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Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data

BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.m4743 (Published 13 January 2021) Cite this as: BMJ 2021;372:m4743
  1. Joshua Z Goldenberg, research investigator1 2,
  2. Andrew Day, physician3,
  3. Grant D Brinkworth, professor4,
  4. Junko Sato, professor5,
  5. Satoru Yamada, professor6,
  6. Tommy Jönsson, professor7,
  7. Jennifer Beardsley, research librarian8,
  8. Jeffrey A Johnson, professor9,
  9. Lehana Thabane, professor, director10 11,
  10. Bradley C Johnston, associate professor, methodologist1 10
  1. 1Department of Nutrition, Texas A&M University, College Station, TX, USA
  2. 2Helfgott Research Institute, National University of Natural Medicine, Portland, OR, USA
  3. 3Day Family Medicine, Poulsbo, WA, USA
  4. 4Commonwealth Scientific and Industrial Research Organisation (CSIRO) - Health and Biosecurity, Sydney, NSW, Australia
  5. 5Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
  6. 6Diabetes Center, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan
  7. 7Center for Primary Health Care Research, Lund University/Region Skåne, Skåne University Hospital, Malmö, Sweden
  8. 8Independent research librarian, Seattle, WA, USA
  9. 9School of Public Health, University of Alberta, Edmonton, AB, Canada
  10. 10Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
  11. 11Biostatistics Unit, St Joseph's Healthcare, Hamilton, ON, Canada
  1. Correspondence to: B C Johnston bradley.johnston{at}tamu.edu (or @methodsnerd on Twitter)
  • Accepted 30 October 2020

Abstract

Objective To determine the efficacy and safety of low carbohydrate diets (LCDs) and very low carbohydrate diets (VLCDs) for people with type 2 diabetes.

Design Systematic review and meta-analysis.

Data sources Searches of CENTRAL, Medline, Embase, CINAHL, CAB, and grey literature sources from inception to 25 August 2020.

Study selection Randomized clinical trials evaluating LCDs (<130 g/day or <26% of a 2000 kcal/day diet) and VLCDs (<10% calories from carbohydrates) for at least 12 weeks in adults with type 2 diabetes were eligible.

Data extraction Primary outcomes were remission of diabetes (HbA1c <6.5% or fasting glucose <7.0 mmol/L, with or without the use of diabetes medication), weight loss, HbA1c, fasting glucose, and adverse events. Secondary outcomes included health related quality of life and biochemical laboratory data. All articles and outcomes were independently screened, extracted, and assessed for risk of bias and GRADE certainty of evidence at six and 12 month follow-up. Risk estimates and 95% confidence intervals were calculated using random effects meta-analysis. Outcomes were assessed according to a priori determined minimal important differences to determine clinical importance, and heterogeneity was investigated on the basis of risk of bias and seven a priori subgroups. Any subgroup effects with a statistically significant test of interaction were subjected to a five point credibility checklist.

Results Searches identified 14 759 citations yielding 23 trials (1357 participants), and 40.6% of outcomes were judged to be at low risk of bias. At six months, compared with control diets, LCDs achieved higher rates of diabetes remission (defined as HbA1c <6.5%) (76/133 (57%) v 41/131 (31%); risk difference 0.32, 95% confidence interval 0.17 to 0.47; 8 studies, n=264, I2=58%). Conversely, smaller, non-significant effect sizes occurred when a remission definition of HbA1c <6.5% without medication was used. Subgroup assessments determined as meeting credibility criteria indicated that remission with LCDs markedly decreased in studies that included patients using insulin. At 12 months, data on remission were sparse, ranging from a small effect to a trivial increased risk of diabetes. Large clinically important improvements were seen in weight loss, triglycerides, and insulin sensitivity at six months, which diminished at 12 months. On the basis of subgroup assessments deemed credible, VLCDs were less effective than less restrictive LCDs for weight loss at six months. However, this effect was explained by diet adherence. That is, among highly adherent patients on VLCDs, a clinically important reduction in weight was seen compared with studies with less adherent patients on VLCDs. Participants experienced no significant difference in quality of life at six months but did experience clinically important, but not statistically significant, worsening of quality of life and low density lipoprotein cholesterol at 12 months. Otherwise, no significant or clinically important between group differences were found in terms of adverse events or blood lipids at six and 12 months.

Conclusions On the basis of moderate to low certainty evidence, patients adhering to an LCD for six months may experience remission of diabetes without adverse consequences. Limitations include continued debate around what constitutes remission of diabetes, as well as the efficacy, safety, and dietary satisfaction of longer term LCDs.

Systematic review registration PROSPERO CRD42020161795.

Footnotes

  • Contributors: JZG and BCJ conceived the study. JZG, LT, and BCJ designed the study. JZG, JJ, and BCJ developed a priori estimates of the minimal clinically important difference. JB designed and executed the search. JG and AD selected the articles and extracted the data. JZG, AD, and BCJ analyzed the data. JZG and BCJ wrote the first draft of the manuscript. GB, JS, SY, and TJ provided unpublished trial data and reviewed and interpreted the data of the draft manuscript. JZG, BCJ, AD, JB, LT, GB, JS, SY, TJ, and JJ interpreted the data and contributed to the writing of the final version of the manuscript. All authors agreed with the results and conclusions of this article. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. JZG and BCJ are the guarantors.

  • Funding: This study was funded in part by Texas A&M University. The university had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from Texas A&M University; BCJ receives funds from Texas A&M AgriLife Research to support investigator initiated research related to saturated and polyunsaturated fats for a separate research project, as part of his recent recruitment to Texas A&M University (support from Texas A&M AgriLife institutional funds are from interest and investment earnings, not a sponsoring organization, industry, or company); GB is author of the CSIRO Low Carb Diet Book that aims to translate clinical research outcomes of low carbohydrate diet studies for the general public in Australia, but he does not personally receive any financial royalties or funds either directly or indirectly from this publication, and any royalties received by his employment institution (CSIRO) do not contribute to his salary, nor have they been used to execute this work; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not needed. All the work was developed using aggregate level data.

  • Data sharing: Further data are available on request through the corresponding author at bradley.johnston@tamu.edu.

  • The lead and senior authors (manuscript’s guarantors) affirm that this 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, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: We plan to reach out to diabetes and obesity patient advocacy groups (eg, Obesity Canada) as well as professional medical, nutrition, and agricultural organizations (eg, Practice-based Evidence in Nutrition, Royal Australian College of General Practitioners, USDA) to help to disseminate this work. Additionally, all authors will work with their home institutions to leverage their unique dissemination platforms including social media communication and organizational websites.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

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