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

BMJ 2018; 363 doi: (Published 14 November 2018) Cite this as: BMJ 2018;363:k4583
  1. Cara B Ebbeling, principal investigator, and associate professor1 2,
  2. Henry A Feldman, principal biostatistician, and associate professor2 3,
  3. Gloria L Klein, study director1,
  4. Julia M W Wong, associate study director, and instructor1 2,
  5. Lisa Bielak, nutrition research manager1,
  6. Sarah K Steltz, data and quality manager1,
  7. Patricia K Luoto, professor4,
  8. Robert R Wolfe, professor5,
  9. William W Wong, professor6,
  10. David S Ludwig, principal investigator, and professor1 2
  1. 1New Balance Foundation Obesity Prevention Center, Division of Endocrinology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
  2. 2Harvard Medical School, Boston, MA, USA
  3. 3Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA, USA
  4. 4Department of Food and Nutrition, Framingham State University, Framingham, MA, USA
  5. 5University of Arkansas for Medical Sciences, Little Rock, AR, USA
  6. 6USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
  1. Correspondence to: D S Ludwig david.ludwig{at} (or @davidludwigmd on Twitter)
  • Accepted 24 October 2018


Objective To determine the effects of diets varying in carbohydrate to fat ratio on total energy expenditure.

Design Randomized trial.

Setting Multicenter collaboration at US two sites, August 2014 to May 2017.

Participants 164 adults aged 18-65 years with a body mass index of 25 or more.

Interventions After 12% (within 2%) weight loss on a run-in diet, participants were randomly assigned to one of three test diets according to carbohydrate content (high, 60%, n=54; moderate, 40%, n=53; or low, 20%, n=57) for 20 weeks. Test diets were controlled for protein and were energy adjusted to maintain weight loss within 2 kg. To test for effect modification predicted by the carbohydrate-insulin model, the sample was divided into thirds of pre-weight loss insulin secretion (insulin concentration 30 minutes after oral glucose).

Main outcome measures The primary outcome was total energy expenditure, measured with doubly labeled water, by intention-to-treat analysis. Per protocol analysis included participants who maintained target weight loss, potentially providing a more precise effect estimate. Secondary outcomes were resting energy expenditure, measures of physical activity, and levels of the metabolic hormones leptin and ghrelin.

Results Total energy expenditure differed by diet in the intention-to-treat analysis (n=162, P=0.002), with a linear trend of 52 kcal/d (95% confidence interval 23 to 82) for every 10% decrease in the contribution of carbohydrate to total energy intake (1 kcal=4.18 kJ=0.00418 MJ). Change in total energy expenditure was 91 kcal/d (95% confidence interval −29 to 210) greater in participants assigned to the moderate carbohydrate diet and 209 kcal/d (91 to 326) greater in those assigned to the low carbohydrate diet compared with the high carbohydrate diet. In the per protocol analysis (n=120, P<0.001), the respective differences were 131 kcal/d (−6 to 267) and 278 kcal/d (144 to 411). Among participants in the highest third of pre-weight loss insulin secretion, the difference between the low and high carbohydrate diet was 308 kcal/d in the intention-to-treat analysis and 478 kcal/d in the per protocol analysis (P<0.004). Ghrelin was significantly lower in participants assigned to the low carbohydrate diet compared with those assigned to the high carbohydrate diet (both analyses). Leptin was also significantly lower in participants assigned to the low carbohydrate diet (per protocol).

Conclusions Consistent with the carbohydrate-insulin model, lowering dietary carbohydrate increased energy expenditure during weight loss maintenance. This metabolic effect may improve the success of obesity treatment, especially among those with high insulin secretion.

Trial registration NCT02068885.


  • Contributors: CBE (principal investigator) designed the study, secured funding, interpreted the data, and wrote the first draft of the manuscript. HAF (co-investigator, biostatistician) designed the study, and analyzed and interpreted the data. GLK (study director) acquired the data. JMWW (associate study director) calculated the diets and acquired the data. LB (nutrition research manager) calculated the diets and managed the dietary intervention. SKS (data and quality manager) performed randomization and monitored quality control of data acquisition. PKL (study director for Framingham State University) maintained partnerships. RRW (consultant) provided expertise on stable isotope modeling. WWW (co-investigator) conducted isotope-ratio mass spectrometry. DSL (principal investigator) designed the study, secured funding, interpreted the data, and wrote the first draft of the manuscript. CBE and DSL are the guarantors. CBE, HAF, and DSL had access to all of the data (including statistical reports and tables) in the study, take responsibility for the integrity of the data and the accuracy of the data analysis. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This work was conducted with grants from Nutrition Science Initiative (made possible by gifts from the Laura and John Arnold Foundation and Robert Lloyd Corkin Charitable Foundation), New Balance Foundation, Many Voices Foundation, and Blue Cross Blue Shield. DSL was supported by a mid-career mentoring award from the National Institute of Diabetes and Digestive and Kidney Diseases (K24DK082730). Nutrition Science Initiative monitored study progress and was given an opportunity to comment on the manuscript. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; approval of the manuscript; and decision to submit the manuscript for publication. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the study sponsors.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: research support for the submitted work as described above; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work except as follows: CBE and DSL have conducted research studies examining the carbohydrate-insulin model funded by the National Institutes of Health and philanthropic organizations unaffiliated with the food industry; DSL received royalties for books on obesity and nutrition that recommend a low glycemic load diet.

  • Ethical approval: The study protocol was approved by the institutional review board at Boston Children’s Hospital.

  • Data sharing: The full dataset and statistical codes are available at Open Science Framework (

  • Transparency: The manuscript’s guarantors (CBE and DSL) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned and registered have been explained.

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