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 , 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 . 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 ; in this cohort from 1980, moreover, the Atkin’s diet was reportedly virtually unknown . 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% , which is exactly the median carbohydrate intake of the Acceptable Macronutrient Distribution Range recommended by the 2015-2020 Dietary Guidelines for Americans . 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 . 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” .
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 . 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 , as well as lower rates of colorectal cancer [8–11], breast , 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 , breast cancer , inflammatory markers , and insulin sensitivity, possibly via novel betainized compounds , while diets higher in nuts show an inverse association with total mortality , with a recent meta-analysis pointing toward an association between nut intake and lower cancer risk . A recent meta-analysis of observational trials suggested that diets high in whole grains and cereal fibers was inversely associated with type 2 diabetes , established as a robust risk factor for cancer in 121 cohorts and 20 million people , while red meat and sugar-sweetened beverages were positively associated with risk . 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 . Meanwhile, a recent meta-analyses has suggested a relationship between saturated fat intake and breast cancer ; 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 , between random blood glucose, HbA1c, and fasting blood glucose readings and survival in patients with solid tumors , between glycemic index and load and risk of mortality , between fiber intake and survival after cancer diagnosis , and between dietary insulin load and survival after chemotherapy for stage 3 colon cancer . 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 . 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 . 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 . 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 , 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 . 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 . Similar findings have been observed for cohorts analyzed along the lines of animal vs. plant protein intake, with plant protein consistently associated with neutral  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 . 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 , 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)  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.
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