The ketogenic diet and weight loss: a critical look at the science in humans

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This is a draft of a subsection that I have written for an upcoming review paper on the ketogenic diet. This is comprehensive look at what we know about the usefulness of the ketogenic diet for the treatment of overweight and obesity. The review of which this subsection is a part will be published later this year.

Without further ado…

Ketogenic diets show appetite suppression

The most well-known application of ketogenic dietary therapy (KDT) is for weight loss. This form of KDT popularly takes the form of a diet high in meat, eggs, dairy, high-fat nuts, non-starchy vegetables, and restricted in foods containing carbohydrate (such as most fruits, grains, legumes, etc.) (Volek, Phinney, Kossoff, Eberstein, & Moore, 2011). Less commonly, plant-based versions of this diet rich in seeds, nuts, and oils—so-called Eco-Atkins—are also possible (Jenkins et al., 2014). Acute dosing studies using exogenous ketones suggest that ketones may cause appetite suppression owing to lower ghrelin secretion peripherally (possibly via activation of GPR41 on enteroendocrine cells), as well as direct effects on the brain (Stubbs et al., 2018). One study investigating the changes caused by the classical KD for refractory epilepsy in children have found an even more robust chronic reduction in ghrelin (Marchiò et al., 2019). Still another study showed that, after 13% weight loss over 8 weeks in 39 individuals, reintroduction of a carbohydrate containing diet over two weeks caused increases in ghrelin and hunger to above baseline, whereas prior to reintroduction, ghrelin and hunger had remained suppressed at baseline levels, defying typical changes in ghrelin during weight loss (Sumithran et al., 2013). Correspondingly, systematic review and meta-analysis suggests a modest reduction in self-reported hunger and increase in self-reported fullness and satiety during adherence to the ketogenic diet compared to baseline, pre-diet levels (Gibson et al., 2015).

Ketogenic diets may or may not provide a metabolic advantage

Findings from a recent Mendelian randomization study have further suggested that reduction in post-prandial plasma insulin levels as achievable by KD (Hall et al., 2016) might be capable of reducing the prevalence of between 1 and 10% of obesity at the population level (Astley et al., 2018). Consistent with this, (Ebbeling et al., 2018a, 2012) reported a “metabolic advantage” of isocaloric carbohydrate restriction that may substantially increase energy expenditure. However, in a widely circulated critical re-analysis by Kevin Hall and Juen Guo available in pre-print (Hall & Guo, 2019), the latest of these findings have been contested on a number of technical grounds. Moreover, as shown by recent meta-analysis, the findings of these studies (Ebbeling et al., 2018b, 2012) are themselves extreme outliers among more than 30 similar controlled feeding studies, which on average show a slight metabolic advantage in fact for low-fat diets (Hall & Guo, 2017).

Twelve-month weight loss: low-carb vs. low-fat diets

More importantly, the highest-quality reviews of free-living trials comparing 12-month outcomes of low-carbohydrate versus low-fat diets in free-living conditions show negligible weight loss difference—less than a kilogram—which might itself be fully accounted for by the glycogen- (and thus water-) depleting effect of the diet (Churuangsuk, Kherouf, Combet, & Lean, 2018). That the above mechanistic advantages do not seem to translate into a clinically substantial weight loss advantage for the KD may be indicative that such advantages are short-lived (Stubbs et al., 2018) or that other factors, such as socioeconomics, social support, and other life circumstances (Hall, 2018), in the context of chronic hyperpalatable food cue exposure (Lutter & Nestler, 2009), are more biologically important. Indeed, according to a recent study, among the high-quality systematic reviews with meta-analyses on low-carbohydrate diets (Churuangsuk et al., 2018), only one used for its study inclusion criteria a carbohydrate intake sufficiently low to produce ketonemia (Bueno, de Melo, de Oliveira, & da Rocha Ataide, 2013), and in only one RCT of the included 13 were low-carbohydrate dieters still in the ketogenic range of carbohydrate intake by study end, with a 59% completion rate (Brinkworth, Noakes, Buckley, Keogh, & Clifton, 2009). The DIETFITS trial, which had 609 participants and a 79% completion rate, had subjects start well into the ketogenic range (<20g) in the low-carbohydrate group for 8 weeks, adding carbohydrates back to their diets in increments of 5-15g/week “until they reached the lowest level of intake they believed could be maintained indefinitely”. By the twelfth week, just four weeks later, dieters were on average consuming nearly twice the carbohydrate grams as is generally recommended to maintain nutritional ketosis, and by twelve months, nearly triple (Gardner et al., 2018).

Adherence is the central issue for all diets, including the ketogenic diet

Indeed, as with other weight loss regimens, studies on low-carb diets show, on average, the start of progressive weight regain between 6 and 12 months (Athinarayanan et al., 2019; Hall, 2018), with the subjects exiting the ketogenic carbohydrate intake range earlier (Hallberg et al., 2018). Accordingly, while at 6 months the ketogenic diet shows a weight loss advantage, at 12 months the results for the KD are similar to those for other well-formulated diets that attempt to exclude hypercaloric, high-reward, low-satiety foods, and there is little or no significant detectable difference in 12-month weight loss in the best designed studies and highest quality reviews (Churuangsuk et al., 2018; Gardner et al., 2018), and the postulated mechanisms above of appetite suppression and metabolic advantage may not be clinically relevant for this reason, or if they are, they may only be relevant in marginal cases not yet captured by the RCT literature. It is possible that in the context of an adequately characterized and implemented behavioral modification intervention, the above-postulated mechanisms may prove to make ketogenic diets superior to other approaches. However, what is most striking about the literature given current crude approaches to behavioral modification is that the macronutrient composition—beyond a focus on whole foods—is relatively insignificant a factor for determining the degree of long-term weight loss.

Conclusion: leveraging ketogenesis for weight loss will require addressing the adherence problem

Astley, C. M., Todd, J. N., Salem, R. M., Vedantam, S., Ebbeling, C. B., Huang, P. L., … Florez, J. C. (2018). Genetic evidence that carbohydrate-stimulated insulin secretion leads to obesity. Clinical Chemistry, 64(1), 192–200. https://doi.org/10.1373/clinchem.2017.280727

Athinarayanan, S. J., Adams, R. N., Hallberg, S. J., McKenzie, A. L., Bhanpuri, N. H., Campbell, W. W., … McCarter, J. P. (2019). Long-Term Effects of a Novel Continuous Remote Care Intervention Including Nutritional Ketosis for the Management of Type 2 Diabetes: A 2-Year Non-randomized Clinical Trial. Frontiers in Endocrinology, 10, 348. https://doi.org/10.3389/fendo.2019.00348

Brinkworth, G. D., Noakes, M., Buckley, J. D., Keogh, J. B., & Clifton, P. M. (2009). Long-term effects of a very-low-carbohydrate weight loss diet compared with an isocaloric low-fat diet after 12 mo. The American Journal of Clinical Nutrition, 90(1), 23–32. https://doi.org/10.3945/ajcn.2008.27326

Bueno, N. B., de Melo, I. S. V., de Oliveira, S. L., & da Rocha Ataide, T. (2013). Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. British Journal of Nutrition, 110(7), 1178–1187. https://doi.org/10.1017/S0007114513000548

Churuangsuk, C., Kherouf, M., Combet, E., & Lean, M. (2018). Low-carbohydrate diets for overweight and obesity: a systematic review of the systematic reviews. Obesity Reviews, 19(12), 1700–1718. https://doi.org/10.1111/obr.12744

Ebbeling, C. B., Feldman, H. A., Klein, G. L., Wong, J. M. W., Bielak, L., Steltz, S. K., … Ludwig, D. S. (2018a). Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial. BMJ (Clinical Research Ed.), 363, k4583. https://doi.org/10.1136/bmj.k4583

Ebbeling, C. B., Feldman, H. A., Klein, G. L., Wong, J. M. W., Bielak, L., Steltz, S. K., … Ludwig, D. S. (2018b). Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial. BMJ (Clinical Research Ed.), 363, k4583. https://doi.org/10.1136/bmj.k4583

Ebbeling, C. B., Swain, J. F., Feldman, H. A., Wong, W. W., Hachey, D. L., Garcia-Lago, E., & Ludwig, D. S. (2012). Effects of Dietary Composition on Energy Expenditure During Weight-Loss Maintenance. JAMA, 307(24), 2627–2634. https://doi.org/10.1001/jama.2012.6607

Gardner, C. D., Trepanowski, J. F., Del Gobbo, L. C., Hauser, M. E., Rigdon, J., Ioannidis, J. P. A., … King, A. C. (2018). Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association With Genotype Pattern or Insulin Secretion. JAMA, 319(7), 667. https://doi.org/10.1001/jama.2018.0245

Gibson, A. A., Seimon, R. V., Lee, C. M. Y., Ayre, J., Franklin, J., Markovic, T. P., … Sainsbury, A. (2015). Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. Obesity Reviews, 16(1), 64–76. https://doi.org/10.1111/obr.12230

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Hall, K. D., Chen, K. Y., Guo, J., Lam, Y. Y., Leibel, R. L., Mayer, L. E., … Ravussin, E. (2016). Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men. The American Journal of Clinical Nutrition, 104(2), 324–333. https://doi.org/10.3945/ajcn.116.133561

Hall, K. D., & Guo, J. (2017). Obesity Energetics: Body Weight Regulation and the Effects of Diet Composition. Gastroenterology, 152(7), 1718-1727.e3. https://doi.org/10.1053/J.GASTRO.2017.01.052

Hall, K. D., & Guo, J. (2019). Carbs versus fat: does it really matter for maintaining lost weight? BioRxiv, 476655. https://doi.org/10.1101/476655

Hallberg, S. J., McKenzie, A. L., Williams, P. T., Bhanpuri, N. H., Peters, A. L., Campbell, W. W., … Volek, J. S. (2018). Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study. Diabetes Therapy, 9(2), 583–612. https://doi.org/10.1007/s13300-018-0373-9

Jenkins, D. J. A., Wong, J. M. W., Kendall, C. W. C., Esfahani, A., Ng, V. W. Y., Leong, T. C. K., … Singer, W. (2014). Effect of a 6-month vegan low-carbohydrate (‘Eco-Atkins’) diet on cardiovascular risk factors and body weight in hyperlipidaemic adults: a randomised controlled trial. BMJ Open, 4(2), e003505. https://doi.org/10.1136/BMJOPEN-2013-003505

Lutter, M., & Nestler, E. J. (2009). Homeostatic and Hedonic Signals Interact in the Regulation of Food Intake. The Journal of Nutrition, 139(3), 629–632. https://doi.org/10.3945/jn.108.097618

Marchiò, M., Roli, L., Lucchi, C., Costa, A. M., Borghi, M., Iughetti, L., … Biagini, G. (2019). Ghrelin Plasma Levels After 1 Year of Ketogenic Diet in Children With Refractory Epilepsy. Frontiers in Nutrition, 6, 112. https://doi.org/10.3389/fnut.2019.00112

Stubbs, B. J., Cox, P. J., Evans, R. D., Cyranka, M., Clarke, K., & de Wet, H. (2018). A Ketone Ester Drink Lowers Human Ghrelin and Appetite. Obesity, 26(2), 269–273. https://doi.org/10.1002/oby.22051

Sumithran, P., Prendergast, L. A., Delbridge, E., Purcell, K., Shulkes, A., Kriketos, A., & Proietto, J. (2013). Ketosis and appetite-mediating nutrients and hormones after weight loss. European Journal of Clinical Nutrition, 67(7), 759–764. https://doi.org/10.1038/ejcn.2013.90

Volek, J., Phinney, S. D., Kossoff, E., Eberstein, J. A., & Moore, J. (2011). The art and science of low carbohydrate living : an expert guide to making the life-saving benefits of carbohydrate restriction sustainable and enjoyable. Retrieved from https://www.goodreads.com/book/show/11476367-the-art-and-science-of-low-carbohydrate-living?ac=1&from_search=true

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3 Comments

  1. So there’s no long term advantages of keto, and this doesn’t go into the possible negatives of high red meat and saturated fats that the diet encourages, plus the avoidance of whole grains and fruits.

  2. 1)which on average show a slight metabolic advantage in fact for low-fat diets (Hall & Guo, 2017).

    This article says nothing about ketogenic diet. The tables shown there state Low carb which we dont know even what this means. If you want to be precise and say the truth you have to write all these different studies that are labeled there and tell us if they are ketogenic or not. Which I suspect are not since very few of them are new and I am sure have no idea what ketogenic diet it.

    2)Title: “The ketogenic diet and weight loss: a critical look at the science in humans”
    Your argument: “Twelve-month weight loss: low-carb vs. low-fat diets”
    Find the mistake.

    You are comparing wrong diets. Just the title is catchy I guess.

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