The following is an early draft of a section of a scientific review article in preparation.

Observational studies are largely consistent in showing an association between low-carbohydrate dietary patterns and increased risk of cancer, cardiovascular, and all-cause mortality [1], which would seem to recommend against low-carbohydrate diets for the purpose of health or cancer prevention. One well-known study from Japan seemingly contradicts this trend [2]. However, the cutoff of the lowest decile of carbohydrate intake percent in this study as a fraction of total macronutrients was 53.5%, while the mean intake in this decile was 51.5%, suggesting a very narrow range of carbohydrate intake well outside the low-carbohydrate or carbohydrate-restricted range [1]; in this cohort from 1980, moreover, the Atkin’s diet was reportedly virtually unknown [2]. These results are not unlike those found in the Prospective Urban and Rural Epidemiological (PURE) study, which too has been recently cited as providing evidence in favor of low-carbohydrate diets: while there was a dose-response relationship between carbohydrate intake and mortality risk in PURE, the carbohydrate intake of those with the lowest all-cause mortality was slightly lower than 55% [3], which is exactly the median carbohydrate intake of the Acceptable Macronutrient Distribution Range recommended by the 2015-2020 Dietary Guidelines for Americans [4]. This is also almost the exact same intake value found in the recently published Atherosclerosis Risk in Communities (ARIC) study and its associated meta-analysis of previous studies, including PURE [5]. A recent editorial written by PURE principal investigators looked at all eight major cohort studies examining this question and concluded: “Taking all the studies into account, the message of moderation is perhaps the most convincing one of all— diets that focus too heavily on a single macronutrient, whether extreme protein, carbohydrate, or fat intake, may adversely impact health” [6].


Lending confidence to the conclusions of these studies are the sophisticated study designs in these studies. In ARIC, for example, sensitivity analyses ruled out an impact of major chronic disease on diet (reverse causation); a dose-response relationship between low-carbohydrate diet quintile and mean soft drink consumption for that quintile suggested that this dietary pattern was intentional for a large proportion of individuals rather than incidental; and control for a variety of disease confounders further reduced the potential for reverse causality [5]. However, these findings are qualified by their observational nature and residual confounding cannot be ruled out.

Moreover, individually, diets high in fiber have been shown in meta-analyses to be consistently associated with lower all-cause and specific-cause mortality [7], as well as lower rates of colorectal cancer [8–11], breast [12], and ovarian cancer [13,14]. Diets higher in fiber, fruit, and vegetables during adolescence have each been associated with lower rates of breast cancer in later life [15–17]. Diets high in whole grains have been associated with lower risk of colorectal cancer [10], breast cancer [18], inflammatory markers [19], and insulin sensitivity, possibly via novel betainized compounds [20], while diets higher in nuts show an inverse association with total mortality [21], with a recent meta-analysis pointing toward an association between nut intake and lower cancer risk [22]. A recent meta-analysis of observational trials suggested that diets high in whole grains and cereal fibers was inversely associated with type 2 diabetes [23], established as a robust risk factor for cancer in 121 cohorts and 20 million people [24], while red meat and sugar-sweetened beverages were positively associated with risk [23]. Likewise, a recent and largest meta-analysis to date published on the topic shows a robust inverse relationship between fiber intake and cancer and all-cause mortality [25]. Meanwhile, a recent meta-analyses has suggested a relationship between saturated fat intake and breast cancer [26]; a recent cohort study in prostate cancer patients a link between saturated fat intake and cancer aggressiveness; and many studies, a link red and processed meat and cancer-specific and all-cause mortality, which is widely regarded as causal for processed meat [21,27,28]. Epidemiological associations between consumption of minimally processed plant foods and low disease risk, on the one hand, and between consumption of animal foods and high disease risk are consistent with short-term biomarker RCTs and animal studies and current widely accepted theories of disease (refs).

On the other hand, recent observational studies have established a link between simple carbohydrate intake and survival in head-and-neck cancer patients [29], between random blood glucose, HbA1c, and fasting blood glucose readings and survival in patients with solid tumors [30], between glycemic index and load and risk of mortality [31], between fiber intake and survival after cancer diagnosis [32], and between dietary insulin load and survival after chemotherapy for stage 3 colon cancer [32]. In a cohort study of 1011 stage III colon cancer patients, dietary carbohydrate and glycemic load was associated with decreased disease-free survival and cancer recurrence in obese and overweight but not lean patients [33]. A review of the current evidence concluded that the evidence for an effect of glycemic index and load on cancer is inconsistent, with findings from the largest meta-analyses that are either positive or null [34]. Likewise, in a recent systematic review of cohort studies, most studies were reported to have shown a null association between sugar intake and cancer, but some associations were suggested for added sugars and sugary beverages [35]. This suggests a modest or contextually dependent effect of glycemic load, glycemic index, and/or carbohydrate on cancer.

Despite the consistent relationship of low-carbohydrate diets on cancer mortality in prospective cohort studies, and consistent with the above findings, when investigators have defined two populations of low-carbohydrate eaters—those with high animal-based and those with high plant-based scores [2,36]—the animal-based low-carbohydrate diet was associated with higher total and cancer mortality, while plant-based low-carbohydrate diets decrease it. For instance, in a Nurses’ Health Study/Health Professionals Follow-up Study cohort of 1575 patients diagnosed with colorectal cancer, a low-carbohydrate, plant-rich diet was associated with a 30% reduced risk of all-cause mortality and a 63% reduced risk of cancer mortality, while a low-carbohydrate, animal-rich diet was associated with a higher or neutral risk of all-cause and cancer mortality [37], consistent with a study from the same group showing that persons consuming diets high in fiber also show a reduced all-cause and cancer mortality after colorectal cancer diagnosis [32]. This finding has been consistently observed in the general population for total and cancer mortality in multiple, diverse cohorts [5,38], with the exception of NIPPON DATA80, which found no difference in mortality risk between plant- and animal-based diets with a low-carbohydrate score [2]. Similar findings have been observed for cohorts analyzed along the lines of animal vs. plant protein intake, with plant protein consistently associated with neutral [39] or lower risk [40–43] and animal protein with higher risk of total and cancer mortality [41–44].

Despite these findings, it should be pointed out that none of the quantiles analyzed in the above studies were in the ketogenic range, with ARIC reporting the lowest carbohydrate intake of all, in one analysis in the lowest quantile a mean of 26.3%, far above that normally required for ketogenesis. This lack of epidemiological analysis of very low-carbohydrate diets may be due to long-term adherence to ketogenic diets being uncommon. It may be possible, therefore, that while animal-based low-carbohydrate diets are associated with higher mortality out of the ketogenic range due to interactions with other components of the diet, animal-based ketogenic diets might not show this disadvantage. This possibility is suggested by two recent rodent longevity studies comparing the ketogenic diet to high-fat and control diets. The high-fat and control diets had comparable health effects, while when carbohydrate was completely excluded, a substantial increase in both healthspan and median lifespan was obtained [45,46], with one of these studies reporting a statistically significant reduction in cancer in the ketogenic diet group [46]. If a similar effect occurs in humans, then the reported findings of a higher mortality in those with lower-carbohydrate diets in the epidemiological literature could still be consistent with a longevity advantage of an animal-based ketogenic diet. Indeed, a recent exploratory report showed that a small glucose bolus given to subjects on a ketogenic diet produced markers of acute cardiovascular damage [47], suggesting one potential mechanism (in addition to elevation in apolipoprotein B from high saturated fat intake) for elevated cardiovascular disease risk for subjects in the cohort studies.

Two further considerations warrant caution. First, if as DIETFITS suggests (discussed above) [48] and the paucity of very low-carbohydrate subjects in the above-discussed cohorts points to, then long-term adherence to a very low-carbohydrate ketogenic diet is possibly very low. With substantial carbohydrate intake thwarting ketogenesis and placing subjects in the carbohydrate intake range indicated by these studies, then recommendations to consume a ketogenic diet might pose inherent health risk due to variation in adherence in a substantial proportion of the population to which such recommendations might be directed. In other words, if non-adherence with the ketogenic diet is the rule rather than the exception, population-level recommendations for a ketogenic diet are inappropriate if animal-based lower-carb but not ketogenic dietary intakes are the norm among ketogenic dieters. Second, if the above findings point to a health advantage of plants and a disadvantage of meat and other animal products, then these health effects would be conceivably maintained even at ketogenic macronutrient compositions, even if ketosis itself offers independent advantages. In other words, the above studies, while not in those on ketogenic dieters, nonetheless point toward a ketogenic diet higher in plants as being preferable to one higher in animal products. Therefore, if a ketogenic diet may be substantially cancer preventive or curative, one that is higher in fiber and plants and lower in saturated fats and animal products is, according to current evidence, most likely to be the most healthful version, absent RCT data to the contrary.

1.        Mazidi, M.; Katsiki, N.; Mikhailidis, D.P.; Sattar, N.; Banach, M. Lower carbohydrate diets and all-cause and cause-specific mortality: a population-based cohort study and pooling of prospective studies. Eur. Heart J. 2019.

2.        Nakamura, Y.; Okuda, N.; Okamura, T.; Kadota, A.; Miyagawa, N.; Hayakawa, T.; Kita, Y.; Fujiyoshi, A.; Nagai, M.; Takashima, N.; et al. Low-carbohydrate diets and cardiovascular and total mortality in Japanese: a 29-year follow-up of NIPPON DATA80. Br. J. Nutr. 2014, 112, 916–924.

3.        Dehghan, M.; Mente, A.; Zhang, X.; Swaminathan, S.; Li, W.; Mohan, V.; Iqbal, R.; Kumar, R.; Wentzel-Viljoen, E.; Rosengren, A.; et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet (London, England) 2017, 390, 2050–2062.

4.        Odphp 2015-2020 Dietary Guidelines for Americans; 2015;

5.        Seidelmann, S.B.; Claggett, B.; Cheng, S.; Henglin, M.; Shah, A.; Steffen, L.M.; Folsom, A.R.; Rimm, E.B.; Willett, W.C.; Solomon, S.D. Articles Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis. Lancet Public Heal. 2018, 3, e419–e428.

6.        de Souza, R.J.; Dehghan, M.; Anand, S.S. Low carb or high carb? Everything in moderation … until further notice. Eur. Heart J. 2019.

7.        Veronese, N.; Solmi, M.; Caruso, M.G.; Giannelli, G.; Osella, A.R.; Evangelou, E.; Maggi, S.; Fontana, L.; Stubbs, B.; Tzoulaki, I. Dietary fiber and health outcomes: an umbrella review of systematic reviews and meta-analyses. Am. J. Clin. Nutr. 2018, 107, 436–444.

8.        Ma, Y.; Hu, M.; Zhou, L.; Ling, S.; Li, Y.; Kong, B.; Huang, P. Dietary fiber intake and risks of proximal and distal colon cancers: A meta-analysis. Medicine (Baltimore). 2018, 97, e11678.

9.        Gianfredi, V.; Salvatori, T.; Villarini, M.; Moretti, M.; Nucci, D.; Realdon, S. Is dietary fibre truly protective against colon cancer? A systematic review and meta-analysis. Int. J. Food Sci. Nutr. 2018, 69, 904–915.

10.      Schwingshackl, L.; Schwedhelm, C.; Hoffmann, G.; Knüppel, S.; Laure Preterre, A.; Iqbal, K.; Bechthold, A.; De Henauw, S.; Michels, N.; Devleesschauwer, B.; et al. Food groups and risk of colorectal cancer. Int. J. Cancer 2018, 142, 1748–1758.

11.      Aicr; WCRF Wholegrains, vegetables and fruit and the risk of cancer;

12.      Chen, S.; Chen, Y.; Ma, S.; Zheng, R.; Zhao, P.; Zhang, L.; Liu, Y.; Yu, Q.; Deng, Q.; Zhang, K. Dietary fibre intake and risk of breast cancer: A systematic review and meta-analysis of epidemiological studies. Oncotarget 2016, 7, 80980–80989.

13.      Zheng, B.; Shen, H.; Han, H.; Han, T.; Qin, Y. Dietary fiber intake and reduced risk of ovarian cancer: a meta-analysis. Nutr. J. 2018, 17, 99.

14.      Huang, X.; Wang, X.; Shang, J.; Lin, Y.; Yang, Y.; Song, Y.; Yu, S. Association between dietary fiber intake and risk of ovarian cancer: a meta-analysis of observational studies. J. Int. Med. Res. 2018, 46, 3995–4005.

15.      Farvid, M.S.; Eliassen, A.H.; Cho, E.; Liao, X.; Chen, W.Y.; Willett, W.C. Dietary Fiber Intake in Young Adults and Breast Cancer Risk. Pediatrics 2016, 137, e20151226.

16.      Farvid, M.S.; Chen, W.Y.; Michels, K.B.; Cho, E.; Willett, W.C.; Eliassen, A.H. Fruit and vegetable consumption in adolescence and early adulthood and risk of breast cancer: population based cohort study. BMJ 2016, 353, i2343.

17.      Farvid, M.S.; Chen, W.Y.; Rosner, B.A.; Tamimi, R.M.; Willett, W.C.; Eliassen, A.H. Fruit and vegetable consumption and breast cancer incidence: Repeated measures over 30 years of follow-up. Int. J. Cancer 2019, 144, 1496–1510.

18.      Xiao, Y.; Ke, Y.; Wu, S.; Huang, S.; Li, S.; Lv, Z.; Yeoh, E.; Lao, X.; Wong, S.; Kim, J.H.; et al. Association between whole grain intake and breast cancer risk: a systematic review and meta-analysis of observational studies. Nutr. J. 2018, 17, 87.

19.      Xu, Y.; Wan, Q.; Feng, J.; Du, L.; Li, K.; Zhou, Y. Whole grain diet reduces systemic inflammation: A meta-analysis of 9 randomized trials. Med. (United States) 2018, 97.

20.      Kärkkäinen, O.; Lankinen, M.A.; Vitale, M.; Jokkala, J.; Leppänen, J.; Koistinen, V.; Lehtonen, M.; Giacco, R.; Rosa-Sibakov, N.; Micard, V.; et al. Diets rich in whole grains increase betainized compounds associated with glucose metabolism. Am. J. Clin. Nutr. 2018, 108, 971–979.

21.      Schwingshackl, L.; Schwedhelm, C.; Hoffmann, G.; Lampousi, A.-M.; Knüppel, S.; Iqbal, K.; Bechthold, A.; Schlesinger, S.; Boeing, H. Food groups and risk of all-cause mortality: a systematic review and meta-analysis of prospective studies. Am. J. Clin. Nutr. 2017, 105, 1462–1473.

22.      Wu, L.; Wang, Z.; Zhu, J.; Murad, A.L.; Prokop, L.J.; Murad, M.H. Nut consumption and risk of cancer and type 2 diabetes: A systematic review and meta-analysis. Nutr. Rev. 2015, 73, 409–425.

23.      Neuenschwander, M.; Ballon, A.; Weber, K.S.; Norat, T.; Aune, D.; Schwingshackl, L.; Schlesinger, S. Role of diet in type 2 diabetes incidence: Umbrella review of meta-analyses of prospective observational studies. BMJ 2019, 366.

24.      Ohkuma, T.; Peters, S.A.E.; Woodward, M. Sex differences in the association between diabetes and cancer: a systematic review and meta-analysis of 121 cohorts including 20 million individuals and one million events. Diabetologia 2018, 61, 2140–2154.

25.      Reynolds, A.; Mann, J.; Cummings, J.; Winter, N.; Mete, E.; Te Morenga, L. Carbohydrate quality and human health: a series of systematic reviews and meta-analyses. Lancet (London, England) 2019, 393, 434–445.

26.      Brennan, S.F.; Woodside, J. V; Lunny, P.M.; Cardwell, C.R.; Cantwell, M.M. Dietary fat and breast cancer mortality: A systematic review and meta-analysis. Crit. Rev. Food Sci. Nutr. 2017, 57, 1999–2008.

27.      Wolk, A. Potential health hazards of eating red meat. J. Intern. Med. 2017, 281, 106–122.

28.      Etemadi, A.; Sinha, R.; Ward, M.H.; Graubard, B.I.; Inoue-Choi, M.; Dawsey, S.M.; Abnet, C.C. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study. BMJ 2017, 357, j1957.

29.      Arthur, A.E.; Goss, A.M.; Demark-Wahnefried, W.; Mondul, A.M.; Fontaine, K.R.; Chen, Y.T.; Carroll, W.R.; Spencer, S.A.; Rogers, L.Q.; Rozek, L.S.; et al. Higher carbohydrate intake is associated with increased risk of all-cause and disease-specific mortality in head and neck cancer patients: results from a prospective cohort study. Int. J. Cancer 2018, 143, 1105–1113.

30.      Barua, R.; Templeton, A.J.; Seruga, B.; Ocana, A.; Amir, E.; Ethier, J.-L. Hyperglycaemia and Survival in Solid Tumours: A Systematic Review and Meta-analysis. Clin. Oncol. 2018, 30, 215–224.

31.      Shahdadian, F.; Saneei, P.; Milajerdi, A.; Esmaillzadeh, A. Dietary glycemic index, glycemic load, and risk of mortality from all causes and cardiovascular diseases: a systematic review and dose-response meta-analysis of prospective cohort studies. Am. J. Clin. Nutr. 2019.

32.      Song, M.; Wu, K.; Meyerhardt, J.A.; Ogino, S.; Wang, M.; Fuchs, C.S.; Giovannucci, E.L.; Chan, A.T. Fiber Intake and Survival After Colorectal Cancer Diagnosis. JAMA Oncol. 2018, 4, 71.

33.      Meyerhardt, J.A.; Sato, K.; Niedzwiecki, D.; Ye, C.; Saltz, L.B.; Mayer, R.J.; Mowat, R.B.; Whittom, R.; Hantel, A.; Benson, A.; et al. Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J. Natl. Cancer Inst. 2012, 104, 1702–11.

34.      Maino Vieytes, C.A.; Taha, H.M.; Burton-Obanla, A.A.; Douglas, K.G.; Arthur, A.E. Carbohydrate Nutrition and the Risk of Cancer. Curr. Nutr. Rep. 2019.

35.      Makarem, N.; Bandera, E. V.; Nicholson, J.M.; Parekh, N. Consumption of Sugars, Sugary Foods, and Sugary Beverages in Relation to Cancer Risk: A Systematic Review of Longitudinal Studies. Annu. Rev. Nutr. 2018, 38, 17–39.

36.      Fung, T.T.; Willett, W.C.; Stampfer, M.J.; Manson, J.A.E.; Hu, F.B. Dietary patterns and the risk of coronary heart disease in women. Arch. Intern. Med. 2001, 161, 1857–1862.

37.      Song, M.; Wu, K.; Meyerhardt, J.A.; Yilmaz, O.; Wang, M.; Ogino, S.; Fuchs, C.S.; Giovannucci, E.L.; Chan, A.T. Low-Carbohydrate Diet Score and Macronutrient Intake in Relation to Survival After Colorectal Cancer Diagnosis. JNCI Cancer Spectr. 2018, 2.

38.      Fung, T.T.; Van Dam, R.M.; Hankinson, S.E.; Stampfer, M.; Willett, W.C.; Hu, F.B. Low-carbohydrate diets and all-cause and cause-specific mortality: Two cohort studies. Ann. Intern. Med. 2010, 153, 289–298.

39.      Nilsson, L.M.; Winkvist, A.; Johansson, I.; Lindahl, B.; Hallmans, G.; Lenner, P.; Van Guelpen, B. Low-carbohydrate, high-protein diet score and risk of incident cancer; A prospective cohort study. Nutr. J. 2013, 12.

40.      Kelemen, L.E.; Kushi, L.H.; Jacobs, D.R.; Cerhan, J.R. Associations of dietary protein with disease and mortality in a prospective study of postmenopausal women. Am. J. Epidemiol. 2005, 161, 239–249.

41.      Levine, M.E.; Suarez, J.A.; Brandhorst, S.; Balasubramanian, P.; Cheng, C.W.; Madia, F.; Fontana, L.; Mirisola, M.G.; Guevara-Aguirre, J.; Wan, J.; et al. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab. 2014, 19, 407–417.

42.      Song, M.; Fung, T.T.; Hu, F.B.; Willett, W.C.; Longo, V.D.; Chan, A.T.; Giovannucci, E.L. Association of animal and plant protein intake with all-cause and cause-specific mortality. JAMA Intern. Med. 2016, 176, 1453–1463.

43.      Virtanen, H.E.K.; Voutilainen, S.; Koskinen, T.T.; Mursu, J.; Kokko, P.; Ylilauri, M.P.T.; Tuomainen, T.P.; Salonen, J.T.; Virtanen, J.K. Dietary proteins and protein sources and risk of death: The Kuopio ischaemic heart disease risk factor study. Am. J. Clin. Nutr. 2019, 109, 1462–1471.

44.      Hernández-Alonso, P.; Salas-Salvadó, J.; Ruiz-Canela, M.; Corella, D.; Estruch, R.; Fitó, M.; Arós, F.; Gómez-Gracia, E.; Fiol, M.; Lapetra, J.; et al. High dietary protein intake is associated with an increased body weight and total death risk. Clin. Nutr. 2016, 35, 496–506.

45.      Newman, J.C.; Covarrubias, A.J.; Zhao, M.; Yu, X.; Gut, P.; Ng, C.P.; Huang, Y.; Haldar, S.; Verdin, E. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice. Cell Metab. 2017, 26, 547-557.e8.

46.      Roberts, M.N.; Wallace, M.A.; Tomilov, A.A.; Zhou, Z.; Marcotte, G.R.; Tran, D.; Perez, G.; Gutierrez-Casado, E.; Koike, S.; Knotts, T.A.; et al. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab. 2017, 26, 539-546.e5.

47.      Durrer, C.; Lewis, N.; Wan, Z.; Ainslie, P.N.; Jenkins, N.T.; Little, J.P. Short-term low-carbohydrate high-fat diet in healthy young males renders the endothelium susceptible to hyperglycemia-induced damage, an exploratory analysis. Nutrients 2019, 11.

48.      Gardner, C.D.; Trepanowski, J.F.; Del Gobbo, L.C.; Hauser, M.E.; Rigdon, J.; Ioannidis, J.P.A.; Desai, M.; King, A.C. 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 2018, 319, 667.

Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

Enjoy this content? Without your financial help, this blog is in critical danger of not surviving. Donate here: