3 studies were from France (5), Australia (13), or 8 protein effect was analyzed by comparing the green tea/high- European countries (multicenter study) (15). protein with the green tea/adequate-protein group. The study by Kamphuis et al (25) included 2 different doses of conjugated VLCD/LCD period linoleic acid (1.8 and 3.6 g) compared with placebo (1.8 and 3.6 g). Both doses were included. During the weight-loss phase preceding the randomization, 18 Two reviewers (KJ and EH) independently evaluated the in- of the 20 studies used a VLCD (,800 kcal/d), whereas 2 studies dividual studies regarding the extent of loss to follow-up and (15, 18) used an LCD of 800 to 1000 kcal/d. Eight of the studies the adequacy of randomization and concealment of allocation, used a strict VLCD, ie, no other food was allowed except for the blinding of patients, data collectors, and outcome assessors. VLCD powder mixed with water (6, 7, 10, 11, 20, 22, 23, 25). In 16 JOHANSSON ET AL the intervention and control groups were advised to consume a 600-kcal deficit diet based on their estimated energy expen- diture. In the third study the participants were advised to follow the French nutrition guidelines (5). Diet studies Of the diet studies/study arms, 6 evaluated a high-protein diet, 6 dietary supplements with a suggested satiating or thermic effect, 4 meal replacements or a prolonged refeeding, and 3 macronutrients other than protein, including low glycemic index, low fat, and eating according to the Healthy Eating Pyramid (32). In addition to the specific maintenance intervention, 10 of the 15 diet studies reported using a co-intervention, such as in- structions to the participants to maintain their habitual physical activity levels, dietitian visits, and cooking classes. Two of the studies also supplied the participants with free food from a study supermarket (15, 18). Exercise studies The 3 exercise studies (22, 23, 26) investigated resistance training, walking, and arthritis-adapted knee exercises, respec- tively. During the active treatment period, both groups were given dietary counseling based on the LEARN manual (33) in the study by Borg et al (22), and group meetings were given in the study by Fogelholm et al (23); only arthritis-tailored knee exercises were given in the study by Christensen et al (26). Risk of bias Most studies did not report the randomization process, but simply stated that the participants were randomized. All studies specified the eligibility criteria, and characteristics were similar FIGURE 1. Flowchart of included studies. RCT, randomized controlled for the intervention and control groups at randomization in all trial. studies. Seven (5–7, 14, 19, 25, 31) of the studies were double- 7 of the studies, the participants were allowed to consume blind. Most of the studies only analyzed and reported data on vegetables (12–17, 19), and in 2 of the studies the powder for- completers, except for the anti-obesity drug studies and the diet mulas were mixed with milk (26) or a small ad libitum breakfast and exercise study by Christensen et al (26), which analyzed all was allowed within the 800-kcal/d limit (31). the included participants. (An intention-to-treat analysis with last observation carried forward analysis for missing data were Weight-loss maintenance period used in all the anti-obesity drug studies, whereas baseline ob- servation carried forward was used in the diet and exercise study After the weight-loss phase the participants were randomly by Christensen et al). assigned to a maintenance intervention or a control group. Most (n = 11; 55%) of the studies randomly assigned participants only if they had lost 5–10% of the initial weight during the VLCD or Main findings LCD period. This applied for all of the drug studies (5–7) and VLCD/LCD period 8 of the 14 diet studies (12, 13, 15, 16, 18, 20, 30, 31) but not for During the VLCD or LCD run-in period, before random- the exercise studies, for which all the participants were ran- ization, the pooled mean weight change was 212.4 kg (95% domly assigned despite weight loss. CI: 216.6, 28.2; median weight-loss phase duration: 8 wk) for The duration of the maintenance period ranged from 3 mo to 3 y the anti-obesity drug studies, 211.1 kg (95% CI: 212.1, 210.1; (Figure 2). Twelve of the 20 studies had a maintenance period median weight-loss phase duration: 8 wk) for the diet studies, of ,1 y, with an overrepresentation of short maintenance pe- and 213.5 kg (95% CI: 214.0, 213.0 median weight-loss phase riods among the diet studies (10 of 14). All included drug duration: 12 wk) for the exercise studies (Figure 3). studies had a maintenance period of .1 y. The 2 studies that studied exercise exclusively had an active maintenance period of Weight-loss maintenance period ,1 y, but both included a 2-y unsupervised follow-up (22, 23). Weight regain during the maintenance period differed between Anti-obesity drug studies individual studies, ranging from a further mean weight change Of the 3 anti-obesity drug studies, 2 evaluated sibutramine (5, of 25 kg to a regain of 14 kg in the intervention groups and 6) and 1 orlistat (7). In 2 (6, 7) of the 3 studies, participants in both from 21 kg to a gain of 13 kg in the control groups (Figure 2). WEIGHT-LOSS MAINTENANCE AFTER VLCD/LCD 17 TABLE 1 Description of included randomized controlled trials (n = 20) that evaluated the success of drugs, diet, and exercise strategies at improving weight-loss maintenance after an initial period of weight loss with a VLCD or LCD (,1000 kcal/d) Characteristics before weight loss Weight-loss period (VLCD/LCD) Weight-loss maintenance period Participants Participants who Weight randomly assigned completed Author Age Women BMI Weight Subjects Energy Duration loss Intervention Control (Trt/Ctrl) (Trt/Ctrl) Duration y % kg/m kg n kcal/d mo kg n n mo Anti-obesity drugs Richelsen, 2007 (7) 47 51 37.5 111 383 600–800 2 214.4 Orlistat (360 mg/d) Placebo 309 (153/156) 201 (103/98) 36 Mathus-Vliegen, 2005 (6) 43 86 36.6 105 221 480 3 215.2 Sibutramine (10 mg/d) Placebo 189 (94/95) 120 (62/58) 18 Apfelbaum, 1999 (5) 38 79 38.3 104 205 220–800 1 27.6 Sibutramine (10 mg/d) Placebo 160 (82/78) 108 (60/48) 12 Diet: protein Delbridge, 2009 (13) 44 50 39.0 112 179 500–550 3 216.5 High protein: 30 E% High carbohydrate: 15 E% 141 (71/70) 82 (42/40) 12 protein, ,30 E% fat protein, ,30 E% fat Claessens, 2009 (12) 45 65 32.9 97 60 500 1.25 29.4 High protein: 25 E% High carbohydrate: 15 E% 54 (NR/NR) 48 (32/16) 3 protein, 30 E% fat protein, 30 E% fat Lejeune, 2005 (16) 45 NR 29.3 83 120 502 1 26.3 High protein: +30 g/ Habitual diet 113 (53/60) 113 (53/60) 6 d(w18–20 E%) Westerterp-Plantenga, 44 NR 29.5 87 180 502 1 26.4 High protein: +48 g/ Habitual diet 150 (NR/NR) 148 (73/75) 3 2004 (17) d(w18–20 E%) Diet: protein and other macronutrients Larsen, 2010 (15) 42 NR 34.2 99 938 800–1000 2 211 Low protein (13 E%) & Country-specific dietary 773 (150/154) 548 (106/114) 6.5 low GI guidelines (in all 5 diets: fat 25–30 E%) Low protein (13 E%) & Country-specific dietary (155/154) (97/114) high GI guidelines (in all 5 diets: fat 25–30 E%) High protein (25 E%) & Country-specific dietary (159/154) (124/114) low GI guidelines (in all 5 diets: fat 25–30 E%) High protein (25 E%) & Country-specific dietary (155/154) (107/114) high GI guidelines (in all 5 diets: fat 25–30 E%) Due, 2008 (18) 28 58 31.5 95 154 800–1000 2 212.8 Healthy Pyramid: 35–45 Western diet 35 E% fat, 131 (54/26) 106 (39/24) 6 E% fat, 10–20 E% 10–20 E% protein protein Low fat: 20–30 E% fat, Western diet 35 E% fat, (51/26) (43/24) 10–20 E% protein 10–20 E% protein (Continued) 18 JOHANSSON ET AL TABLE 1 (Continued) Characteristics before weight loss Weight-loss period (VLCD/LCD) Weight-loss maintenance period Participants Participants who Weight randomly assigned completed Author Age Women BMI Weight Subjects Energy Duration loss Intervention Control (Trt/Ctrl) (Trt/Ctrl) Duration Diet: protein and supplements Hursel 2009 (14) 44 55 29.6 85 92 502 1 27.0 Green tea (2.7 g/d) + Placebo + protein (10 E%) 80 (20/20) 80 (20/20) 3 protein (10 E%) Green tea (2.7 g/d) + high Placebo + high protein (20 80 (20/20) 80 (20/20) 3 protein (20 E%) E%) Kovacs, 2004 (19) NR 75 29.7 85 120 502 1 26.4 Green tea capsules (2.7 g/ Placebo 104 (51/53) 104 (51/53) 3.25 d) Pasman, 1997 (30) 41 100 32.9 89 49 478 2 210.7 Fiber supplement (guar Habitual diet (no fiber 39 (NR/NR) 20 (10/10) 14 gum 20 g/d) supplement) Kamphuis, 2003 (25) 38 52 27.9 84 60 502 0.75 25.9 CLA 1.8 g/d Placebo 1.8 g/d NR (NR/NR) 54 (14/13) 3.25 CLA 3.6 g/d Placebo 3.6 g/d NR (NR/NR) NR (13/14) 3.25 Olsson, 2011 (31) 48 100 28.3 94 54 444–557 1.5 27.1 Meal replacement for Meal replacement for 46 (23/23) 43 (22/21) 3 lunch (adding lunch (placebo; vegetable-oil emulsion; containing dairy fat 160 160 kcal/d) kcal/d) Diet: meal replacement and prolonged refeeding Gripeteg, 2010 (20) 41 64 41.6 124 269 479–813 3 216.5 Prolonged refeeding (6 Normal refeeding (1 wk) 169 (85/84) 123 (65/58) 10 wk) Ryttig, 1997 (10) 44 56 37.7 113 54 420 2 218.9 Meal replacement (1600 Hypocaloric (1600 kcal/d) 54 (27/27) 26 (15/11) 26 kcal/d; 240 kcal as replacement) Ryttig, 1995 (11) 42 80 39.1 112 60 330 3 220.8 Meal replacement (1600 Hypocaloric (1600 kcal/d) 52 (NR/NR) 45 (23/22) 12 kcal/d; 220 kcal/d as replacement) Diet and exercise Christensen, 2013 (26) 63 81 37.3 103.2 192 415–810 2+2 212.8 Meal replacement with Usual care 192 (64/64) 159 (55/52) 12 + 1200 dietary education (one 137-kcal meal replacement/d) Exercise Usual care 192 (64/64) 159 (52/52) 12 Exercise 6mo 4 Borg, 2002 (22) 43 0 32.9 106 90 500 2 214.3 Walking Diet counseling 82 (25/29) 68 (25/28/29 )6+23 23mo Exercise Diet counseling (28/29) (20/26/22 ) 10mo 4 Fogelholm, 2000 (23) 40 100 34.0 92 85 646 3 213.1 Walking: 1004 kcal/wk Diet counseling 82 (26/29) 80 (25/27/28 )10 + 24 24mo Walking: 2008 kcal/wk Diet counseling (27/29) (25/27/28 ) CLA, conjugated linoleic acid; Ctrl, control group; E%, percentage of energy; GI, glycemic index; LCD, low-calorie diet; NR, not reported; Trt, treatment group; VLCD, very-low-calorie diet. In this study, the dietary guidelines group is called “the high-carbohydrate group.” The composition of the diet, however, is equivalent to the Nordic Nutrition Recommendations 2004 (55 E% carbohydrates, 15 E% protein, 30 E% fat); hence, it was used as the control group. Healthy Pyramid corresponds to Willett’s new Healthy Eating Pyramid, which is high in MUFAs and has a low GI; .20% of the prescribed fat was MUFAs. The low-fat diet corresponded to the Nordic Nutrition Recommendations (low in fat and a medium GI), and the average Danish diet (similar to the Western diet; high in SUFAs and a high GI) represented the control group. Unsupervised follow-up. WEIGHT-LOSS MAINTENANCE AFTER VLCD/LCD 19 FIGURE 2. Overview of body weight changes in the included randomized controlled trials (n = 20) that evaluated different anti-obesity drugs, diet, and exercise weight-loss maintenance strategies after an initial very-low-calorie diet or low-calorie diet (,1000 kcal/d). CLA, conjugated linoleic acid; GI, glycemic index. 20 JOHANSSON ET AL Exercise Exercise as compared with diet counseling did not improve weight-loss maintenance (weighted mean difference: 0.8 kg; 95% CI: 21.2, 2.8; P = 0.43; median maintenance phase duration: 10 mo). There was significant heterogeneity in the exercise trials (I = 78%, P = 0.001), which was explained by the study by Christensen et al (26), which had a negative treatment effect, ie, worse weight-loss maintenance (Figure 4). When only the 2 studies that focused solely on exercise (22, 23) were included, weight-loss maintenance was significantly improved (weighted mean difference: 1.6 kg; 95% CI: 0.3, 2.9 kg; P = 0.02; median maintenance phase duration: 8 mo; I = 10%, P = 0.34). In the analysis of the unsupervised follow-up included in these 2 studies (22, 23), weight-loss maintenance was not improved (weighted mean difference: 20.7 kg; 95% CI: 23.0, 1.8; P = 0.63; median unsupervised follow-up duration: 24 mo). FIGURE 3. Overview of changes in body weight during the rapid weight- loss phase and the weight-loss maintenance period in 20 randomized con- trolled trials that evaluated different anti-obesity drug, diet, and exercise Publication bias and meta-regression weight-loss maintenance strategies after an initial very-low-calorie diet or low-calorie diet (,1000 kcal/d). The gray lines represent the control subjects No evidence of publication bias could be detected for any in each subcategory. Anti-obesity drugs: sibutramine and orlistat. Dietary of the maintenance strategies neither based on the Egger’s test supplements: green tea, high fiber, oil supplement, and conjugated linoleic (P-drug = 0.28, P-diet = 0.88, P-exercise = 0.08) nor by visual acid. Other macronutrients: low fat, low glycemic index, and Healthy Eating inspection of funnel plots (see Supplemental Figure 1 under Pyramid. The random-effects model was used to weight and pool the studies within each treatment arm (intervention and control) after the very-low- “Supplemental data” in the online issue). The heterogeneity calorie diet or low-calorie diet period and maintenance period. The mean in- within each treatment category was largely diminished after crease for each month was estimated from these 2 measurements. Weighted conducting subgroup analyses as described above and was not mean differences between the intervention and control groups at follow-up explained by varying weight-loss magnitudes across the control were estimated by using a random-effects model. groups (b: 20.2; 95% CI: 20.4, 0.1; P = 0.2) or by differences in study duration when investigated via meta-regression (b: 0.1; 95% CI: 20.2, ,0.1; P = 0.2; see Supplemental Figure 2 under Anti-obesity drug studies “Supplemental data” in the online issue). Use of an anti-obesity drug compared with placebo improved weight-loss maintenance by 3.5 kg (95% CI: 1.5, 5.5 kg; P , DISCUSSION 0.001; median maintenance phase duration: 18 mo; Figure 3 and Figure 4). There was evidence of significant heterogeneity (I = Summary 70%, P = 0.04). This heterogeneity was explained by the study by Apfelbaum et al (5), in which the participants in the sibutr- In this meta-analysis of 20 randomized controlled trials, we amine arm continued to lose weight during the maintenance found that both anti-obesity drugs and extended use of low- period. In a sensitivity analysis that excluded this study, the calorie meal replacements improved weight-loss maintenance heterogeneity disappeared (I = 0%, P = 0.88). relative to controls. A high-protein diet was also associated with improved maintenance, although smaller than for meal re- placements and drugs. A combined category consisting of low Diet studies fat, low glycemic index, and the Healthy Eating Pyramid was Overall, the diet maintenance strategies improved weight-loss also associated with improved maintenance, similar in effect to maintenance by 1.4 kg (95% CI: 0.7, 2.1 kg; P , 0.001; median eating a high-protein diet. Exercise and dietary supplementation maintenance phase duration: 6 mo) compared with the control strategies—such as green tea, high fiber, conjugated linoleic group. A significant degree of heterogeneity (I = 63%, P , acid, and oil supplementation—were not associated with im- 0.001) was explained by the different dietary strategies. proved maintenance. After the dietary studies were stratified into subcategories, extended use of meal replacements and prolonged refeeding Previous research improved weight-loss maintenance by 3.9 kg (95% CI: 2.8, 5.5 kg; P , 0.001; median maintenance phase duration: 12 mo) Previous meta-analyses investigating long-term effects of compared with controls. A high-protein diet improved weight- a VLCD or LCD (1, 24) have not included analyses of weight- loss maintenance by 1.5 kg (95% CI: 0.8, 2.1 kg; P , 0.001; loss-maintenance strategies. Tsai and Wadden (1) included median maintenance phase duration: 5 mo), nonprotein macro- studies that randomly assigned participants to either a VLCD or nutrients improved weight-loss maintenance by 1.2 kg (95% CI: LCD at baseline. VLCDs were found to induce significantly 0.4, 2.0 kg; P = 0.003; median maintenance phase duration: 6 greater short-term weight change than were LCDs (216% mo), and the use of dietary supplements showed no effect (0.0 compared with 210%), but similar long-term changes (26% kg; 95% CI: 21.4, 1.4 kg; P = 0.99; median maintenance phase compared with 25%) after a 1.9-y follow-up. In most of the duration: 3 mo; Figures 3 and 4). included studies, the maintenance programs did not incorporate WEIGHT-LOSS MAINTENANCE AFTER VLCD/LCD 21 FIGURE 4. Forest plot of control group subtracted weight change (kg) at the end of a weight-loss maintenance program, after an initial very-low-calorie diet or low-calorie diet (,1000 kcal/d), in 20 randomized controlled trials. Data are weighted mean differences from a random-effects model. Error bars depict 95% CIs. The I statistic refers to heterogeneity. CLA, conjugated linoleic acid; E%, percentage of energy; GI, glycemic index. those strategies that the current meta-analysis identified as being derson et al (24) for all the subgroups, except for the anti-obesity beneficial for weight-loss maintenance (anti-obesity drugs, meal drug studies that had a similar follow-up of 22 mo. replacements, and high-protein diets). Weight regain was common during the maintenance phase Anderson et al (24) performed a meta-analysis of 29 long-term (Figures 2 and 3), which highlights the need for an increased observational studies using VLCDs or hypoenergetic balanced understanding of weight-loss defenses. There appear to be $3 diets and found that the VLCD group maintained significantly different drivers behind weight regain after a large weight loss, more net weight loss than the hypoenergetic balanced diet par- including adaptive thermogenesis and reduced energy expendi- ticipants after 5 y (29% compared with 18%). Indeed, an in- ture (37), increased circulation of appetite-mediating hormones creasing number of studies now indicate that a substantial initial (38), and relapse into old habits (39). At least some, if not all, of weight loss predicts a larger long-term net weight loss (2, 34–36). these defenses are mobilized in relation to weight loss (40). In comparison, the current analysis found that most of the weight loss was maintained at the end of follow-up (92% in the Mechanisms behind improved weight-loss maintenance protein studies compared with 75% in the control group, 91% in the anti-obesity drug studies compared with 65% in the control In terms of drug mechanisms, orlistat works by reducing fat group, 86% in the combined category compared with 75% in the uptake, whereas sibutramine reduces appetite. Apart from the 2 control group, 74% in the supplement category compared with randomized controlled trials on sibutramine included in the 74% in the control group; and 66% compared with 49% in the current meta-analysis, James et al (41) also found a large effect of meal replacement category). However, the mean duration of sibutramine on weight-loss maintenance after a 600-kcal/d deficit follow-up in the studies in our meta-analysis of weight main- weight-loss program. Similarly, topiramate (one of the compo- tenance was much shorter (mean follow-up of 5–22 mo, de- nents in Qsymia that is currently approved in the United States)— pending on category) than that in the randomized controlled which acts to reduce energy intake, possibly through increased trials in the meta-analyses by Tsai and Wadden (1) and An- satiety—has been evaluated specifically for weight-loss maintenance 22 JOHANSSON ET AL after a VLCD with similar results to sibutramine (8), which equal importance. A third limitation was that most of the studies indicates that other anti-obesity drugs also may improve weight- analyzed only the participants who completed the studies. The loss maintenance. anti-obesity drug trials (5–7) and the diet and exercise study (26) Meal replacements, rich in nutrients but low in caloric content, were the only studies that provided data from intention-to-treat work both directly and indirectly to reduce energy intake. Be- analyses. The anti-obesity drug studies used last observation cause many obese patients underestimate energy intake (42), carried forward, which includes the last measured value, and, meal replacements can be effective at reducing food choices and similar to the completers analysis, could lead to an overesti- therefore facilitate a balanced energy intake. High-protein diets mation of the treatment effect. Baseline observation carried (w20–30 of energy) have been shown to increase satiety, pre- forward, which includes the baseline values of each missing serve fat-free mass, and sustain energy expenditure via diet- value, could on the other hand lead to an underestimation of the induced thermogenesis (43). treatment effect. Low-glycemic-index foods may also be beneficial in weight control by increasing satiety and possibly by promoting fat Conclusions oxidation at the expense of carbohydrate oxidation. Even though In this meta-analysis of randomized controlled trials, the we did not find that exercise improved weight-loss maintenance, largest improvements in weight-loss maintenance after a VLCD other studies have found exercise to be effective at promoting or LCD were seen for anti-obesity drugs and meal replacements. long-term weight control (4, 44), including after periods of A high-protein diet also improved weight-loss maintenance, as weight loss (36, 45). Indeed, 2 of the 3 included randomized did a combined category consisting of low fat, low glycemic controlled trials on exercise in the current study (22, 23) indicated index, and the Healthy Eating Pyramid. Exercise and dietary improved weight-loss maintenance in the short term. The long- supplements were not associated with improved weight-loss term follow-up data from the same trials were negative, however, maintenance. Future studies are needed to clarify the potential probably because of reduced compliance with the high amounts effect of combining several successful maintenance strategies in of exercise needed for weight control (60–90 min/d) (4, 45). obesity-treatment programs. The authors’ responsibilities were as follows—KJ, MN, and EH: designed Limitations and strengths the research (project conception, development of overall research plan, and Our study had several strengths. First, this was the first meta- study oversight); KJ and EH: conducted the research (hands-on conduct of analysis of randomized controlled trials of weight-loss mainte- the experiments and data collection) and wrote the manuscript; and KJ: had nance strategies after treatment with a VLCD or LCD. Second, primary responsibility for the final content and provided the essential re- agents or materials (applies to authors who contributed by providing ani- we only included randomized controlled trials, meaning they had mals, constructs, databases, etc, necessary for research), analyzed the data, a low probability of bias and other confounding factors in the and performed the statistical analysis. All authors read and approved the final original studies. There was also little variation in effect direction, manuscript. EH received a grant from Cambridge Manufacturing Ltd, North- that is, most studies indicated a positive treatment effect. We were ants, United Kingdom, for the current study. KJ received a grant from Cam- also able to directly test the effects of all 3 investigated treatment bridge Manufacturing Ltd for 2 studies that examined the effect of weight principles: drugs, diet, and exercise. We also synthesized data loss on obstructive sleep apnea (published in the British Medical Journal in from different dietary strategies, which provides clarity in terms 2009 and 2011). MN has been a consultant for Abbott, Sanofi-Aventis, Itrim of which diets promote weight-loss maintenance. Meta-analysis International, and Strategic Health Research. The funders had no role in the design or conduct of the study; analysis or interpretation of the data; or as a method also allows for greater statistical power than in- preparation, review, or approval of the manuscript. dividual trials, which is a common limitation in obesity lifestyle- intervention studies. There were also benefits of studying maintenance after a REFERENCES VLCD or LCD, as opposed to diets with a higher caloric intake. A 1. Tsai AG, Wadden TA. The evolution of very-low-calorie diets: an VLCD induces a larger short-term weight loss than a does a update and meta-analysis. Obesity (Silver Spring) 2006;14:1283–93. standard 1500–1800-kcal/d diet (2), although there is also more 2. Hemmingsson E, Johansson K, Eriksson J, Sundstrom J, Neovius M, Marcus C. Weight loss and dropout during a commercial weight-loss regain (1, 2). We were therefore able to analyze data from trials program including a very-low-calorie diet, a low-calorie diet, or re- in which a large proportion of participants were likely to regain stricted normal food: observational cohort study. Am J Clin Nutr 2012; lost weight. 96:953–61. Our study also had several limitations. Considerable variation 3. Bond DS, Phelan S, Leahey TM, Hill JO, Wing RR. Weight-loss maintenance in successful weight losers: surgical vs non-surgical was observed in study protocols, mainly relating to type of methods. Int J Obes (Lond) 2009;33:173–80. strategy for preventing weight regain and study duration. Most of 4. Klem ML, Wing RR, McGuire MT, Seagle HM, Hill JO. A descriptive the evidence came from dietary strategies, with only 3 ran- study of individuals successful at long-term maintenance of substantial domized controlled trials on the effects of exercise and 3 on anti- weight loss. Am J Clin Nutr 1997;66:239–46. 5. Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, Leutenegger obesity drugs. Whereas our analysis clearly supports the use of E. Long-term maintenance of weight loss after a very-low-calorie diet: anti-obesity drugs, 2 of the 3 drug studies were of sibutramine, a randomized blinded trial of the efficacy and tolerability of sibutr- which was withdrawn in 2010. amine. Am J Med 1999;106:179–84. A second limitation was in the maintenance-phase duration of 6. Mathus-Vliegen EM. Long-term maintenance of weight loss with si- butramine in a GP setting following a specialist guided very-low- the included studies, which varied from 3 to 36 mo (Figure 3). calorie diet: a double-blind, placebo-controlled, parallel group study. Because there were so few studies on weight-loss maintenance Eur J Clin Nutr 2005;59(suppl 1):S31–9. after a VLCD or LCD, we chose not to include a duration re- 7. Richelsen B, Tonstad S, Rossner S, Toubro S, Niskanen L, Madsbad S, striction. Hence, short- and long-term studies were assigned Mustajoki P, Rissanen A. Effect of orlistat on weight regain and WEIGHT-LOSS MAINTENANCE AFTER VLCD/LCD 23 cardiovascular risk factors following a very-low-energy diet in ab- 25. Kamphuis MM, Lejeune MP, Saris WH, Westerterp-Plantenga MS. dominally obese patients: a 3-year randomized, placebo-controlled The effect of conjugated linoleic acid supplementation after weight study. Diabetes Care 2007;30:27–32. loss on body weight regain, body composition, and resting metabolic 8. Astrup A, Caterson I, Zelissen P, Guy-Grand B, Carruba M, Levy B, rate in overweight subjects. Int J Obes Relat Metab Disord 2003;27(7): Sun X, Fitchet M. Topiramate: long-term maintenance of weight loss 840–7. induced by a low-calorie diet in obese subjects. Obes Res 2004;12: 26. Christensen P, Frederiksen P, Bliddal H, Riecke BF, Bartels EM, 1658–69. Henriksen M, Juul-Sorensen T, Gudbergsen H, Winther K, Astrup A, 9. Wadden TA, Fujioka K, Toubro S, Gantz I, Erondu NE, Chen M, et al. Comparison of three different weight maintenance programs on Suryawanshi S, Carofano W, Johnson-Levonas AO, Shapiro DR, et al. cardiovascular risk, bone, and vitamins in sedentary older adults. A randomized trial of lifestyle modification and taranabant for main- Obesity (Silver Spring) (in press). taining weight loss achieved with a low-calorie diet. Obesity (Silver 27. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta- Spring) 2010;18:2301–10. analysis. Stat Med 2002;21:1539–58. 10. Ryttig KR, Flaten H, Rossner S. Long-term effects of a very low 28. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring in- calorie diet (Nutrilett) in obesity treatment. A prospective, randomized, consistency in meta-analyses. BMJ 2003;327:557–60. comparison between VLCD and a hypocaloric diet+behavior modifi- 29. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta- cation and their combination. Int J Obes Relat Metab Disord 1997;21 analysis detected by a simple, graphical test. BMJ 1997;315:629–34. (7):574–9. 30. Pasman WJ, Westerterp-Plantenga MS, Muls E, Vansant G, van Ree J, 11. Ryttig KR, Rossner S. Weight maintenance after a very low calorie diet Saris WH. The effectiveness of long-term fibre supplementation on (VLCD) weight reduction period and the effects of VLCD supple- weight maintenance in weight-reduced women. Int J Obes Relat Metab mentation. A prospective, randomized, comparative, controlled long- Disord 1997;21(7):548–55. term trial. J Intern Med 1995;238:299–306. 31. Olsson J, Sundberg B, Viberg A, Haenni A. Effect of a vegetable-oil 12. Claessens M, van Baak MA, Monsheimer S, Saris WH. The effect of emulsion on body composition; a 12-week study in overweight women a low-fat, high-protein or high-carbohydrate ad libitum diet on weight on a meal replacement therapy after an initial weight loss: a random- loss maintenance and metabolic risk factors. Int J Obes (Lond) 2009; ized controlled trial. Eur J Nutr 2011;50:235–42. 33:296–304. 32. Willett WC. Eat, drink, and be healthy the Harvard Medical School 13. Delbridge EA, Prendergast LA, Pritchard JE, Proietto J. One-year guide to healthy eating. New York, NY: Simon & Schuster, 2001. weight maintenance after significant weight loss in healthy overweight 33. Brownell KD. The LEARN program for weight management: lifestyle, and obese subjects: does diet composition matter? Am J Clin Nutr exercise, attitudes, relationships, nutrition. Dallas, TX: American 2009;90:1203–14. Health Pub. Co, 2004. 14. Hursel R, Westerterp-Plantenga MS. Green tea catechin plus caffeine 34. Astrup A, Rossner S. Lessons from obesity management programmes: supplementation to a high-protein diet has no additional effect on body greater initial weight loss improves long-term maintenance. Obes Rev weight maintenance after weight loss. Am J Clin Nutr 2009;89:822–30. 2000;1:17–9. 15. Larsen TM, Dalskov SM, van Baak M, Jebb SA, Papadaki A, Pfeiffer 35. Wadden TA, Neiberg RH, Wing RR, Clark JM, Delahanty LM, Hill JO, AF, Martinez JA, Handjieva-Darlenska T, Kunesova M, Pihlsgard M, Krakoff J, Otto A, Ryan DH, Vitolins MZ. Four-year weight losses in et al. Diets with high or low protein content and glycemic index for the Look AHEAD study: factors associated with long-term success. weight-loss maintenance. N Engl J Med 2010;363:2102–13. Obesity (Silver Spring) 2011;19:1987–98. 16. Lejeune MP, Kovacs EM, Westerterp-Plantenga MS. Additional protein 36. Saris WH. Very-low-calorie diets and sustained weight loss. Obes Res intake limits weight regain after weight loss in humans. Br J Nutr 2005; 2001;9(suppl 4):295S–301S. 93:281–9. 37. Rosenbaum M, Hirsch J, Gallagher DA, Leibel RL. Long-term per- 17. Westerterp-Plantenga MS, Lejeune MP, Nijs I, van Ooijen M, Kovacs sistence of adaptive thermogenesis in subjects who have maintained EM. High protein intake sustains weight maintenance after body weight a reduced body weight. Am J Clin Nutr 2008;88:906–12. loss in humans. Int J Obes Relat Metab Disord 2004;28(1):57–64. 38. Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, 18. Due A, Larsen TM, Mu H, Hermansen K, Stender S, Astrup A. Kriketos A, Proietto J. Long-term persistence of hormonal adaptations Comparison of 3 ad libitum diets for weight-loss maintenance, risk of to weight loss. N Engl J Med 2011;365:1597–604. cardiovascular disease, and diabetes: a 6-mo randomized, controlled 39. Elfhag K, Rossner S. Who succeeds in maintaining weight loss? A trial. Am J Clin Nutr 2008;88:1232–41. conceptual review of factors associated with weight loss maintenance 19. Kovacs EM, Lejeune MP, Nijs I, Westerterp-Plantenga MS. Effects of and weight regain. Obes Rev 2005;6:67–85. green tea on weight maintenance after body-weight loss. Br J Nutr 40. Maclean PS, Bergouignan A, Cornier MA, Jackman MR. Biology’s 2004;91:431–7. response to dieting: the impetus for weight regain. Am J Physiol Regul 20. Gripeteg L, Torgerson J, Karlsson J, Lindroos AK. Prolonged refeeding Integr Comp Physiol 2011;301:R581–600. improves weight maintenance after weight loss with very-low-energy 41. James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris diets. Br J Nutr 2010;103:141–8. WH, Van Gaal LF. Effect of sibutramine on weight maintenance after 21. Wikstrand I, Torgerson J, Bostrom KB. Very low calorie diet (VLCD) weight loss: a randomised trial. STORM Study Group. Sibutramine followed by a randomized trial of corset treatment for obesity in pri- Trial of Obesity Reduction and Maintenance. Lancet 2000;356: mary care. Scand J Prim Health Care 2010;28:89–94. 2119–25. 22. Borg P, Kukkonen-Harjula K, Fogelholm M, Pasanen M. Effects of 42. Lichtman SW, Pisarska K, Berman ER, Pestone M, Dowling H, Of- walking or resistance training on weight loss maintenance in obese, fenbacher E, Weisel H, Heshka S, Matthews DE, Heymsfield SB. middle-aged men: a randomized trial. Int J Obes Relat Metab Disord Discrepancy between self-reported and actual caloric intake and ex- 2002;26(5):676–83. ercise in obese subjects. N Engl J Med 1992;327:1893–8. 23. Fogelholm M, Kukkonen-Harjula K, Nenonen A, Pasanen M. Effects 43. Westerterp-Plantenga MS, Lemmens SG, Westerterp KR. Dietary of walking training on weight maintenance after a very-low-energy diet protein—its role in satiety, energetics, weight loss and health. Br J Nutr in premenopausal obese women: a randomized controlled trial. Arch 2012;108(suppl 2):S105–12. Intern Med 2000;160:2177–84. 44. Curioni CC, Lourenco PM. Long-term weight loss after diet and ex- 24. Anderson JW, Konz EC, Frederich RC, Wood CL. Long-term weight- ercise: a systematic review. Int J Obes (Lond) 2005;29:1168–74. loss maintenance: a meta-analysis of US studies. Am J Clin Nutr 2001; 45. Fogelholm M, Kukkonen-Harjula K. Does physical activity prevent 74:579–84. weight gain–a systematic review. Obes Rev 2000;1:95–111. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The American Journal of Clinical Nutrition Pubmed Central

Effects of anti-obesity drugs, diet, and exercise on weight-loss maintenance after a very-low-calorie diet or low-calorie diet: a systematic review and meta-analysis of randomized controlled trials123

The American Journal of Clinical Nutrition , Volume 99 (1) – Oct 30, 2013

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Pubmed Central
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© 2014 American Society for Nutrition
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0002-9165
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1938-3207
DOI
10.3945/ajcn.113.070052
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Abstract

Effects of anti-obesity drugs, diet, and exercise on weight-loss maintenance after a very-low-calorie diet or low-calorie diet: a systematic review and meta-analysis of randomized 1–3 controlled trials Kari Johansson, Martin Neovius, and Erik Hemmingsson ABSTRACT loss requires substantial behavioral efforts, especially when non- Background: Weight-loss maintenance remains a major challenge bariatric surgical methods are used (3, 4). in obesity treatment. Effects of different maintenance strategies after a VLCD have Objective: The objective was to evaluate the effects of anti-obesity been tested in randomized trials, such as anti-obesity drugs (5–9), drugs, diet, or exercise on weight-loss maintenance after an ini- meal replacements (10, 11), high-protein diets (12–17), low- tial very-low-calorie diet (VLCD)/low-calorie diet (LCD) period glycemic-index diets (15), low-fat diets (18), green tea extracts (,1000 kcal/d). (14, 19), a prolonged refeeding period (20), waist corsets (21), Design: We conducted a systematic review by using MEDLINE, the and exercise (22, 23). The effects of these maintenance strategies Cochrane Controlled Trial Register, and EMBASE from January remain unclear, and previous meta-analyses that investigated 1981 to February 2013. We included randomized controlled trials long-term effects of a VLCD have only compared the effects of that evaluated weight-loss maintenance strategies after a VLCD/ VLCDs with LCDs (1, 24). LCD period. Two authors performed independent data extraction The aim of this systematic review and meta-analysis was to by using a predefined data template. All pooled analyses were based quantify the effects of anti-obesity drugs, diet, and exercise on on random-effects models. weight-loss maintenance after a VLCD or LCD. We included Results: Twenty studies with a total of 27 intervention arms and 3017 randomized controlled trials in which all participants started with participants were included with the following treatment categories: a VLCD or LCD (caloric intake cutoff set at ,1000 kcal/d) and anti-obesity drugs (3 arms; n = 658), meal replacements (4 arms; thereafter were randomly assigned to either a maintenance n = 322), high-protein diets (6 arms; n = 865), dietary supplements strategy or control or placebo. (6 arms; n = 261), other diets (3 arms; n = 564), and exercise (5 arms; n = 347). During the VLCD/LCD period, the pooled mean weight change was 212.3 kg (median duration: 8 wk; range 3–16 wk). MATERIALS AND METHODS Compared with controls, anti-obesity drugs improved weight-loss Data sources and searches maintenance by 3.5 kg [95% CI: 1.5, 5.5 kg; median duration: 18 mo (12–36 mo)], meal replacements by 3.9 kg [95% CI: 2.8, 5.0 kg; A systematic search of 3 bibliographic databases [MEDLINE median duration: 12 mo (10–26 mo)], and high-protein diets by 1.5 kg (http://www.ncbi.nlm.nih.gov/pubmed), EMBASE (http://www. [95% CI: 0.8, 2.1 kg; median duration: 5 mo (3–12 mo)]. Exercise embase.com), and Cochrane Controlled Trials Register (http:// [0.8 kg; 95% CI: 21.2, 2.8 kg; median duration: 10 mo (6–12 mo)] www.thecochranelibrary.com)] from 1981 to February 2013 was and dietary supplements [0.0 kg; 95% CI: 21.4, 1.4 kg; median performed by using 3 search strings: 1)“VLED”or“VLCD” or “very duration: 3 mo (3–14 mo)] did not significantly improve weight-loss low energy diet” or “very low calorie diet,” 2) “LED” or “LCD” or maintenance compared with control. “low energy diet” or “low calorie diet,” and 3) “weight loss main- Conclusion: Anti-obesity drugs, meal replacements, and high- tenance” or “maintained weight loss” or “weight maintenance” or protein diets were associated with improved weight-loss maintenance after a VLCD/LCD period, whereas no significant improvements 1 From the Clinical Epidemiology Unit (KJ and MN) and the Obesity Center were seen for dietary supplements and exercise. Am J Clin (EH), Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Nutr 2014;99:14–23. Supported in part by a grant from Cambridge Manufacturing Ltd, North- ants, United Kingdom (to EH). This is a free access article, distributed under terms (http://www.nutrition.org/publications/guidelines-and-policies/license/) that permit unrestricted noncommercial use, distribution, and reproduction in INTRODUCTION any medium, provided the original work is properly cited. Treatment with a very-low-calorie diet (VLCD; ,800 kcal/d) Address correspondence and reprint requests to K Johansson, Clinical Ep- or low-calorie diet (LCD; ,1200 kcal/d) is associated with idemiology Unit, Department of Medicine, Karolinska Institutet, SE-171 76, substantial initial weight loss, but also greater weight regain Stockholm, Sweden. E-mail: kari.johansson@ki.se. compared with weight loss achieved through a more moderate Received July 9, 2013. Accepted for publication October 10, 2013. restriction in energy intake (1, 2). Maintaining a large weight First published online October 30, 2013; doi: 10.3945/ajcn.113.070052. 14 Am J Clin Nutr 2014;99:14–23. Printed in USA.  2014 American Society for Nutrition WEIGHT-LOSS MAINTENANCE AFTER VLCD/LCD 15 “weight regain.” The search was limited to humans, randomized Data synthesis and analysis controlled trials, English language publications, and adults in Primary outcome the databases where limitations were possible (MEDLINE and The primary outcome was the weighted mean difference in EMBASE). The reference lists of identified articles were also weight change (kg) during the weight-loss maintenance phase searched for additional studies, as were reference lists of previously between the intervention and control groups. The random-effects published reviews. Two reviewers (KJ and EH) separately screened model was used to weight and pool the studies within each the abstracts for inclusion or exclusion. Full text articles were maintenance category (anti-obesity drug, diet, and exercise). The retrieved from all abstracts that were potentially relevant and were diet studies were further subdivided into high-protein diet, meal reviewed independently by the 2 researchers. In case of conflicting replacement, dietary supplements, and macronutrients other than views, a third researcher (MN) was asked to resolve the conflict. protein, including low glycemic index, low fat, and eating ac- cording to the Healthy Eating Pyramid. Heterogeneity between studies was assessed by the I statistic Study selection (27), and if this exceeded 50% or was statistically significant, Studies were included if they were randomized controlled the reasons for heterogeneity were explored by subgroup anal- trials of adults (age $18 y), and consisted of an initial weight- yses or meta-regression. Low, moderate, and high heterogeneity loss period with a VLCD or LCD (,1000 kcal/d) followed by were defined according to cutoffs of 25%, 50%, and 75%, re- randomization to a maintenance strategy (anti-obesity drug, diet, spectively (28). To investigate possible publication bias, a funnel and/or exercise) or control. No restrictions regarding study du- plot of the inverse of the SE was inspected visually, and statistical ration were imposed. Studies were excluded if they evaluated significance was calculated by using Egger’s test (29). anti-obesity drugs that never reached approval by regulatory agencies or if the weight-loss period did not include a VLCD or Secondary outcome LCD. Sibutramine and rimonabant were eligible for inclusion A secondary aim was to illustrate weight change after the because they had been approved and widely used as anti-obesity VLCD or LCD phase and weight-loss maintenance phase within drugs before being withdrawn from the market in 2010 and each treatment arm. The random-effects model was used to weight 2009, respectively. and pool the weight changes within each treatment and control arm during the maintenance period. The mean monthly change was es- Data extraction and quality assessment timated from these 2 measurements. The statistical analyses were Data on participants, interventions, weight loss, and weight- conducted by using Comprehensive Meta Analysis (version 2; Biostat Inc). P values ,0.05 were regarded as statistically significant. loss maintenance were extracted by 2 researchers (KJ and EH) independently by using predefined data templates. Disagree- ments were resolved through discussion. For the meta-analysis, RESULTS data on number of subjects and mean changes with corresponding SDs in the intervention and control arm were extracted. Many Study selection studies did not report these values. In those cases, SDs and mean The systematic search resulted in 20 randomized controlled changes were calculated from other data (see “Supplemental trials that met the inclusion criteria (Figure 1), which included data” in the online issue). 27 intervention arms with 3017 participants. Of these, 3 arms Five studies included .2 arms (14, 15, 18, 25, 26). Weighted evaluated anti-obesity drugs (n = 658), 4 meal replacements mean differences were calculated between the 2 groups that (n = 322), 6 high-protein diets (n = 865), 6 dietary supplements showed the most resemblance to other studies in the treatment (n = 261), 3 other diets (n = 564), and 5 exercise (n = 347). category. Larsen et al (15) reported both the isolated and com- bined effects of a high-protein diet and a low-glycemic-index diet. In the meta-analysis, the isolated main effects of high protein Study characteristics compared with low protein and low glycemic index compared Participants with high glycemic index were included. Due et al (18) reported Participant characteristics were similar, with a greater pro- the effect of 2 interventions (low fat and the Healthy Eating portion of women than men in most of the studies (Table 1). The Pyramid, which is high in MUFAs and has a low glycemic in- mean age ranged between 28 and 48 y and mean BMI (kg/m ) dex), and both treatment arms were included and compared with between 27.9 and 41.6. All studies but one were from Europe; the control group. In the study by Hursel et al (14), the green tea most were from the Netherlands (6, 12, 14, 16, 17, 19, 25, 30) effect was analyzed by comparing the green tea/adequate-protein and Scandinavia (7, 10, 11, 18, 20, 22, 23, 26, 31), and the re- group with the placebo/adequate-protein group, and the high- maining 3 studies were from France (5), Australia (13), or 8 protein effect was analyzed by comparing the green tea/high- European countries (multicenter study) (15). protein with the green tea/adequate-protein group. The study by Kamphuis et al (25) included 2 different doses of conjugated VLCD/LCD period linoleic acid (1.8 and 3.6 g) compared with placebo (1.8 and 3.6 g). Both doses were included. During the weight-loss phase preceding the randomization, 18 Two reviewers (KJ and EH) independently evaluated the in- of the 20 studies used a VLCD (,800 kcal/d), whereas 2 studies dividual studies regarding the extent of loss to follow-up and (15, 18) used an LCD of 800 to 1000 kcal/d. Eight of the studies the adequacy of randomization and concealment of allocation, used a strict VLCD, ie, no other food was allowed except for the blinding of patients, data collectors, and outcome assessors. VLCD powder mixed with water (6, 7, 10, 11, 20, 22, 23, 25). In 16 JOHANSSON ET AL the intervention and control groups were advised to consume a 600-kcal deficit diet based on their estimated energy expen- diture. In the third study the participants were advised to follow the French nutrition guidelines (5). Diet studies Of the diet studies/study arms, 6 evaluated a high-protein diet, 6 dietary supplements with a suggested satiating or thermic effect, 4 meal replacements or a prolonged refeeding, and 3 macronutrients other than protein, including low glycemic index, low fat, and eating according to the Healthy Eating Pyramid (32). In addition to the specific maintenance intervention, 10 of the 15 diet studies reported using a co-intervention, such as in- structions to the participants to maintain their habitual physical activity levels, dietitian visits, and cooking classes. Two of the studies also supplied the participants with free food from a study supermarket (15, 18). Exercise studies The 3 exercise studies (22, 23, 26) investigated resistance training, walking, and arthritis-adapted knee exercises, respec- tively. During the active treatment period, both groups were given dietary counseling based on the LEARN manual (33) in the study by Borg et al (22), and group meetings were given in the study by Fogelholm et al (23); only arthritis-tailored knee exercises were given in the study by Christensen et al (26). Risk of bias Most studies did not report the randomization process, but simply stated that the participants were randomized. All studies specified the eligibility criteria, and characteristics were similar FIGURE 1. Flowchart of included studies. RCT, randomized controlled for the intervention and control groups at randomization in all trial. studies. Seven (5–7, 14, 19, 25, 31) of the studies were double- 7 of the studies, the participants were allowed to consume blind. Most of the studies only analyzed and reported data on vegetables (12–17, 19), and in 2 of the studies the powder for- completers, except for the anti-obesity drug studies and the diet mulas were mixed with milk (26) or a small ad libitum breakfast and exercise study by Christensen et al (26), which analyzed all was allowed within the 800-kcal/d limit (31). the included participants. (An intention-to-treat analysis with last observation carried forward analysis for missing data were Weight-loss maintenance period used in all the anti-obesity drug studies, whereas baseline ob- servation carried forward was used in the diet and exercise study After the weight-loss phase the participants were randomly by Christensen et al). assigned to a maintenance intervention or a control group. Most (n = 11; 55%) of the studies randomly assigned participants only if they had lost 5–10% of the initial weight during the VLCD or Main findings LCD period. This applied for all of the drug studies (5–7) and VLCD/LCD period 8 of the 14 diet studies (12, 13, 15, 16, 18, 20, 30, 31) but not for During the VLCD or LCD run-in period, before random- the exercise studies, for which all the participants were ran- ization, the pooled mean weight change was 212.4 kg (95% domly assigned despite weight loss. CI: 216.6, 28.2; median weight-loss phase duration: 8 wk) for The duration of the maintenance period ranged from 3 mo to 3 y the anti-obesity drug studies, 211.1 kg (95% CI: 212.1, 210.1; (Figure 2). Twelve of the 20 studies had a maintenance period median weight-loss phase duration: 8 wk) for the diet studies, of ,1 y, with an overrepresentation of short maintenance pe- and 213.5 kg (95% CI: 214.0, 213.0 median weight-loss phase riods among the diet studies (10 of 14). All included drug duration: 12 wk) for the exercise studies (Figure 3). studies had a maintenance period of .1 y. The 2 studies that studied exercise exclusively had an active maintenance period of Weight-loss maintenance period ,1 y, but both included a 2-y unsupervised follow-up (22, 23). Weight regain during the maintenance period differed between Anti-obesity drug studies individual studies, ranging from a further mean weight change Of the 3 anti-obesity drug studies, 2 evaluated sibutramine (5, of 25 kg to a regain of 14 kg in the intervention groups and 6) and 1 orlistat (7). In 2 (6, 7) of the 3 studies, participants in both from 21 kg to a gain of 13 kg in the control groups (Figure 2). WEIGHT-LOSS MAINTENANCE AFTER VLCD/LCD 17 TABLE 1 Description of included randomized controlled trials (n = 20) that evaluated the success of drugs, diet, and exercise strategies at improving weight-loss maintenance after an initial period of weight loss with a VLCD or LCD (,1000 kcal/d) Characteristics before weight loss Weight-loss period (VLCD/LCD) Weight-loss maintenance period Participants Participants who Weight randomly assigned completed Author Age Women BMI Weight Subjects Energy Duration loss Intervention Control (Trt/Ctrl) (Trt/Ctrl) Duration y % kg/m kg n kcal/d mo kg n n mo Anti-obesity drugs Richelsen, 2007 (7) 47 51 37.5 111 383 600–800 2 214.4 Orlistat (360 mg/d) Placebo 309 (153/156) 201 (103/98) 36 Mathus-Vliegen, 2005 (6) 43 86 36.6 105 221 480 3 215.2 Sibutramine (10 mg/d) Placebo 189 (94/95) 120 (62/58) 18 Apfelbaum, 1999 (5) 38 79 38.3 104 205 220–800 1 27.6 Sibutramine (10 mg/d) Placebo 160 (82/78) 108 (60/48) 12 Diet: protein Delbridge, 2009 (13) 44 50 39.0 112 179 500–550 3 216.5 High protein: 30 E% High carbohydrate: 15 E% 141 (71/70) 82 (42/40) 12 protein, ,30 E% fat protein, ,30 E% fat Claessens, 2009 (12) 45 65 32.9 97 60 500 1.25 29.4 High protein: 25 E% High carbohydrate: 15 E% 54 (NR/NR) 48 (32/16) 3 protein, 30 E% fat protein, 30 E% fat Lejeune, 2005 (16) 45 NR 29.3 83 120 502 1 26.3 High protein: +30 g/ Habitual diet 113 (53/60) 113 (53/60) 6 d(w18–20 E%) Westerterp-Plantenga, 44 NR 29.5 87 180 502 1 26.4 High protein: +48 g/ Habitual diet 150 (NR/NR) 148 (73/75) 3 2004 (17) d(w18–20 E%) Diet: protein and other macronutrients Larsen, 2010 (15) 42 NR 34.2 99 938 800–1000 2 211 Low protein (13 E%) & Country-specific dietary 773 (150/154) 548 (106/114) 6.5 low GI guidelines (in all 5 diets: fat 25–30 E%) Low protein (13 E%) & Country-specific dietary (155/154) (97/114) high GI guidelines (in all 5 diets: fat 25–30 E%) High protein (25 E%) & Country-specific dietary (159/154) (124/114) low GI guidelines (in all 5 diets: fat 25–30 E%) High protein (25 E%) & Country-specific dietary (155/154) (107/114) high GI guidelines (in all 5 diets: fat 25–30 E%) Due, 2008 (18) 28 58 31.5 95 154 800–1000 2 212.8 Healthy Pyramid: 35–45 Western diet 35 E% fat, 131 (54/26) 106 (39/24) 6 E% fat, 10–20 E% 10–20 E% protein protein Low fat: 20–30 E% fat, Western diet 35 E% fat, (51/26) (43/24) 10–20 E% protein 10–20 E% protein (Continued) 18 JOHANSSON ET AL TABLE 1 (Continued) Characteristics before weight loss Weight-loss period (VLCD/LCD) Weight-loss maintenance period Participants Participants who Weight randomly assigned completed Author Age Women BMI Weight Subjects Energy Duration loss Intervention Control (Trt/Ctrl) (Trt/Ctrl) Duration Diet: protein and supplements Hursel 2009 (14) 44 55 29.6 85 92 502 1 27.0 Green tea (2.7 g/d) + Placebo + protein (10 E%) 80 (20/20) 80 (20/20) 3 protein (10 E%) Green tea (2.7 g/d) + high Placebo + high protein (20 80 (20/20) 80 (20/20) 3 protein (20 E%) E%) Kovacs, 2004 (19) NR 75 29.7 85 120 502 1 26.4 Green tea capsules (2.7 g/ Placebo 104 (51/53) 104 (51/53) 3.25 d) Pasman, 1997 (30) 41 100 32.9 89 49 478 2 210.7 Fiber supplement (guar Habitual diet (no fiber 39 (NR/NR) 20 (10/10) 14 gum 20 g/d) supplement) Kamphuis, 2003 (25) 38 52 27.9 84 60 502 0.75 25.9 CLA 1.8 g/d Placebo 1.8 g/d NR (NR/NR) 54 (14/13) 3.25 CLA 3.6 g/d Placebo 3.6 g/d NR (NR/NR) NR (13/14) 3.25 Olsson, 2011 (31) 48 100 28.3 94 54 444–557 1.5 27.1 Meal replacement for Meal replacement for 46 (23/23) 43 (22/21) 3 lunch (adding lunch (placebo; vegetable-oil emulsion; containing dairy fat 160 160 kcal/d) kcal/d) Diet: meal replacement and prolonged refeeding Gripeteg, 2010 (20) 41 64 41.6 124 269 479–813 3 216.5 Prolonged refeeding (6 Normal refeeding (1 wk) 169 (85/84) 123 (65/58) 10 wk) Ryttig, 1997 (10) 44 56 37.7 113 54 420 2 218.9 Meal replacement (1600 Hypocaloric (1600 kcal/d) 54 (27/27) 26 (15/11) 26 kcal/d; 240 kcal as replacement) Ryttig, 1995 (11) 42 80 39.1 112 60 330 3 220.8 Meal replacement (1600 Hypocaloric (1600 kcal/d) 52 (NR/NR) 45 (23/22) 12 kcal/d; 220 kcal/d as replacement) Diet and exercise Christensen, 2013 (26) 63 81 37.3 103.2 192 415–810 2+2 212.8 Meal replacement with Usual care 192 (64/64) 159 (55/52) 12 + 1200 dietary education (one 137-kcal meal replacement/d) Exercise Usual care 192 (64/64) 159 (52/52) 12 Exercise 6mo 4 Borg, 2002 (22) 43 0 32.9 106 90 500 2 214.3 Walking Diet counseling 82 (25/29) 68 (25/28/29 )6+23 23mo Exercise Diet counseling (28/29) (20/26/22 ) 10mo 4 Fogelholm, 2000 (23) 40 100 34.0 92 85 646 3 213.1 Walking: 1004 kcal/wk Diet counseling 82 (26/29) 80 (25/27/28 )10 + 24 24mo Walking: 2008 kcal/wk Diet counseling (27/29) (25/27/28 ) CLA, conjugated linoleic acid; Ctrl, control group; E%, percentage of energy; GI, glycemic index; LCD, low-calorie diet; NR, not reported; Trt, treatment group; VLCD, very-low-calorie diet. In this study, the dietary guidelines group is called “the high-carbohydrate group.” The composition of the diet, however, is equivalent to the Nordic Nutrition Recommendations 2004 (55 E% carbohydrates, 15 E% protein, 30 E% fat); hence, it was used as the control group. Healthy Pyramid corresponds to Willett’s new Healthy Eating Pyramid, which is high in MUFAs and has a low GI; .20% of the prescribed fat was MUFAs. The low-fat diet corresponded to the Nordic Nutrition Recommendations (low in fat and a medium GI), and the average Danish diet (similar to the Western diet; high in SUFAs and a high GI) represented the control group. Unsupervised follow-up. WEIGHT-LOSS MAINTENANCE AFTER VLCD/LCD 19 FIGURE 2. Overview of body weight changes in the included randomized controlled trials (n = 20) that evaluated different anti-obesity drugs, diet, and exercise weight-loss maintenance strategies after an initial very-low-calorie diet or low-calorie diet (,1000 kcal/d). CLA, conjugated linoleic acid; GI, glycemic index. 20 JOHANSSON ET AL Exercise Exercise as compared with diet counseling did not improve weight-loss maintenance (weighted mean difference: 0.8 kg; 95% CI: 21.2, 2.8; P = 0.43; median maintenance phase duration: 10 mo). There was significant heterogeneity in the exercise trials (I = 78%, P = 0.001), which was explained by the study by Christensen et al (26), which had a negative treatment effect, ie, worse weight-loss maintenance (Figure 4). When only the 2 studies that focused solely on exercise (22, 23) were included, weight-loss maintenance was significantly improved (weighted mean difference: 1.6 kg; 95% CI: 0.3, 2.9 kg; P = 0.02; median maintenance phase duration: 8 mo; I = 10%, P = 0.34). In the analysis of the unsupervised follow-up included in these 2 studies (22, 23), weight-loss maintenance was not improved (weighted mean difference: 20.7 kg; 95% CI: 23.0, 1.8; P = 0.63; median unsupervised follow-up duration: 24 mo). FIGURE 3. Overview of changes in body weight during the rapid weight- loss phase and the weight-loss maintenance period in 20 randomized con- trolled trials that evaluated different anti-obesity drug, diet, and exercise Publication bias and meta-regression weight-loss maintenance strategies after an initial very-low-calorie diet or low-calorie diet (,1000 kcal/d). The gray lines represent the control subjects No evidence of publication bias could be detected for any in each subcategory. Anti-obesity drugs: sibutramine and orlistat. Dietary of the maintenance strategies neither based on the Egger’s test supplements: green tea, high fiber, oil supplement, and conjugated linoleic (P-drug = 0.28, P-diet = 0.88, P-exercise = 0.08) nor by visual acid. Other macronutrients: low fat, low glycemic index, and Healthy Eating inspection of funnel plots (see Supplemental Figure 1 under Pyramid. The random-effects model was used to weight and pool the studies within each treatment arm (intervention and control) after the very-low- “Supplemental data” in the online issue). The heterogeneity calorie diet or low-calorie diet period and maintenance period. The mean in- within each treatment category was largely diminished after crease for each month was estimated from these 2 measurements. Weighted conducting subgroup analyses as described above and was not mean differences between the intervention and control groups at follow-up explained by varying weight-loss magnitudes across the control were estimated by using a random-effects model. groups (b: 20.2; 95% CI: 20.4, 0.1; P = 0.2) or by differences in study duration when investigated via meta-regression (b: 0.1; 95% CI: 20.2, ,0.1; P = 0.2; see Supplemental Figure 2 under Anti-obesity drug studies “Supplemental data” in the online issue). Use of an anti-obesity drug compared with placebo improved weight-loss maintenance by 3.5 kg (95% CI: 1.5, 5.5 kg; P , DISCUSSION 0.001; median maintenance phase duration: 18 mo; Figure 3 and Figure 4). There was evidence of significant heterogeneity (I = Summary 70%, P = 0.04). This heterogeneity was explained by the study by Apfelbaum et al (5), in which the participants in the sibutr- In this meta-analysis of 20 randomized controlled trials, we amine arm continued to lose weight during the maintenance found that both anti-obesity drugs and extended use of low- period. In a sensitivity analysis that excluded this study, the calorie meal replacements improved weight-loss maintenance heterogeneity disappeared (I = 0%, P = 0.88). relative to controls. A high-protein diet was also associated with improved maintenance, although smaller than for meal re- placements and drugs. A combined category consisting of low Diet studies fat, low glycemic index, and the Healthy Eating Pyramid was Overall, the diet maintenance strategies improved weight-loss also associated with improved maintenance, similar in effect to maintenance by 1.4 kg (95% CI: 0.7, 2.1 kg; P , 0.001; median eating a high-protein diet. Exercise and dietary supplementation maintenance phase duration: 6 mo) compared with the control strategies—such as green tea, high fiber, conjugated linoleic group. A significant degree of heterogeneity (I = 63%, P , acid, and oil supplementation—were not associated with im- 0.001) was explained by the different dietary strategies. proved maintenance. After the dietary studies were stratified into subcategories, extended use of meal replacements and prolonged refeeding Previous research improved weight-loss maintenance by 3.9 kg (95% CI: 2.8, 5.5 kg; P , 0.001; median maintenance phase duration: 12 mo) Previous meta-analyses investigating long-term effects of compared with controls. A high-protein diet improved weight- a VLCD or LCD (1, 24) have not included analyses of weight- loss maintenance by 1.5 kg (95% CI: 0.8, 2.1 kg; P , 0.001; loss-maintenance strategies. Tsai and Wadden (1) included median maintenance phase duration: 5 mo), nonprotein macro- studies that randomly assigned participants to either a VLCD or nutrients improved weight-loss maintenance by 1.2 kg (95% CI: LCD at baseline. VLCDs were found to induce significantly 0.4, 2.0 kg; P = 0.003; median maintenance phase duration: 6 greater short-term weight change than were LCDs (216% mo), and the use of dietary supplements showed no effect (0.0 compared with 210%), but similar long-term changes (26% kg; 95% CI: 21.4, 1.4 kg; P = 0.99; median maintenance phase compared with 25%) after a 1.9-y follow-up. In most of the duration: 3 mo; Figures 3 and 4). included studies, the maintenance programs did not incorporate WEIGHT-LOSS MAINTENANCE AFTER VLCD/LCD 21 FIGURE 4. Forest plot of control group subtracted weight change (kg) at the end of a weight-loss maintenance program, after an initial very-low-calorie diet or low-calorie diet (,1000 kcal/d), in 20 randomized controlled trials. Data are weighted mean differences from a random-effects model. Error bars depict 95% CIs. The I statistic refers to heterogeneity. CLA, conjugated linoleic acid; E%, percentage of energy; GI, glycemic index. those strategies that the current meta-analysis identified as being derson et al (24) for all the subgroups, except for the anti-obesity beneficial for weight-loss maintenance (anti-obesity drugs, meal drug studies that had a similar follow-up of 22 mo. replacements, and high-protein diets). Weight regain was common during the maintenance phase Anderson et al (24) performed a meta-analysis of 29 long-term (Figures 2 and 3), which highlights the need for an increased observational studies using VLCDs or hypoenergetic balanced understanding of weight-loss defenses. There appear to be $3 diets and found that the VLCD group maintained significantly different drivers behind weight regain after a large weight loss, more net weight loss than the hypoenergetic balanced diet par- including adaptive thermogenesis and reduced energy expendi- ticipants after 5 y (29% compared with 18%). Indeed, an in- ture (37), increased circulation of appetite-mediating hormones creasing number of studies now indicate that a substantial initial (38), and relapse into old habits (39). At least some, if not all, of weight loss predicts a larger long-term net weight loss (2, 34–36). these defenses are mobilized in relation to weight loss (40). In comparison, the current analysis found that most of the weight loss was maintained at the end of follow-up (92% in the Mechanisms behind improved weight-loss maintenance protein studies compared with 75% in the control group, 91% in the anti-obesity drug studies compared with 65% in the control In terms of drug mechanisms, orlistat works by reducing fat group, 86% in the combined category compared with 75% in the uptake, whereas sibutramine reduces appetite. Apart from the 2 control group, 74% in the supplement category compared with randomized controlled trials on sibutramine included in the 74% in the control group; and 66% compared with 49% in the current meta-analysis, James et al (41) also found a large effect of meal replacement category). However, the mean duration of sibutramine on weight-loss maintenance after a 600-kcal/d deficit follow-up in the studies in our meta-analysis of weight main- weight-loss program. Similarly, topiramate (one of the compo- tenance was much shorter (mean follow-up of 5–22 mo, de- nents in Qsymia that is currently approved in the United States)— pending on category) than that in the randomized controlled which acts to reduce energy intake, possibly through increased trials in the meta-analyses by Tsai and Wadden (1) and An- satiety—has been evaluated specifically for weight-loss maintenance 22 JOHANSSON ET AL after a VLCD with similar results to sibutramine (8), which equal importance. A third limitation was that most of the studies indicates that other anti-obesity drugs also may improve weight- analyzed only the participants who completed the studies. The loss maintenance. anti-obesity drug trials (5–7) and the diet and exercise study (26) Meal replacements, rich in nutrients but low in caloric content, were the only studies that provided data from intention-to-treat work both directly and indirectly to reduce energy intake. Be- analyses. The anti-obesity drug studies used last observation cause many obese patients underestimate energy intake (42), carried forward, which includes the last measured value, and, meal replacements can be effective at reducing food choices and similar to the completers analysis, could lead to an overesti- therefore facilitate a balanced energy intake. High-protein diets mation of the treatment effect. Baseline observation carried (w20–30 of energy) have been shown to increase satiety, pre- forward, which includes the baseline values of each missing serve fat-free mass, and sustain energy expenditure via diet- value, could on the other hand lead to an underestimation of the induced thermogenesis (43). treatment effect. Low-glycemic-index foods may also be beneficial in weight control by increasing satiety and possibly by promoting fat Conclusions oxidation at the expense of carbohydrate oxidation. Even though In this meta-analysis of randomized controlled trials, the we did not find that exercise improved weight-loss maintenance, largest improvements in weight-loss maintenance after a VLCD other studies have found exercise to be effective at promoting or LCD were seen for anti-obesity drugs and meal replacements. long-term weight control (4, 44), including after periods of A high-protein diet also improved weight-loss maintenance, as weight loss (36, 45). Indeed, 2 of the 3 included randomized did a combined category consisting of low fat, low glycemic controlled trials on exercise in the current study (22, 23) indicated index, and the Healthy Eating Pyramid. Exercise and dietary improved weight-loss maintenance in the short term. The long- supplements were not associated with improved weight-loss term follow-up data from the same trials were negative, however, maintenance. Future studies are needed to clarify the potential probably because of reduced compliance with the high amounts effect of combining several successful maintenance strategies in of exercise needed for weight control (60–90 min/d) (4, 45). obesity-treatment programs. The authors’ responsibilities were as follows—KJ, MN, and EH: designed Limitations and strengths the research (project conception, development of overall research plan, and Our study had several strengths. First, this was the first meta- study oversight); KJ and EH: conducted the research (hands-on conduct of analysis of randomized controlled trials of weight-loss mainte- the experiments and data collection) and wrote the manuscript; and KJ: had nance strategies after treatment with a VLCD or LCD. Second, primary responsibility for the final content and provided the essential re- agents or materials (applies to authors who contributed by providing ani- we only included randomized controlled trials, meaning they had mals, constructs, databases, etc, necessary for research), analyzed the data, a low probability of bias and other confounding factors in the and performed the statistical analysis. All authors read and approved the final original studies. There was also little variation in effect direction, manuscript. EH received a grant from Cambridge Manufacturing Ltd, North- that is, most studies indicated a positive treatment effect. We were ants, United Kingdom, for the current study. KJ received a grant from Cam- also able to directly test the effects of all 3 investigated treatment bridge Manufacturing Ltd for 2 studies that examined the effect of weight principles: drugs, diet, and exercise. We also synthesized data loss on obstructive sleep apnea (published in the British Medical Journal in from different dietary strategies, which provides clarity in terms 2009 and 2011). MN has been a consultant for Abbott, Sanofi-Aventis, Itrim of which diets promote weight-loss maintenance. Meta-analysis International, and Strategic Health Research. The funders had no role in the design or conduct of the study; analysis or interpretation of the data; or as a method also allows for greater statistical power than in- preparation, review, or approval of the manuscript. dividual trials, which is a common limitation in obesity lifestyle- intervention studies. There were also benefits of studying maintenance after a REFERENCES VLCD or LCD, as opposed to diets with a higher caloric intake. A 1. Tsai AG, Wadden TA. The evolution of very-low-calorie diets: an VLCD induces a larger short-term weight loss than a does a update and meta-analysis. Obesity (Silver Spring) 2006;14:1283–93. standard 1500–1800-kcal/d diet (2), although there is also more 2. Hemmingsson E, Johansson K, Eriksson J, Sundstrom J, Neovius M, Marcus C. Weight loss and dropout during a commercial weight-loss regain (1, 2). We were therefore able to analyze data from trials program including a very-low-calorie diet, a low-calorie diet, or re- in which a large proportion of participants were likely to regain stricted normal food: observational cohort study. Am J Clin Nutr 2012; lost weight. 96:953–61. Our study also had several limitations. Considerable variation 3. Bond DS, Phelan S, Leahey TM, Hill JO, Wing RR. Weight-loss maintenance in successful weight losers: surgical vs non-surgical was observed in study protocols, mainly relating to type of methods. Int J Obes (Lond) 2009;33:173–80. strategy for preventing weight regain and study duration. Most of 4. Klem ML, Wing RR, McGuire MT, Seagle HM, Hill JO. A descriptive the evidence came from dietary strategies, with only 3 ran- study of individuals successful at long-term maintenance of substantial domized controlled trials on the effects of exercise and 3 on anti- weight loss. Am J Clin Nutr 1997;66:239–46. 5. Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, Leutenegger obesity drugs. Whereas our analysis clearly supports the use of E. Long-term maintenance of weight loss after a very-low-calorie diet: anti-obesity drugs, 2 of the 3 drug studies were of sibutramine, a randomized blinded trial of the efficacy and tolerability of sibutr- which was withdrawn in 2010. amine. Am J Med 1999;106:179–84. A second limitation was in the maintenance-phase duration of 6. Mathus-Vliegen EM. Long-term maintenance of weight loss with si- butramine in a GP setting following a specialist guided very-low- the included studies, which varied from 3 to 36 mo (Figure 3). calorie diet: a double-blind, placebo-controlled, parallel group study. Because there were so few studies on weight-loss maintenance Eur J Clin Nutr 2005;59(suppl 1):S31–9. after a VLCD or LCD, we chose not to include a duration re- 7. Richelsen B, Tonstad S, Rossner S, Toubro S, Niskanen L, Madsbad S, striction. Hence, short- and long-term studies were assigned Mustajoki P, Rissanen A. Effect of orlistat on weight regain and WEIGHT-LOSS MAINTENANCE AFTER VLCD/LCD 23 cardiovascular risk factors following a very-low-energy diet in ab- 25. Kamphuis MM, Lejeune MP, Saris WH, Westerterp-Plantenga MS. dominally obese patients: a 3-year randomized, placebo-controlled The effect of conjugated linoleic acid supplementation after weight study. Diabetes Care 2007;30:27–32. loss on body weight regain, body composition, and resting metabolic 8. Astrup A, Caterson I, Zelissen P, Guy-Grand B, Carruba M, Levy B, rate in overweight subjects. Int J Obes Relat Metab Disord 2003;27(7): Sun X, Fitchet M. Topiramate: long-term maintenance of weight loss 840–7. induced by a low-calorie diet in obese subjects. Obes Res 2004;12: 26. Christensen P, Frederiksen P, Bliddal H, Riecke BF, Bartels EM, 1658–69. Henriksen M, Juul-Sorensen T, Gudbergsen H, Winther K, Astrup A, 9. Wadden TA, Fujioka K, Toubro S, Gantz I, Erondu NE, Chen M, et al. Comparison of three different weight maintenance programs on Suryawanshi S, Carofano W, Johnson-Levonas AO, Shapiro DR, et al. cardiovascular risk, bone, and vitamins in sedentary older adults. A randomized trial of lifestyle modification and taranabant for main- Obesity (Silver Spring) (in press). taining weight loss achieved with a low-calorie diet. Obesity (Silver 27. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta- Spring) 2010;18:2301–10. analysis. Stat Med 2002;21:1539–58. 10. Ryttig KR, Flaten H, Rossner S. Long-term effects of a very low 28. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring in- calorie diet (Nutrilett) in obesity treatment. A prospective, randomized, consistency in meta-analyses. BMJ 2003;327:557–60. comparison between VLCD and a hypocaloric diet+behavior modifi- 29. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta- cation and their combination. Int J Obes Relat Metab Disord 1997;21 analysis detected by a simple, graphical test. BMJ 1997;315:629–34. (7):574–9. 30. Pasman WJ, Westerterp-Plantenga MS, Muls E, Vansant G, van Ree J, 11. Ryttig KR, Rossner S. Weight maintenance after a very low calorie diet Saris WH. The effectiveness of long-term fibre supplementation on (VLCD) weight reduction period and the effects of VLCD supple- weight maintenance in weight-reduced women. Int J Obes Relat Metab mentation. A prospective, randomized, comparative, controlled long- Disord 1997;21(7):548–55. term trial. J Intern Med 1995;238:299–306. 31. Olsson J, Sundberg B, Viberg A, Haenni A. Effect of a vegetable-oil 12. Claessens M, van Baak MA, Monsheimer S, Saris WH. The effect of emulsion on body composition; a 12-week study in overweight women a low-fat, high-protein or high-carbohydrate ad libitum diet on weight on a meal replacement therapy after an initial weight loss: a random- loss maintenance and metabolic risk factors. Int J Obes (Lond) 2009; ized controlled trial. Eur J Nutr 2011;50:235–42. 33:296–304. 32. Willett WC. Eat, drink, and be healthy the Harvard Medical School 13. Delbridge EA, Prendergast LA, Pritchard JE, Proietto J. One-year guide to healthy eating. New York, NY: Simon & Schuster, 2001. weight maintenance after significant weight loss in healthy overweight 33. Brownell KD. The LEARN program for weight management: lifestyle, and obese subjects: does diet composition matter? Am J Clin Nutr exercise, attitudes, relationships, nutrition. Dallas, TX: American 2009;90:1203–14. Health Pub. Co, 2004. 14. Hursel R, Westerterp-Plantenga MS. Green tea catechin plus caffeine 34. Astrup A, Rossner S. Lessons from obesity management programmes: supplementation to a high-protein diet has no additional effect on body greater initial weight loss improves long-term maintenance. Obes Rev weight maintenance after weight loss. Am J Clin Nutr 2009;89:822–30. 2000;1:17–9. 15. Larsen TM, Dalskov SM, van Baak M, Jebb SA, Papadaki A, Pfeiffer 35. Wadden TA, Neiberg RH, Wing RR, Clark JM, Delahanty LM, Hill JO, AF, Martinez JA, Handjieva-Darlenska T, Kunesova M, Pihlsgard M, Krakoff J, Otto A, Ryan DH, Vitolins MZ. Four-year weight losses in et al. Diets with high or low protein content and glycemic index for the Look AHEAD study: factors associated with long-term success. weight-loss maintenance. N Engl J Med 2010;363:2102–13. Obesity (Silver Spring) 2011;19:1987–98. 16. Lejeune MP, Kovacs EM, Westerterp-Plantenga MS. Additional protein 36. Saris WH. Very-low-calorie diets and sustained weight loss. Obes Res intake limits weight regain after weight loss in humans. Br J Nutr 2005; 2001;9(suppl 4):295S–301S. 93:281–9. 37. Rosenbaum M, Hirsch J, Gallagher DA, Leibel RL. Long-term per- 17. Westerterp-Plantenga MS, Lejeune MP, Nijs I, van Ooijen M, Kovacs sistence of adaptive thermogenesis in subjects who have maintained EM. High protein intake sustains weight maintenance after body weight a reduced body weight. Am J Clin Nutr 2008;88:906–12. loss in humans. Int J Obes Relat Metab Disord 2004;28(1):57–64. 38. Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, 18. Due A, Larsen TM, Mu H, Hermansen K, Stender S, Astrup A. Kriketos A, Proietto J. Long-term persistence of hormonal adaptations Comparison of 3 ad libitum diets for weight-loss maintenance, risk of to weight loss. N Engl J Med 2011;365:1597–604. cardiovascular disease, and diabetes: a 6-mo randomized, controlled 39. Elfhag K, Rossner S. Who succeeds in maintaining weight loss? A trial. Am J Clin Nutr 2008;88:1232–41. conceptual review of factors associated with weight loss maintenance 19. Kovacs EM, Lejeune MP, Nijs I, Westerterp-Plantenga MS. Effects of and weight regain. Obes Rev 2005;6:67–85. green tea on weight maintenance after body-weight loss. Br J Nutr 40. Maclean PS, Bergouignan A, Cornier MA, Jackman MR. Biology’s 2004;91:431–7. response to dieting: the impetus for weight regain. Am J Physiol Regul 20. Gripeteg L, Torgerson J, Karlsson J, Lindroos AK. Prolonged refeeding Integr Comp Physiol 2011;301:R581–600. improves weight maintenance after weight loss with very-low-energy 41. James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris diets. Br J Nutr 2010;103:141–8. WH, Van Gaal LF. Effect of sibutramine on weight maintenance after 21. Wikstrand I, Torgerson J, Bostrom KB. Very low calorie diet (VLCD) weight loss: a randomised trial. STORM Study Group. Sibutramine followed by a randomized trial of corset treatment for obesity in pri- Trial of Obesity Reduction and Maintenance. Lancet 2000;356: mary care. Scand J Prim Health Care 2010;28:89–94. 2119–25. 22. Borg P, Kukkonen-Harjula K, Fogelholm M, Pasanen M. Effects of 42. Lichtman SW, Pisarska K, Berman ER, Pestone M, Dowling H, Of- walking or resistance training on weight loss maintenance in obese, fenbacher E, Weisel H, Heshka S, Matthews DE, Heymsfield SB. middle-aged men: a randomized trial. Int J Obes Relat Metab Disord Discrepancy between self-reported and actual caloric intake and ex- 2002;26(5):676–83. ercise in obese subjects. N Engl J Med 1992;327:1893–8. 23. Fogelholm M, Kukkonen-Harjula K, Nenonen A, Pasanen M. Effects 43. Westerterp-Plantenga MS, Lemmens SG, Westerterp KR. Dietary of walking training on weight maintenance after a very-low-energy diet protein—its role in satiety, energetics, weight loss and health. Br J Nutr in premenopausal obese women: a randomized controlled trial. Arch 2012;108(suppl 2):S105–12. Intern Med 2000;160:2177–84. 44. Curioni CC, Lourenco PM. Long-term weight loss after diet and ex- 24. Anderson JW, Konz EC, Frederich RC, Wood CL. Long-term weight- ercise: a systematic review. Int J Obes (Lond) 2005;29:1168–74. loss maintenance: a meta-analysis of US studies. Am J Clin Nutr 2001; 45. Fogelholm M, Kukkonen-Harjula K. Does physical activity prevent 74:579–84. weight gain–a systematic review. Obes Rev 2000;1:95–111.

Journal

The American Journal of Clinical NutritionPubmed Central

Published: Oct 30, 2013

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