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Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial

BMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4583 (Published 14 November 2018) Cite this as: BMJ 2018;363:k4583

No Significant Effect of Dietary Carbohydrate versus Fat on the Reduction in Total Energy Expenditure During Maintenance of Lost Weight

The question of whether the ratio of dietary carbohydrates to fat substantially impacts total energy expenditure (TEE) or body fat has been investigated for decades, with most studies pointing to no clinically meaningful effect 1. However, a recent study by Ebbeling et al. reported substantial differences in TEE between diets varying in their ratio of carbohydrate to fat 2.

The original pre-registered statistical analysis plan for the primary study outcome of Ebbeling et al. addressed the question of whether the reduction in TEE during weight loss maintenance compared to the pre-weight loss baseline depended on the dietary carbohydrate to fat ratio – a design similar to a previous study by many of the same authors 3. However, the final analysis plan was modified to make the diet comparisons with the TEE measurements collected in the immediate post-weight loss period rather than at the pre-weight loss baseline. As fully described in a manuscript available on the bioRxiv pre-print server (https://www.biorxiv.org/content/early/2018/11/28/476655), reanalyzing the data according to the original analysis plan of Ebbeling et al. found that the TEE differences were no longer statistically significant between the diet groups and the nominal diet differences of ~100 kcal/d were much smaller than the ~250 kcal/d differences reported in the final publication. In other words, when conducting the analysis originally planned by the authors we found that the significant increases in TEE with the low carbohydrate diet that were reported by Ebbeling et al. disappeared. Furthermore, the significant TEE effect modification by baseline insulin secretion also disappeared.

As justification for our reanalysis, we note that most of the history of the study (7 of 8 versions of the protocol spanning from 2014-2016) the planned primary outcome calculations used the pre-weight loss TEE baseline as the anchor point for the subsequent diet comparisons during weight loss maintenance. Prior to unmasking the randomization blind, but after all cohorts had completed the trial, the final protocol amendment in 2017 altered the previously planned statistical analysis to use the post-weight loss TEE measurement as the anchor point to make the subsequent diet comparisons.

The reasons for the change in the analysis plan were not provided in the protocol amendment or the final statistical analysis plan, but the Supplemental Materials in the final publication provided three reasons. First, the post-weight loss TEE measurement was chosen as the new anchor point because it occurred closer to the point of diet randomization. Second, the pre-weight loss TEE measurement would be “strongly confounded by weight loss”. How this might happen and why the post weight loss measure would not be similarly affected is difficult to imagine. Finally, Ebbeling et al. argued that the pre-weight loss baseline would have been inappropriate because the TEE measurements were insufficiently accurate or precise and therefore the study would be under-powered. However, the power calculations in the protocol were based on TEE data from a pilot study using the pre-weight loss TEE measurements as the basis for comparing how different diets affected the absolute reduction in TEE during weight loss maintenance 3. The pilot study did not measure TEE in the period immediately post-weight loss and therefore could not have been used to power the recent study in question.

Despite a request by the BMJ Editors to report the results of their original analysis plan, Ebbeling et al. refused because they were “concerned that the additional analysis would provide no meaningful biological insights – that is, no useful information about the nature of the relationship between dietary composition and energy expenditure. Rather, inclusion of the additional analysis would tend to elevate and give undue attention to an error, and therefore potentially cause confusion.”

We believe that the revised analysis plan has caused confusion and that the original statistical analysis plan that used pre-weight loss TEE as the anchor point is preferable for several reasons. First, it specifically addresses the question of whether the typical reduction in TEE that accompanies maintenance of lost weight depends on the carbohydrate to fat ratio of the weight loss maintenance diet. Second, the revised plan is potentially confounded by the substantial adaptive thermogenesis that occurs immediately post-weight loss that typically becomes less severe after a period of energy balance and weight loss maintenance 4 5. Finally, the pre-weight loss baseline TEE measurements were obtained in the situation where the doubly labeled water method is routinely employed: free-living people maintaining their habitual weight. Ideally, a post-weight loss TEE measurement should have first stabilized subjects at the lower body weight for several weeks prior to dosing with doubly labeled water 6. In contrast, the post-weight loss TEE measurements conducted by Ebbeling et al. were obtained during the same 2-week weight stabilization period when diet calories were being progressively increased at a rate determined by each individual subject’s recent rate of weight loss. While the doubly labeled water method generally provides a robust and valid estimate of TEE, this situation of simultaneous refeeding immediately post-weight loss potentially introduces uncertainty into the conversion of CO2 production into TEE. For example, the daily respiratory quotient during this period was clearly not equal to the food quotient as was assumed by Ebbeling et al. While such an effect can be appropriately modeled 7, this was not done in their TEE calculations.

In conclusion, when analyzed using the original statistical plan that was not confounded by the immediate post-weight loss period, the data of Ebbeling et al. do not support the conclusion that the ratio of dietary carbohydrate to fat affects the reduction in TEE during weight loss maintenance. While there are many reasons people could benefit from consuming healthy low carbohydrate diets 8, such diets are unlikely to help offset the usual reduction in TEE during maintenance of lost weight.

References
1. Hall KD, Guo J. Obesity Energetics: Body Weight Regulation and the Effects of Diet Composition. Gastroenterology 2017;152(7):1718-27 e3. doi: 10.1053/j.gastro.2017.01.052 [published Online First: 2017/02/15]
2. Ebbeling CB, Feldman HA, Klein GL, et al. Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial. Bmj 2018;363:k4583. doi: 10.1136/bmj.k4583 [published Online First: 2018/11/16]
3. Ebbeling CB, Swain JF, Feldman HA, et al. Effects of dietary composition on energy expenditure during weight-loss maintenance. Jama 2012;307(24):2627-34.
4. Hall KD. Computational Modeling of Energy Metabolism and Body Composition Dynamics. In: Krentz AW, Heinemann L, Hompesch M, eds. Translational Research Methods for Diabetes, Obesity and Cardiometabolic Drug Development. London: Springer-Verlag 2015:265-82.
5. Weinsier RL, Nagy TR, Hunter GR, et al. Do adaptive changes in metabolic rate favor weight regain in weight-reduced individuals? An examination of the set-point theory. Am J Clin Nutr 2000;72(5):1088-94.
6. Bhutani S, Racine N, Shriver T, et al. Special Considerations for Measuring Energy Expenditure with Doubly Labeled Water under Atypical Conditions. Journal of obesity & weight loss therapy 2015;5(Suppl 5) doi: 10.4172/2165-7904.S5-002 [published Online First: 2016/03/11]
7. Hall KD, Guo J, Chen KY, et al. Methodologic Issues in Doubly Labeled Water Measurements of Energy Expenditure During Very Low-Carbohydrate Diets. bioRxiv 2018 doi: 10.1101/403931
8. Hall KD, Chung ST. Low-carbohydrate diets for the treatment of obesity and type 2 diabetes. Curr Opin Clin Nutr Metab Care 2018;21(4):308-12. doi: 10.1097/mco.0000000000000470 [published Online First: 2018/04/21]

Competing interests: KDH has participated in a series of debates with Dr. David S. Ludwig, the senior author of the main study in question, regarding the merits and demerits of the carbohydrate-insulin model of obesity as well as the physiological response of the human body to isocaloric diets varying in the ratio of carbohydrates to fat.

28 November 2018
Kevin D Hall
Senior Investigator
Juen Guo
National Institutes of Health
Bethesda, MD 20892 USA