the eff ect of rate of weight loss on long-term weight management: a randomised controlled trial

954 www.thelancet.com/diabetes-endocrinology Vol 2 December 2014

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The e ect of rate of weight loss on long-term weight management: a randomised controlled trialKatrina Purcell, Priya Sumithran, Luke A Prendergast, Celestine J Bouniu, Elizabeth Delbridge, Joseph Proietto

SummaryBackground Guidelines recommend gradual weight loss for the treatment of obesity, indicative of a widely held opinion that weight lost rapidly is more quickly regained. We aimed to investigate the e ect of the rate of weight loss on the rate of regain in obese people.

Methods For this two phase, randomised, non-masked, dietary intervention trial in a Melbourne metropolitan hospital, we enrolled 204 participants (51 men and 153 women) aged 1870 years with a BMI between 30 and 45 kg/m. During phase 1, we randomly assigned (1:1) participants with a block design (block sizes of 2, 4, and 6) to account for sex, age, and BMI, to either a 12-week rapid weight loss or a 36-week gradual programme, both aimed at 15% weight loss. We placed participants who lost 125% or more weight during phase 1 on a weight maintenance diet for 144 weeks (phase 2). The primary outcome was mean weight loss maintained at week 144 of phase 2. We investigated the primary outcome by both completers only and intention-to-treat analyses. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000190909.

Findings 200 participants were randomly assigned to the gradual weight loss (n=103) or rapid weight loss (n=97) programme between Aug 8, 2008, and March 9, 2010. After phase 1, 51 (50%) participants in the gradual weight loss group and 76 (81%) in the rapid weight loss group achieved 125% or more weight loss in the allocated time and started phase 2. At the end of phase 2, both gradual weight loss and rapid weight loss participants who completed the study (n=43 in gradual weight loss and n=61 in rapid weight loss) had regained most of their lost weight (gradual weight loss 712% regain, 95% CI 581843 vs rapid weight loss 705%, 578832). Intention-to-treat analysis showed similar results (gradual weight loss 763% regain, 95% CI 652874 vs rapid weight loss 763%, 658868). In phase 1, one participant in the rapid weight loss group developed cholecystitis, requiring cholecystectomy. In phase 2, two participants in the rapid weight loss group developed cancer.

Interpretation The rate of weight loss does not a ect the proportion of weight regained within 144 weeks. These ndings are not consistent with present dietary guidelines which recommend gradual over rapid weight loss, based on the belief that rapid weight loss is more quickly regained.

Funding The Australian National Health and Medical Research Council and the Sir Edward Dunlop Medical Research Foundation.

IntroductionDuring the past decade, the prevalence of obesity has increased signi cantly, and it now represents a major health problem in both low-income and high-income countries.1 Dietary weight loss is generally unsuccessful in the long-term,2,3 and optimum non-invasive methods to achieve and maintain weight loss remain elusive. Guidelines worldwide recommend gradual weight loss for the treatment of obesity,46 re ecting a widely-held opinion that rapid weight loss is associated with poorer long-term outcomes than is gradual weight loss. This notion probably stems from the belief that obesity is caused by bad social habits and that gradual weight loss allows more time to change such habits.

The widespread belief in the superiority of gradual over rapid weight loss has recently been questioned,7,8 and scienti c evidence does not support the superiority of a gradual approach in achieving or maintaining weight loss.9 Findings of a non-randomised study10 showed that participants who lost weight rapidly achieved and

maintained greater weight loss than did those who lost weight gradually. However, individuals who chose rapid weight loss might have been more motivated than those who did not.

We aimed to investigate whether the rate of weight loss a ects the rate of regain, and whether weight loss-induced changes in circulating appetite-mediating hormones and subjective appetite are a ected by the rate of weight loss.

MethodsStudy design and participantsWe did a two-phase, randomised, non-masked, dietary intervention trial between August, 2008, and July, 2013, in a Clinical Research Unit at a Melbourne metropolitan hospital.

We recruited volunteers using radio and newspaper advertisements and by word of mouth. Eligible patients at screening were obese (BMI 300450 kg/m), otherwise healthy, and aged between 18 and 70 years. Key

Lancet Diabetes Endocrinol 2014; 2: 95462

Published OnlineOctober 16, 2014

http://dx.doi.org/10.1016/S2213-8587(14)70200-1

See Comment page 927

The University of Melbourne, Department of Medicine

(Austin Health), Heidelberg VIC, Australia (K Purcell BSc,

P Sumithran PhD, L A Prendergast PhD,

C J Bouniu MBBS, E Delbridge PhD,

Prof J Proietto PhD); and La Trobe University, Department

of Mathematics and Statistics, Bundoora, VIC, Australia

(L A Prendergast)

Correspondence to:Prof Joseph Proietto, University

of Melbourne, Department of Medicine (Austin Health),

Heidelberg Repatriation Hospital, Heidelberg, VIC 3081,

[email protected]

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exclusion criteria included use of a very low energy diet or weight loss drugs in the previous 3 months, pregnancy or lactation, smoking, current use of drugs known to a ect bodyweight, previous weight loss surgery, and the presence of clinically signi cant disease (including diabetes). The appendix shows full inclusion and exclusion criteria. The trial protocol is available online.

The study was approved and monitored by the Austin Health Human Research Ethics Committee. Each participant provided written informed consent.

Randomisation and maskingIn phase 1, we randomly allocated (1:1) patients to either a rapid or gradual weight loss programme. Randomisation was done with a computer-generated randomisation sequence with a block design accounting for the potential confounding factors of sex, age (40 and >40 years), and BMI (

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concentration of 3--hydroxybutyrate, which is related to ketone concentration in the blood, during phase 1 in a subset of 40 sequential participants at baseline, and after 5%, 10%, and 15% weight loss. To study the physiological changes induced by weight loss irrespective of the rate of weight loss, we combined data from completers of both groups in post-hoc analyses of changes in ghrelin and subjective hunger at the end of phase 1 and at weeks 48

and 144 of phase 2, and changes in leptin and ghrelin strati ed according to percentage of lost weight regained at week 144 of phase 2. We recorded and graded adverse events for the duration of the trial.

Statistical analysisOn the basis of an expected 50% attrition rate during the trial,13 200 participants were needed at baseline to detect

525 potential participants were screened by telephone contact

206 screened on site

Start of phase 1

319 excluded 27 smokers 40 taking drugs known to cause weight uctuations 33 BMI >45 kg/m2

63 BMI

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a between-group di erence in mean weight regain of more than 5 kg with a power of 09 and signi cance level of 005.

We did analyses of bodyweight on two datasets: one for completers only, and one for intention to treat, in which missing data from participants who discontinued the study were replaced with baseline measures. We compared success rates between groups on the basis of intervals calculated with the Yates continuity correction. Probability of successful weight loss at the end of phase 1 was also modelled with a logistic regression analysis that adjusted for other potential contributing factors. To account for non-completers and other missing values, we did analysis of weight regain with linear mixed e ects models, and adjusted for treatment group, age, sex, and weight loss at the end of phase 1. Data were assumed missing at random after adjusting for these covariates. We did sensitivity analyses to the missing data assumption both assuming 100% weight regain for non-completers, and with multiple imputation (20 imputations with chained equations14 in which linear regression analyses were applied to the imputed data sets at each time point followed by a pooling of results). We found no signi cant di erences in these analyses, therefore we do not report the results here.

For analysis of small samples (ie, 3--hydroxybutyrate data and comparisons of data strati ed according to percentage weight loss) and visual analogue scale scores, we did analyses of medians with Wilcoxon signed-rank tests or Wilcoxon rank-sum tests (for comparisons between groups).

We used linear mixed e ects to analyse percentage changes in fasting hormones in individuals who completed phase 1. A sensitivity analysis to missing data assumptions was done as above, with multiple imputation and adjusting for age and sex, and no di erences in signi cance were detected. We analysed data with the free package R (version 2.15.0)15 and

multiple imputation was done with the mice package.14

The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000190909. Recruitment for a pilot study originally began on the Aug 8, 2008, when pilot studies did not require registration. Due to a misunderstanding between the rst and senior authors, there was a delay in registering the study when funding was obtained to do the full 5 year trial.

Figure 2: Rate of weight loss during phase 1 for successful participants (mean % change, 95% CI) Successful participants were those who achieved at least 125% weight loss from baseline to end of phase 1. *p=0009. p=00001.

0 12 3615

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RapidGradual

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Phase 1 (weight loss phase) Phase 2 (weight maintenance phase)

All (n=200) Rapid weight loss group (n=97)

Gradual weight loss group (n=103)

All (n=127) Rapid weight loss group (n=76)


Age (years) 498 (109) 496 (109) 501 (111) 497 (114) 498 (113) 496 (116)

Sex (men) 255% 268% 243% 283% 276% 294%

Weight (kg) 968 (140) 964 (138) 972 (142) 970 (134) 970 (133) 970 (137)

BMI (kg/m2) 353 (38) 352 (37) 355 (40) 353 (39) 352 (37) 355 (41)

Waist circumference (cm) 1081 (103) 1082 (106) 1079 (100) 1078 (102) 1077 (101) 1081 (104)

Hip circumference (cm) 1185 (102) 1181 (95) 1189 (109) 1183 (104) 1187 (99) 1178 (113)

Systolic blood pressure (mm Hg) 1310 (102) 1304 (157) 1315 (138) 1313 (154) 1303 (156) 1328 (158)

Diastolic blood pressure (mm Hg) 823 (90) 826 (93) 819 ( 88) 825 (95) 829 (89) 819 (104)

Fat mass (kg) 497 (127) 485 (122) 509 (131) 491 (127) 487 (127) 496 (128)

Fat-free mass (kg) 450 ( 124) 446 (126) 454 ( 123) 456 (126) 450 (129) 465 (122)

Daily steps 7319 (2819) 7107 (2599) 7530 (3021) 7344 (2550) 7150 (2397) 7643 (2768)

Data are mean (SD) or n (%).

Table 1: Baseline characteristics of participants entering the weight-loss phase and the subsequent weight-maintenance phase

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Role of the funding sourceThe funders were not involved in the trial design, patient recruitment; data collection, analysis, interpretation, or presentation; writing or editing of the report; or the decision to submit for publication. The corresponding author had full access to all the data in the study and had nal responsibility for the decision to submit for publication.

Results204 participants were randomly assigned to either the rapid weight loss or gradual weight loss group; 200 participants started the diet ( gure 1). Table 1 shows baseline characteristics of the two groups.

179 (895%) participants completed phase 1. Signi cantly more participants discontinued the gradual weight loss programme than the rapid weight loss programme (18 [18%] vs three [3%], p=0002). The main reason given for withdrawal in both groups was di culty adhering to the diet.

Figure 2 shows mean rates of weight loss for participants who achieved 125% or more weight loss. Of those who completed phase 1, 76 of 94 (81%) rapid weight loss participants achieved 125% or more weight loss, compared with 53 of 85 (62%) gradual weight loss participants (p=0009). Intention-to-treat analysis showed similar results (76 of 97 [78%] vs 53 of 103 [51%], p=00001). In those who achieved 125% or more weight loss, hip circumference decreased signi cantly

more in the gradual weight loss group than in the rapid weight loss group (table 2; intention-to-treat results shown in appendix). We detected no signi cant di erences between the changes in fat-free mass and fat mass, or other anthropometric measurements between the two groups. When predicting achievement of target weight (125% weight loss at the end of phase 1) with regression analysis, diet group remained a signi cant factor when adjusting for age, baseline weight, and sex (none of which were signi cant; data not shown).

In the gradual weight loss group, two participants achieved the weight loss goal by week 12 (rather than the allocated 36 weeks) and were therefore excluded, leaving 51 participants in the gradual weight loss group and 76 participants in the rapid weight loss group who started phase 2 (table 1). Attrition in phase 2 was not signi cantly di erent between groups ( gure 1). With the exception of six participants (one in the gradual weight loss group and ve in the rapid weight loss group), all participants started to regain their lost weight during phase 2 and were prescribed a 400500 kcal per day energy de cit diet.

Figure 3 shows weight regain during phase 2. Study completers regained most of their lost weight (table 2). By week 144 of phase 2, average weight regain was 104 kg (95% CI 84124; 712% of lost weight regained, 581843) in gradual weight loss participants and 103 kg (85121; 705%, 578832) in rapid weight loss participants (di erence between groups 009 kg,

End of phase 1 for successful weight loss participants End of phase 2 for all study completers

Rapid weight loss group (n=76)


p value Rapid weight loss group (n=61)


p value

Weight change from baseline (kg)

146 (151 to 140) 143 (151 to 135) 057 41 (61 to 24) 43 (63 to 24) 085

BMI change from baseline (kg/m2)

53 (55 to 52) 52 (55 to 50) 043 15 (22 to 02) 16 (22 to 09) 089

Change in waist circumference from baseline (cm)

155 (167 to 143) 162 (176 to 150) 043 44 (64 to 23) 41 (67 to 16) 088

Change in hip circumference from baseline (cm)

131 (142 to 12 0) 150 (164 to 136) 004 31 (50 to 12) 44 (66 to 21) 041

Change in fat mass from baseline (kg)

127 (138 to 116) 141 (157 to 126) 015 24 (47 to 004) 46 (73 to 19) 022

Change in fat free mass from baseline (kg)

11 (01 to 21) 05 (09 to 19) 048 13 (01 to 24) 03 (20 to 14) 013

Change in ghrelin from baseline (pg/mL)*

2870 (1419 to 4321) 2239 (1145 to 3333) 048 797 (747 to 2340) 612 (50 to 1275) 082

Change in leptin from baseline (ng/mL)

162 (187 to 137) 118 (149 to 87) 003 73 (34 to 113) 56 (10 to 102) 056

Change in physical activity from baseline (steps per day)

2291 (1662 to 2920) 1300 (360 to 2240) 008 347 (496 to 1191) 1386 (355 to 3128) 028

Data are mean (95% CI) or p value. *In phase 1, 34 participants in the in rapid weight loss group and 24 in the gradual weight loss group. In phase 2, 36 participants in the in rapid weight loss group and 24 in the in gradual weight loss group. In phase 1, 75 participants in the rapid weight loss group and 49 in the gradual weight loss group. In phase 2, 57 participants in the in rapid weight loss group and 37 in the in gradual weight loss group.

Table 2: Mean change from baseline in anthropometric, appetite hormones, body composition, and physical activity for participants achieving 125% weight loss or more in phase 1 and for all study completers at the end of phase 2

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95% CI 28 to 26; 072%; 95% CI -18.7173). Weight was not signi cantly di erent between groups after week 48 of phase 2. When we assumed a return to baseline weight in those who discontinued the study during phase 2, there were no signi cant di erences between groups in mean rate of regain or percentage of lost weight regained (mean regain at week 144 in gradual weight loss group 763%, 95% CI 652874; rapid weight loss group 763%, 658868; appendix). Adjustment for age and sex did not a ect this outcome (data not shown). In phase 1, we detected no signi cant di erences in changes in body composition and anthropometric measurements between the rapid weight loss and gradual weight loss groups at the end of phase 2 (table 2; intention-to-treat results shown in appendix).

In a subgroup of 40 patients (20 in the gradual weight loss group and 20 in the rapid weight loss group) in whom 3--hydroxybutyrate was measured at 5% and 10% weight loss during phase 1, concentrations of this metabolite were signi cantly higher in the rapid weight loss group compared with the gradual weight loss group ( gure 4). We detected no signi cant di erences in 3--hydroxybutyrate at the end of phase 1 (mean 15% weight loss) between treatment groups.

Figure 5 shows changes in fasting hormone concentrations throughout the study, and table 2 shows changes from baseline. Leptin decreased during phase 1 in both groups, and the reduction in leptin at the end of phase 1 was more pronounced with rapid weight loss than gradual weight loss (p=003). Leptin concentrations rose in both groups during phase 2, and there was no di erence in leptin between groups at weeks 48 and 144 of phase 2. A repeated measures analysis showed that leptin was not signi cantly di erent from baseline in either group at week 48 of phase 2 (gradual weight loss 18%, 95% CI 16 to 378, p=007 vs baseline; rapid weight loss 55%, 95% CI 215 to 105, p=050), although it was signi cantly increased at week 144 of phase 2 in both groups (gradual weight loss 232%, 95% CI 25438, p=00280; rapid weight loss 436%, 267605, p

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baseline at weeks 48 (mean 219% higher, 95% CI 118319, p75%) and least (25 to 50% 11 81% (130 to 344) 032

>50 to 75% 23 06% (44 to 265) 023

>75 to 100% 21 401% (87 to 882) 0001

>100 to 125% 14 516% (342 to 899) 0002

>125 to 150% 10 365% (152 to 1364) 0004

Data are combined from rapid weight loss and gradual weight loss groups. *p values for median % change in leptin concentration from baseline. 95% CI is for median % change in leptin concentration from baseline.

Table 3: Median percentage change in leptin concentrations strati ed according to proportion of initial weight loss regained during phase 2

Weightloss phase

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BRapidGradual

Figure 5: Mean change from baseline (% change, 95% CI) at end of phase 1, and weeks 48 and 144 of phase 2 for (A) fasting leptin concentration (n=55 in rapid weight loss and n=34 in gradual weight loss group) and (B) fasting total ghrelin concentration (n=34 in rapid weight loss and n=24 in gradual weight loss group)

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expenditure decreases,28 which encourages weight regain. However, whether the rate of weight loss a ects concentrations of appetite-mediating hormones was not clear. Our results show that circulating leptin concentration falls more when 15% weight loss happens rapidly (average 15 kg lost per week) than gradually (average 05 kg lost per week), consistent with previous evidence that leptin secretion is not only a ected by adipose tissue mass, but also energy intake.29

Recently, investigators noted that changes in hunger and concentrations of appetite-regulating hormones after weight loss were sustained for at least 12 months.27 Our ndings show that physiological adaptations encouraging weight regain, such as a rise in ghrelin concentration and hunger, persist for at least 3 years, even after most of the lost weight has been regained. Additionally, participants maintaining a substantial weight loss (eg, weight regain of

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study was not commercially sponsored, and there were no agreements regarding con dentiality of the data between the sponsor and the authors or their institutions.

AcknowledgmentsWe thank Rebecca Sgambellone, Christian Rantzau, and Wynne Pong for technical assistance, and dietitian Jodie Prendergast for counselling participants on diet and exercise, and Nestl Healthcare Nutrition Australia Ltd for supplying Optifast to participants for the duration of the trial.

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The effect of rate of weight loss on long-term weight management: a randomised controlled trialIntroductionMethodsStudy design and participantsRandomisation and maskingProceduresOutcomesStatistical analysisRole of the funding source

ResultsDiscussionAcknowledgmentsReferences

the eff ect of rate of weight loss on long-term weight management: a randomised controlled trial

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