nutrients

Review
The Potential Health Benefits of the Ketogenic Diet:
A Narrative Review
Kathryn Dowis and Simran Banga *

Department of Biology, Western Kentucky University, Bowling Green, KY 42101, USA;

[email protected]
* Correspondence: [email protected]; Tel.: +270-745-4748

Abstract: Considering the lack of a comprehensive, multi-faceted overview of the ketogenic diet
(KD) in relation to health issues, we compiled the evidence related to the use of the ketogenic diet
in relation to its impact on the microbiome, the epigenome, diabetes, weight loss, cardiovascular
health, and cancer. The KD diet could potentially increase genetic diversity of the microbiome and
increase the ratio of Bacteroidetes to Firmicutes. The epigenome might be positively affected by the KD
since it creates a signaling molecule known as β-hydroxybutyrate (BHB). KD has helped patients
with diabetes reduce their HbA1c and reduce the need for insulin. There is evidence to suggest
that a KD can help with weight loss, visceral adiposity, and appetite control. The evidence also
suggests that eating a high-fat diet improves lipid profiles by lowering low-density lipoprotein (LDL),
increasing high-density lipoprotein (HDL), and lowering triglycerides (TG). Due to the Warburg
effect, the KD is used as an adjuvant treatment to starve cancer cells, making them more vulnerable
to chemotherapy and radiation. The potential positive impacts of a KD on each of these areas
warrant further analysis, improved studies, and well-designed randomized controlled trials to
further illuminate the therapeutic possibilities provided by this dietary intervention.





 Keywords: β-hydroxybutyrate (BHB); body mass index (BMI), type 1 diabetes; type 2 diabetes (T2D);
Citation: Dowis, K.; Banga, S. The hemoglobin A1c (HbA1c); visceral adipose tissue (VAT); cardiovascular disease (CVD); high-density
Potential Health Benefits of the lipoprotein (HDL); low-density lipoprotein (LDL); Apolipoprotein B (ApoB)
Ketogenic Diet: A Narrative Review.
Nutrients 2021, 13, 1654. https://
doi.org/10.3390/nu13051654

1. Introduction
Academic Editor: Marcellino Monda
Ketogenic diets have started to increase in popularity as doctors and researchers
investigate the potential benefits. Nutritional ketosis, the aspirational endpoint of ketogenic
Received: 7 April 2021
Accepted: 9 May 2021
diets, is achieved by restricting carbohydrate intake, moderating protein consumption, and
Published: 13 May 2021
increasing the number of calories obtained from fat [1]. Theoretically, this restriction of
carbohydrates causes the body to switch from glucose metabolism as a primary means of
Publisher’s Note: MDPI stays neutral
energy production. This results in the use of ketone bodies from fat metabolism, a metabolic
with regard to jurisdictional claims in
state where the body prefers to utilize fat as its primary fuel source. Recent studies utilizing
published maps and institutional affil- Low-carbohydrate, High-fat (LCHF) diets, such as the ketogenic diet, show promise in
iations. helping patients lose weight, reverse the signs of metabolic syndrome, reduce, or eliminate
insulin requirements for type II diabetics [2], reduce inflammation, improve epigenetic
profiles, alter the microbiome, improve lipid profiles, supplement cancer treatments, and
potentially increase longevity [3] and brain function.
Copyright: © 2021 by the authors.
The number of Americans suffering from obesity, diabetes, and metabolic syndrome
Licensee MDPI, Basel, Switzerland.
is on the rise. The markers of metabolic syndrome include an increase in abdominal
This article is an open access article
adiposity, insulin resistance, elevated triglycerides, and hypertension [4,5]. All of these
distributed under the terms and negative health markers increase the risk of cardiovascular disease, diabetes, stroke, and
conditions of the Creative Commons Alzheimer’s disease. According to WebMD, there are currently 27 million people with
Attribution (CC BY) license (https:// Type 2 diabetes and 86 million with pre-diabetes. In addition, the Centers of Disease
creativecommons.org/licenses/by/ Control and Prevention (CDC) also estimates that almost 40% of adults and around 20% of
4.0/). American children are obese [6,7]. Many researchers believe these diseases are a result of

Nutrients 2021, 13, 1654. https://doi.org/10.3390/nu13051654 https://www.mdpi.com/journal/nutrients

Nutrients 2021, 13, 1654 2 of 29

carbohydrate intolerance and insulin resistance. Thus, a diet that reduces the exposure to
carbohydrates, including whole grains, might become a more logical recommendation for
improving health [8]. In line with this, two dietary regimens, the standard ketogenic diet,
and the therapeutic ketogenic diet (Figure 1), which restrict carbohydrate consumption to
varying degrees are being studied for their health impacts. The therapeutic ketogenic diet,
which severely restricts both carbohydrates and protein, is typically used in the treatment
of epilepsy and cancer. However, the Dietary Guidelines for Americans suggests that
between 45 and 65% of caloric intake should come from carbohydrates (Figure 1). If a
person consumed 2000 calories per day that would equate to an average of 225–325 g of
carbohydrates each day [9].

Figure 1. A comparison between the macronutrient breakdown of the standard American diet, therapeutic ketogenic diet,
and the typical ketogenic diet. The therapeutic ketogenic diet is typically used in epilepsy and cancer treatments.

One emerging diet that is becoming mainstream is a low-carb/high-fat diet. However,

there is a difference between a low-carb and a low-carb ketogenic diet (LCKD). Ketosis
is normally achieved through either fasting or carbohydrate restriction. It is important
to clarify that a low-carb diet typically refers to a diet with an intake of 50 to 150 g of
carbohydrate per day. However, although this is a lower amount of carbohydrates than
the standard American diet, it is not low enough to enter nutritional ketosis. Only when a
patient restricts carbohydrates to less than 50 g/day will the body be incapable of fueling
the body by glucose and will switch to burning fat [10]. The ketogenic diet is a reversal
of the current food pyramid supported by the dietary guidelines. Thus, instead of a diet
rich in carbohydrates, it is high in fat (Figure 2). The resulting carbohydrate restriction
lowers blood glucose levels, and the subsequent insulin changes will instruct the body to
change from a state of storing fat to a state of fat oxidation [10]. Once fats are utilized as the
primary fuel source in the liver, the production of ketone bodies begins, a process known
as ketogenesis. During ketosis, three major ketone bodies are formed and utilized by the
body for energy: acetone, acetoacetate, and β-hydroxybutyrate [11]. All cells that contain
mitochondria can meet their energy demands with ketone bodies, including the brain and
muscle. In addition, research suggests that β-hydroxybutyrate acts as a signal molecule
and may play a role in suppressing appetite [12].
Nutrients 2021, 13, 1654 3 of 29

Figure 2. A visual comparison of the recommended dietary food pyramid, including major macro-
molecule components, to the ketogenic diet food pyramid.

However, there is some heterogeneity in the available data. Thus, the aim of this
review is to highlight the role the ketogenic diet has in altering the microbiome, epigenetics,
weight loss, diabetes, cardiovascular disease, and cancer as summarized below (Figure 3).

Figure 3. The potential therapeutic impacts of the ketogenic diet on the microbiome, epigenome, diabetes, weight loss and
cardiovascular disease.

2. The Effect of the Ketogenic Diet on the Microbiome

The microbiome consists of trillions of microscopic organisms in the human gastroin-
testinal tract. It comprises over 8000 different types of bacteria, viruses, and fungi living
in a complex ecosystem [13]. Recent research suggests that the genetic make-up of a mi-
crobiome can be affected by lifestyle factors which include but are not limited to sleep,
Nutrients 2021, 13, 1654 4 of 29

exercise, antibiotic use, and even diet. These bacteria can alter our response to different
food sources because they differ in their ability to harvest energy from food, affecting the
postprandial glucose response (PPGR) [13]. Since the controlling of glucose levels in the
blood seems to reduce the risk of metabolic disease, diabetes, and obesity, this might be an
innovative way to help reduce disease risk. A study conducted at the Weizmann Institute
demonstrated that a mathematical algorithm could be used to determine an individual’s
microbiome profile and predict their glycemic response to different types of foods [14].
Thus, the patients were able to change from stable blood glucose to unstable levels by
simply eating the foods that the program predicted as good or bad based on their micro-
biome. Their initial results were confirmed by a repeat study at the Mayo Clinic with a
different population [13]. It is important to note that the composition of the microbiome,
which is believed to have a fundamental role in human health, is shaped predominantly
by environmental factors. According to a study conducted by Rothschild et al. [15], the
average heritability of the gut microbiome taxa is only 1.9%, while over 20% of variability
was associated with diet and lifestyle.
Thus, research into the complex interactions that exist between diet, the microbiome,
and host metabolic rates have increased. A study exploring the benefits of prebiotic foods,
such as inulin and oligosaccharides, observed an increase in the number of Bifidobacteria in
the colon and the presence of other critical butyrate-producing bacteria [16]. Another study
determined that the diversity of the gut microbiota was influenced more by a Westernized
diet than by the body mass index of the subjects [17]. The patients who followed the
Westernized diet showed an increase in Firmicutes and a decrease in Bacteroidetes in their
microbiome, which are negative changes. A review article also reported positive changes
in the gut microbiome and overall health in energy-restrictive diets or diets rich in fiber
and vegetables [18]. Thus, people eating processed and bland food had reduced diversity
of their microbiota, while people eating a diet rich in fruit and vegetables had increased
diversity in their gut microbiota [19]. Moreover, gut biomes that lacked genetic diversity
were related to overall adiposity, insulin resistance, dyslipidemia, and an inflammatory
phenotype [20].
Discovering how the gut microbiota and diet interact and how this interaction is
connected to overall health, is critical. It is important to determine whether new dietary
changes, such as a ketogenic diet, will positively or negatively affect overall microbiome di-
versity and species make-up. Some research has found that whole grains play an important
role in the development of a healthy microbiome and are necessary for good health [21].
Thus, a person consuming a ketogenic diet might not consume enough whole grains to
maintain a healthy microbiome [12]. According to Adam-Perrot et al. [12] low-carb diets
are at greater risk of being nutritionally inadequate by lacking in fiber, necessary vitamins,
minerals, and iron. This idea is based on analysis of popular diets and food surveys con-
ducted to determine nutrient intake while consuming varying levels of carbohydrates [22].
Thus, it is even more critical that people on a LCKD choose desirable low carbohydrate
foods that are rich in fiber. In addition, a ketogenic diet should maintain moderate protein
intake of around 1.5 g/day per kg of respective body weight [23]. If people consume red
meat and organ meats, then they should be able to obtain adequate amounts of iron as well.
Additionally, the consumption of small amounts of leafy greens, nuts, berries, and resistant
starchy vegetables, all of which are optional ketogenic foods, could potentially maintain
healthy gut microbiota [23].
Currently, scientists do not have any data on the long-term effects of the ketogenic
diet on the gut microbiome. Based on various studies, many predict that the diet will
positively affect the microbiome by increasing the Bacteroidetes and Bifidobacteria species
associated with improved health and decreasing microbial species known to increase health
risks. In fact, a study found that the disrupted gut microbiota of epileptic infants was
improved with a one-week ketogenic diet, which managed to increase their Bacteroides
amount by ~24% [24]. Another 6-month study on children with refractory epilepsy found
Nutrients 2021, 13, 1654 5 of 29

a significant decrease in Firmicutes and an increase in Bacteroides although the overall

diversity decreased [25].
Studies have shown that a low ratio of Firmicutes to Bacteroidetes is an indicator of a
healthy microbiome [26]. A few studies found that obese patients were more likely to have
a higher Firmicutes to Bacteroidetes ratio [26–28] and higher levels of short chain fatty acids
(SCFAs) in their stool [5]. However, another study found that obese patients showed an
increase in Bacteroidetes, while Firmicutes remained the same [29]. Therefore, it appears
that reducing obesity with the KD may result in positive changes in the microbiome. A
study by Basciani et al. [30] recently analyzed the changes in the gut microbiota in obese,
insulin-resistant patients who followed isocaloric ketogenic diets which varied in their
source of proteins. The very low-calorie ketogenic diets (VLCKDs) contained either whey,
vegetable, or animal proteins. The data indicated all groups had a decrease in relative
abundance of Firmicutes and an increase in Bacteroidetes after 45 days. However, the positive
changes were less pronounced in the group that consumed animal protein sources.
Recently, a few short-term studies tested the impact of the KD on patient microbiomes.
A study by Nagpal et al. [31] analyzed the effect of a modified Mediterranean Ketogenic
Diet (MMKD) vs. the American Heart Association Diet (AHAD) on the microbiome
of patients with normal cognition or mild cognitive impairment. They found that the
MMKD did not show significant changes in the Firmicutes or Bacteroides phyla at 6 weeks.
However, they did see a decrease in the family Bifidobacteriaceae and an increase in family
Verrucomicrobiaceae, which was considered a positive change. Furthermore, the beneficial
SCFA, butyrate, increased in the MMKD. The presence of butyrate has been known to
increase gut health [31].

3. The Effect of the Ketogenic Diet on the Epigenome

Epigenetics refers specifically to changes “on top” of the genome that can modify and
alter levels of gene expression. These epigenetic markers are heritable, yet recent research
suggests that some changes can be reversed or occur through environmental changes [20].
The modifications of the genome involve DNA methylation, changes to chromatin structure,
histone modification, and noncoding RNAs. Most notable are histone modifications. For
example, the N-terminal of histone tails can be acetylated, methylated, phosphorylated,
ubiquitinated, or SUMOylated. Histone deacetylases (HDACs) are enzymes that can
remove acetyl groups and condense the chromatin. Similarly, sirtuins (SIRTs) are also
capable of deacetylating histones. Histone lysine methylation can either activate or repress
a gene’s activity based on the exact location and number of methyl groups added to
the histone tail [32]. Research has found that most epigenetic modification occur during
early embryogenesis, but the genome can acquire changes later in life. Some of the later
epigenetic modifications are caused or modified because of diet [32].
Some ketogenic food sources that positively regulate epigenetic activity are crucif-
erous vegetables, dietary fiber, foods rich in long-chain fatty acids, and berries, such as
raspberries [20]. The benefits of some of these food sources have a multitude of positive
effects. For instance, black raspberries not only positively affect methylation patterns in the
WNT-signaling pathway, but they also profoundly impact the microbiome make-up (in-
creased Lactobacillus, Bacteroidaceae, and anti-inflammatory bacterial species), and increased
production of butyrate by fermentation in the gut [20]. Thus, it appears that diets rich in
certain foods can positively modify genes that increase overall cell health.
The benefits of the ketogenic diet might also go beyond treating existing disease,
and instead help prevent chronic and degenerative disease [23]. A literature review by
Miller et al. [23] argued that a state of nutritional ketosis will positively affect mitochondrial
function and enhance resistance to oxidative stress and noted that the ketones directly
up-regulate bioenergetic proteins that influence antioxidant defenses [23]. According to
Boison [33], “Ketone bodies, such as β-hydroxybutyrate (BHB), and their derivatives have
received the most attention as mediators of the anti-seizure, neuroprotective, and anti-
inflammatory effects of KD therapy” [34–36]. The ketogenic diet’s mechanism of action
Nutrients 2021, 13, 1654 6 of 29

might be due to increased levels of adenosine [37,38], which blocks DNA methylation and,
thus, exerts an epigenetic change. A study in epileptic rats subjected to the KD therapy
found ameliorated DNA methylation mediated changes in gene expression by increasing
adenosine [39], which blocks DNA methylation [40]. It is also being studied for its role in
the aging process since it is linked to the positive regulation of epigenetic modifications,
such as nuclear lamin architecture [41], reduced telomere length [42,43], DNA methylation,
and chromatin structure [44].
The effect of the ketogenic diet on brain health appears to be well supported and is
due specifically to the production of BHB [23]. They found that BHB is more than a fuel
molecule; it plays important roles in cell signaling. The signaling functions of BHB link
the effects of environmental factors on epigenetic regulation and cellular processes since it
is an endogenous class 1 HDAC inhibitor [45]. Thus, a ketogenic diet has been linked to
increased global histone acetylation, with a specific increase in the expression of protective
genes, such as Foxo3a [46].
Evidence also suggests that BHB can have a direct epigenetic effect via a novel histone
modification known as β-hydroxybutyrlation of H3K9, which results in improved gene
regulation in the hypothalamus and improved overall aging [47]. Furthermore, the energy
carrier molecule, nicotinamide adenine dinucleotide (NAD) is important in oxidative
respiration. In its oxidative state (NAD+), NAD also acts as a cofactor for sirtuin enzymes
and poly-ADP-ribose polymerase (PARP). Sirtuins and PARP play roles in gene expression,
DNA damage repair, and fatty acid metabolism [46]. The energy available to a cell is
measured by the NAD+/NADH ratio, which is modified by the utilization of glucose
versus BHB as a fuel source [48]. During a ketogenic state, more NAD is found in the
oxidative state which allows sirtuins and PARP to be more active. Additionally, catabolism
of BHB into acetyl-CoA, another energy carrier molecule, raises acetyl-CoA levels. It has
been found that the production of two moles of acetyl-CoA using BHB as the precursor
reduces only one mole of NAD+ to NADH. However, four moles of NAD+ are produced
by glucose metabolism. Thus, the ketogenic diet creates excess NAD+ for the cell and
has a positive impact on the redox state of the cell [48]. This might have positive impacts
on the activity of NAD+ dependent enzymes, such as sirtuins. Newman et al. [49] found
that increased acetyl-CoA favors both enzymatic and nonenzymatic protein acetylation,
specifically in the mitochondria, which improves overall mitochondrial function.
BHB produced by a ketogenic diet may also increase the efficiency of ATP production
in the mitochondria and reduce the number of free radicals. As a result of the positive
impacts of BHB, one study found that BHB precursor molecules improved cognition and
disease progression in an Alzheimer’s mouse model [50]. Additionally, the presence of
BHB showed improvement in a case study of a patient with Alzheimer’s disease [51]. The
presence of D-β-hydroxybutyrate protect neurons from oxidative damage by reducing the
cytosolic NAD+/NADPH ratio, resulting in an increase in the antioxidant agent known as
reduced glutathione [52]. BHB also inhibits NF-kB, which is known to regulate the expres-
sion of multiple pro-inflammatory genes. This results in a diminished pro-inflammatory
response [52]. Similarly, the BHB precursor, 1,3 butanediol, also modulates the expression
of the inflammasome via histone β-hydroxybutyrlation. Thus, it reduces the expression of
caspase-1, IL-1B, and IL-18 [53], which are inflammation markers. A study in C. elegans
found that BHB alone could extend their life span [3]. Thus, the endogenous effects of BHB
produced by a ketogenic diet might enhance health and increase longevity.

4. The Effect of the Ketogenic Diet on Weight Loss

According to recent Harvard models, 50% of the children today are likely to be obese
by the age of 35 years [9]. As scientists try to determine the most effective strategies
to combat the obesity epidemic, many studies have emerged that compare the health
outcomes of different diets. A recent meta-analysis of seven random-controlled trials using
diazoxide or octreotide for suppressing insulin secretion in obese patients found that it led
to reduced body weight, fat mass, while maintaining lean mass [54]. However, the cost
Nutrients 2021, 13, 1654 7 of 29

of artificially reducing insulin levels was an increase in blood glucose levels. While these
studies seem promising as an indicator of biomarkers that can stimulate weight loss, it
seems more logical to help patients achieve lower insulin levels via changes to their diet.
The reduction of carbohydrate intake naturally reduces blood glucose levels, thus reducing
insulin as a result. Many studies have now demonstrated that the ketogenic diet reduces
both blood glucose and insulin levels [55–57]
A study conducted by Fumagalli et al. [58] analyzed the genetic profiles of patients
and looked at the impacts on metabolism. They specifically looked at human CHC22
clathrin, which plays a central role in intracellular traffic of insulin-responsive glucose
transporter 4 (GLUT4). The GLUT4 pathway is the dominant mechanism used by humans
to remove glucose from the circulating blood after a meal. They found two major gene
variants, one which is more frequent in farming populations than in hunter-gatherers.
Hunter-gatherers have the gene that allows GLUT4 to be sequestered more effectively and
thus have an inherent increased risk of insulin resistance. It is hypothesized that as humans
became farmers and increased glucose in the diet, it was beneficial for the blood sugar to
be lowered more easily with the newer form of CHC22. Thus, people with different forms
of CHC22 are likely to differ in their ability to clear blood sugar after a meal. The people
with the form that allows blood sugar levels to remain elevated could eventually lead to
diabetes in the face of a high-carbohydrate load in the diet. This new finding might explain
why some patients are successful on a high-carbohydrate low-fat diet, while others prefer
to maintain weight with a low-carbohydrate, high-fat diet [58].
The importance of dietary adherence is of great concern for the success of any diet
study. The study conducted by Shai et al. [59] that was able to control for the feeding of
at least one meal a day (cafeteria meal), might better reveal the true effects of a sustained
ketogenic diet. The Shai study [59] compared a low-fat, restricted-calorie diet (LFD),
a Mediterranean, restricted-calorie diet (MD), and a low-carbohydrate, non-restricted
calorie diet (LC) on 322 moderately obese subjects over a period of two years. The dietary
adherence was >85% at the end of two years. This study instructed the LC group to
be ketogenic for the first 2 months (<20 g/day) and gradually increase to 120 g/day of
carbohydrates. The results found that the greatest weight loss occurred in the low-carb
group and both the LC and MD were more effective than the LFD. Although, the weight
loss during the first 3 months in the LC group was significantly greater than either of
the other two groups, as carbohydrates were added back into their diet, their weight
rebounded back to a level close to the MD group. Shai et al. [59] found that one of the
benefits of the LC group was the similar calorie deficit achieved even though it was not a
calorie-restricted diet. The researchers propose that a LC diet may be the optimal choice for
individuals that cannot follow a calorie restricted diet since these subjects will be permitted
to eat until satiated but will still most likely end up lowering their total caloric intake.
A similar long-term (56 week) ketogenic study was conducted on 66 obese people
with a BMI >30 [60]. All patients were instructed to eat <20 g of carbohydrates in the form
of green vegetables and salads for 12 weeks and then they could increase the carbohydrates
to 40 g/day for the remainder of the study. The weight and body mass index of all patients
decreased significantly. More interestingly, the patients were advised to maintain a state
of nutritional ketosis and they were able to show continued decreases in both BW and
BMI throughout the study. Consequently, this study did not show the plateau and gradual
increases seen in the Shai study [59] which allowed the reintroduction of carbohydrates
after the initial weight loss period. A similar study by Samaha et al. [61] also found that
patients lost significantly more weight on a 30 g/carbohydrate per day diet for six months
compared to a LFD. Another possible benefit from the ketogenic diet is that there is a
measurable biomarker that signifies dietary adherence, which is β-hydroxybutyrate (BHB).
When an individual is in ketosis, the body will begin ketone production and the level
of BHB in the blood will be over 0.5 mmol. Studies that include this measurement can
therefore confirm dietary adherence and determine the true effects of the diet on health
outcomes, like weight loss. Mohorko et al. [57] conducted a 12-week ketogenic diet study
Nutrients 2021, 13, 1654 8 of 29

on obese patients who were calorie restricted (1200–1500kcal) for the first two weeks and
then were instructed to eat ad-libitum for hunger for the remaining weeks while eating the
macronutrient composition necessary to remain in a state of nutritional ketosis. BHB was
measured throughout the study and patients maintained levels above 0.5 mmol throughout
the 12 weeks. Patients showed significant weight loss in both the men and women groups
(average of (-)18 kg for men and (-)11 kg for women). Interestingly, as the diet progressed,
the patients Fat Mass (FM) became the largest component of weight loss and it significantly
correlated with BHB. Another valuable outcome in this study was the reduction of the
hunger hormone, leptin, as well as a slight increase in energy expenditure, even while
weight decreased throughout all 12 weeks. Another long-term study was done by Hallberg
et al. [2] which followed diabetic patients on a ketogenic diet for one year. At the beginning
of this study, 92% of the patients in the ketogenic group were obese. These patients were
instructed to eat less than 30 g of total carbohydrates per day and the goal was to maintain
BHB blood levels of 0.5–3.0 mmol/L. These patients had an average of 12% decrease in
body weight, with some patients achieving as high as ~40% change. The patients who
were in the standard care diet group (American Diabetic Association recommended diet)
did not see any significant change in body weight [2].
A short-term, 4-week ketogenic diet (KD) on 20 obese Chinese females had profound
outcomes [62]. In this study, compliance to the diet was measured with urinary ketone
strips. These participants were given a monitored 4-week normal diet which was followed
up with a 4-week KD with the same daily caloric intake but a drastic reduction in carbohy-
drates to <10% of calories. The effect was a significant decrease in body weight, body mass
index, waist circumference, hip circumference, body fat %, and decreased fasting leptin
levels. Similar positive outcomes were seen in other KD diet studies [56,63,64]. Similarly, a
recent meta-analysis concluded that very low-calorie ketogenic diets are a very effective
strategy for treating obesity [65]. An 8-week study conducted by Goss et al. [66] compared
the very low carbohydrate diet (VLCD) (<10% carbohydrates) to a low-fat diet in older
obese adults with BMI between 30 and 40. This study precisely measured fat loss with
DXA and MRI measurements. Both groups exhibited decrease in total fat, but the VLCD
experienced ~3 fold greater decrease in visceral adipose tissue and a significant decrease in
intermuscular adipose tissue with a 5-fold greater reduction in total body fat mass.
Another long-term study monitored weight loss as well as changes in visceral fat mass
using DEXA. The study by Moreno et al. [67] compared a very low-calorie ketogenic diet
(VLCK) to a low-calorie (LC) diet as a treatment for obesity over two years. Participants
in the active stage consumed 600–800 kcal/day and <50 g of carbohydrates per day until
they were 80% of target weight loss goals (stage 1). Urinary ketone strips were used during
stage 1 to confirm a state of ketosis. Then they used a standard low-calorie diet (10% below
total metabolic expenditure) during stage 2 until they achieved another 20% weight loss,
followed by long-term maintenance of weight loss in stage 3. The comparison control
group used the low-calorie diet throughout the study to achieve weight loss. The weight
loss in kilograms in the VLCK diet was double that of the LC diet throughout most of the
study and remained significant. The amount of visceral fat loss in the VLCK diet group
was 3X greater than the control group while preserving lean body and skeletal bone mass.
The main side effects recorded in the VLCK were fatigue, headache, constipation, and
nausea. However, none of these side effects were severe enough to cause the patients to
drop out of the study and most subsided within the first month [67].
A meta-analysis conducted by Bueno et al. [68] compared randomized controlled trials
of very low carb ketogenic diets (VLCKD) with low fat diets for 1 year. This study found
a significant difference in decreased body weight for the VLCKD group. Another study
compared a KD (<30 g carbohydrates/day) with two control groups (standard American
diet (SAD) without exercise and SAD with 3-5 days of exercise for 30 minutes) over ten
weeks [69]. The KD outperformed the other control groups in all variables tested, with
5 out of 7 being statistically significant. The patients showed significant decreases in body
mass index (BMI), body fat mass (BFM), and weight while their resting metabolic rate
Nutrients 2021, 13, 1654 9 of 29

(RMR) increased. The RMR in the experimental group produced a positive, sizeable change
with a magnitude of slope that was more than 10X the two control SAD groups. These
results reveal that diet plays a more significant role in outcomes than exercise [69].
The ability to control hunger is also a key component to weight loss success.
Castro et al. [70] evaluated patients from the very low-calorie ketogenic diet (VLCK) study
and found a negative correlation between BHB levels and the urge to eat and feelings of
hunger during the phase of maximum ketosis, even though there was no significant change
in ghrelin hormone. This result is supported by other large investigations in overweight
and obese adults which also found that low-carbohydrate diets were more effective in
controlling hunger than low-fat diets [71,72]. A 2-week study conducted by Choi et al. [73]
compared varying nutrition drinks on weight loss in obese adults. There were three groups:
4:1 fat to protein and carbohydrate ratio, 1.7:1 ratio with increased protein, and a balanced
nutrition drink with similar carbohydrates to recommended dietary advice. All groups
decreased body weight and body fat mass, but only the 1.7:1 KD-group maintained protein
mass. Furthermore, only the KD groups improved blood lipid levels with appetite reduc-
tion. Since this was a nutritional drink feeding study, all the groups had similar caloric
reduction; thus, results were due to macronutrient composition. In addition, levels of keto-
sis were strongly related to positive differences in food cravings, alcohol cravings, physical
activity, sleep patterns, and sexual activity [73]. This outcome might also be supported
by a recent finding that postprandial glycemic dips were the best predictor of appetite
and energy intake following a meal and large glycemic dips are usually associated with
high carbohydrate consumption [74]. Furthermore, a study showed that high carbohydrate
meals had a greater impact on brain reward and homeostatic activity in ways that could
impede weight loss maintenance [75]. Interestingly, the increased brain activity findings
were partially associated with higher insulin levels, too. Thus, the ability of the KD to
reduce hunger, lower glycemic fluctuations, and reduce influences on areas of the brain
associated with addiction are all positive signs that a ketogenic diet should be considered
as a treatment option for obesity.
One of the major concerns for rapid weight loss is the lowering of the resting metabolic
rate (RMR). This bodily change can lead to weight regain, which is known as adaptive
thermogenesis. Thus, it is typical for hunger to increase and energy expenditure to decrease
during weight loss, which is a hindrance to long-term weight loss maintenance. Gomez-
Arbelaez et al. [76] tested this outcome in subjects on the very low-calorie ketogenic (VLCK)
diet study and followed them for 2 years. In this study, twenty obese patients lost 20.2 kg
of body weight after four months and sustained this weight loss without the expected
reduction in RMR. Authors of the study hypothesize that RMR did not drop because the
subjects maintained their lean body mass. DEXA scans revealed that although they lost
~20 kg of fat mass, they only lost 1 kg of muscle mass. This conclusion was also supported
by normal renal activity and positive nitrogen balance while subjects maintained their fat
loss upon follow-up [76].
A study by Hall et al. [77] hypothesized that the development of obesity is “a con-
sequence of the insulin-driven shift in fat partitioning toward storage and away from
oxidation resulting from an increased proportion of dietary carbohydrates.” To test this
hypothesis, they tested seventeen obese men in metabolic wards with a four-week high-
carbohydrate diet followed by a four week, isocaloric ketogenic diet. The results showed
that a state of ketosis increased energy expenditure (~100 kcal/d), most likely due to beta
oxidation and the partitioning of fuel towards ATP production rather than fat storage [77].
However, this level of energy expenditure change due to a ketogenic diet is not as high as
measured in another study. In the study by Ebbeling et al. [78], it was noted that short-term
feeding studies do not consider the body’s process of fat adaptation, which takes at least
2–3 weeks, if not longer. Thus, the Framingham study by Ebbeling et al. [78] conducted a
randomized trial on 164 patients where they lost weight and were then placed on varying
diets of carbohydrate content for twenty weeks to measure changes in energy expenditure.
The difference in total energy expenditure was 209–278 kcal/d or around 60 kcal/d increase
Nutrients 2021, 13, 1654 10 of 29

for every 10% decrease in the carbohydrate percentage of total energy intake. This study
concluded that dietary quality could affect energy expenditure independently of body
weight. In accordance, Mobbs et al. [79] has suggested that ketogenic diets “reverse obesity
by preventing the inhibitory effects of lipids on glycolysis, thus maintaining relatively ele-
vated post-prandial thermogenesis.” Further studies will need to be conducted to evaluate
and confirm the exact mechanisms of action.
More recent studies on the KD are analyzing the outcomes of the diet in conjunction with
other comorbidities related to obesity. A small study was conducted by Carmen et al. [80] that
followed three obese participants on a 10% carbohydrate KD for 6–7 months that exhibitied
comorbid binge eating and food addiction symptoms. No adverse effects were found, and
participants had reductions in binge eating episodes and food addiction symptoms. All
three lost 10–24% BW and maintained treatment outcomes 9–17 months after initiating
the diet and continued adherence to the diet [80]. Another study looked at the outcomes
for male and female severely obese patients who also suffered from non-alcoholic fatty
liver syndrome (NAFLD) [81]. They used a very low-calorie ketogenic diet of <50 g of
carbohydrates and <800 kcal/day. Both males and females showed significant losses in
body weight. However, males lost significantly more weight and had greater reductions in
waist circumference. The patients also improved their biomarker for NAFLD, which was a
reduction in gamma-glutamyl transferase [81]. To determine if the ketogenic diet negatively
affects kidney function, Bruci et al. [82] conducted a 3-month very low-calorie ketogenic
diet (VLCKD) study for weight loss in obese patients with and without mild kidney
failure. All patients were advised to consume <20 g carbohydrates and 500–800 calories
per day. The average mean weight loss from initial weight was nearly 20%, participants
had significant reduction in fat mass, and 27.7% of the patients with mild kidney failure
acquired normalized glomerular filtrate rate. It was, therefore, concluded that a KD not
only leads to weight loss but also improvement in kidney function.
Please refer to Table S1 in the Supplementary Materials for a comparison of studies
evaluating the KD in relation to weight loss outcomes.

5. The Effect of the Ketogenic Diet on Diabetes

According to the latest CDC report, an estimated 30 million people have diabetes and
around 84 million have pre-diabetes. That statistic predicts that ~45% of Americans are
either diabetic or pre-diabetic. Diabetes is a major health concern that is accompanied by a
long list of secondary complications and diabetics are at increased risk of microvascular
pathology of the retina, renal glomerulus, peripheral neuropathy, and atherosclerotic
disease affecting arteries [83]. Many of these diabetic complications have been linked to
elevated levels of glucose over long periods of time, which is measured as hemoglobin A1c
(HbA1c) [83].
Type 2 diabetes is caused by hyperinsulinemia and insulin levels are directly affected
by carbohydrate consumption. Protein intake can cause slight increases in blood glucose
and subsequent insulin secretion, but fat consumption has no major effect on either [84].
If hyperinsulinemia is directly affected by nutrient intake, then it could be argued that
these blood markers could be controlled by the conscious control of food choices. Of
further note, the American Diabetes Association (ADA) recommends a goal of an HbA1c
less than 7%, and the American College of Endocrinology sets a target level of 6.5%,
even though few patients ever obtain that goal. Thus, Brownlee et al. [83] argued that
patients should increase efforts to minimize glycemic variability since it can reduce risks
of diabetic complications, independent of HbA1c. The DiRECT study by Lean et al. [85]
found that weight loss alone could result in almost 46% of patients achieving diabetes
remission at 12 months. Yet, this does not address the issue of diabetic patients who are
not overweight. Thus, many scientists are now examining the potential benefits related
to diabetes and improved blood markers that can result from eating a ketogenic diet.
Although no professional organization in endocrinology or diabetology has focused on
the rational use of ketogenic diet for either diabetes or obesity conditions, Kalra et al. [86]
Nutrients 2021, 13, 1654 11 of 29

argues nutrition should be considered as an integral part of metabolic management of

diabetes, and the ketogenic diet should at least be offered as a treatment option.
Interestingly, the use of a diet low in carbohydrates for the treatment of diabetes is not
a new or novel idea. In fact, prior to the invention of insulin, diet was the main intervention
used by diabetic patients. The physicians, Dr. Elliot Joslin and Dr. Frederick Allen,
were both recommending their patients in the 1920s to eat foods without carbohydrate
content, and it highly resembled the current ketogenic recommendations [87]. According
to Feinman et al. [88] the number one goal of both type 1 and type 2 diabetics should be
glycemic control. It is argued that carbohydrate restriction can benefit diabetic patient blood
markers even in the absence of weight loss [88]. This is important since many diabetics
are not overweight yet still need to manage their blood glucose levels. The benefits of
carbohydrate restriction in type 1 diabetics reduces the error in determining insulin amount
to match the increased blood glucose since dramatic spikes are less likely [88].
A recent study compared the use of a low-calorie (LC) diet vs. a very low-carbohydrate
ketogenic diet (VLCKD) on health outcomes for type 2 diabetics. The VLCKD group ap-
proached normal blood sugar level in just 24 weeks unlike the LC group [87]. The VLCKD
group reduced insulin doses by half, on average, and sulfonylurea doses were halved or
discontinued. The HbA1c levels dropped significantly in the VLCKD to 6.2% vs. 7.5% in the
LC group. Thus, the VLCKD group managed to reach both the ADA and American College
of Endocrinology target level for HbA1c. According to Hussain et al. [87] the VLCKD was
not found to have an adverse effect on glucose metabolism, insulin resistance, or cause
chronic dehydration. However, they did caution that diabetic patients should only attempt
this nutritional therapy while being closely monitored by a physician to reduce the risk
of hypoglycemia since drugs will need to be quickly reduced to match changes in blood
markers elicited by the diet [87]. A study by Webster et al. [89] found that type 2 diabetic
patients who self-selected to follow a KD reduced their mean HbA1c from 7.5% to 5.9% at
the 15-month follow-up. As a result, their HbA1c levels reached the normal range (which
is under 6.0%), and they had achieved partial or full type 2 diabetes remission.
A study conducted by Westman et al. [8] compared the effects of a low-carbohydrate
ketogenic diet (LCKD) versus a low-glycemic index diet (LGID) on glycemic control
in type 2 diabetic patients which was measured by hemoglobin A1C (HbA1c). They
enrolled forty nine patients and randomly assigned them to the different diets. Both groups
followed group meetings, nutritional advice, and an exercise recommendation. Both
interventions showed improvements in hemoglobin A1c, fasting glucose, fasting insulin,
and weight loss. However, the LCKD had greater improvements, including a reduction
or elimination of diabetes medications in 95% of patients vs. 62% in the LGID group [8].
As mentioned previously, the study by Dashti et al. [60] compared the health outcomes of
a ketogenic diet on obese diabetics with high blood glucose levels to non-diabetic obese
patients over 56 weeks. This study concluded that all markers, such as body weight, body
mass index, blood glucose, total cholesterol, LDL, triglycerides, and urea all showed a
significant decrease in both groups throughout the study, with more positive outcomes
seen in the diabetic group [60]. The kidney tests also showed normal function. This study
demonstrated that the diet is safe to use for longer periods of time in obese diabetic subjects.
A year-long randomized study compared the effects of a very low-carbohydrate keto-
genic diet (LCK) versus a moderate-carbohydrate, calorie-restricted, low-fat diet (MCCR)
in pre-diabetic or type 2 diabetic patients [90]. The results showed that the LCK exhibited
greater improvements in their HbA1c, weight loss, and medication use than those assigned
to the MCCR diet [90]. Another randomized controlled study by the same researcher
compared the LCK against the diet program based on the online American Diabetes Associ-
ations’ “Create Your Plate” diet. The purpose of this study was twofold. The researcher had
already seen the benefits of the LCK in a previous study that had personalized intervention.
They wanted to see if an online program could be just as successful at helping overweight
individuals with type 2 diabetes. The results indicated that the online ketogenic program
was more successful in helping patients manage their diabetes by reducing their HbA1c,
Nutrients 2021, 13, 1654 12 of 29

lowering triglycerides, increasing weight loss, and retention rates were higher than in
the control group [91]. In addition, a previous study has discovered that a carbohydrate
restricted diet was more successful than a low-fat diet in improving diabetic markers for
metabolic syndrome in forty subjects with atherogenic dyslipidemia [92].
A recent study recently conducted at Indiana University was one of the first long-term
studies that required use of routine blood tests to determine the patients’ state of nutritional
ketosis while maintaining a KD diet. Patients were highly compliant, and experienced
improved diabetic conditions [2]. The diet intervention also reversed the diabetic status of
some patients, whose HbA1cs became normal. The 2-year follow-up to this study revealed
that 74% of KD group remained enrolled [93]. This group had a significant improvement
in HbA1c, fasting glucose, and fasting insulin while the usual care group had no changes
from baseline. The mean dose of prescribed insulin decreased by 81% and the diabetes
reversal increased to 53.5%. Diabetes remission was 17.6% and diabetes complete remission
was 6.7% [93]. The long-term success in diabetes treatment for this digitally monitored
continuous care intervention group is evidence of the feasibility and adherence of the KD
in type 2 diabetes treatment [2,93].
Additionally, the study by Shai et al. [59] showed that patients were able to reduce
their fasting blood glucose on a low carbohydrate or a Mediterranean diet, while the
low-fat group saw the opposite effect. The patients in the low carbohydrate group were
also able to significantly decrease their HbA1c [59]. Another meta-analysis that compared
very low-carbohydrate ketogenic diets (VLCKDs) to low-fat diets (LFDs) found that the
VLCKD showed greater improvements in fasting glucose, insulin analysis, HbA1c, and
C-reactive protein [68]. Additionally, a recent meta-analysis of low-carbohydrate or very-
low carbohydrate diets found that patients adhering to the diet for 6 months can have
diabetes remission without severe complications [94]. Several recent studies on the KD
show positive improvements in glycemic profiles [56,66,82,89,95].
Currently, the ADA recommends that type 1 diabetics eat a low-fat diet rich in whole
grain carbohydrates. One study showed the low-fat diet has not been found to improve
HbA1c in all patients, regardless of diabetes state [96]. It looked at the HbA1c outcomes
for type 1 diabetics (T1D) who were advised to reduce carbohydrate intake (<75 g of
carbs/day) to reduce the need for insulin. The patients in this study had a 50% adherence
rate, and those who strictly adhered to the diet reduced their HbA1c by 1.8%. Another
randomized trial [97] determined the feasibility of a LC diet (<75 g/day) versus standard
carb counting in adults with T1D. Of the ten people in the 12-week study, the LC group
exhibited significant decreases in HbA1c, decreased daily insulin use, and reduction in
body weight. All of the outcomes in the carb counting group were unchanged. Thus, these
T1D patients had positive outcomes without meeting the KD threshold of <50 g/day while
consuming significantly less carbohydrates than the typical diet.
Interestingly, some type 1 diabetes patients have taken it upon themselves to treat and
control their diabetes with the very low–carbohydrate diet (VLCD), against the advice of
current medical professionals. Lennerz et al. [98] evaluated the results of this choice by
recruiting type 1 diabetics who self-selected to follow a VLCD (<30 g/day). They found
these patients on a social media site and then asked for permission to contact physicians
and confirm health outcomes. Shockingly, 97% of the patients were able to achieve the
ADA glycemic targets for HbA1c with an average of 5.6% and a mean daily insulin dosage
of 0.40 U/kg per day. Participants in this group reported increased levels of overall
health, increased satisfaction with diabetes management, and decreased number of adverse
events. These results are unprecedented in type 1 diabetic patients. If these outcomes are
confirmed in clinical trials, the chronic health issues associated with type 1 diabetes could
be prevented or significantly reduced by diet alone. Almost one-fourth of these patients
did not discuss their VLCD with their care providers, which means they were making these
changes without the support of their physicians. Even in an intensively treated group in
the Diabetes Control and Complication Trial, the best HbA1c achieved was 7.2%, but that
was coupled with increased rates of hypoglycemia [98].
Nutrients 2021, 13, 1654 13 of 29

Although there are only a few randomized controlled trials evaluating the effects of
the KD on diabetes, there are some recent case studies and qualitative studies that shed
some light on the issue [55,64,99,100]. The positive outcomes in these studies might reflect
the motivation of these patients who opted or volunteered to ensue KD diets. A paper
by Walton et al. [64] presented 11 case studies on women with T2D that volunteered to
eat a KD with <30 g of carbohydrate per day. Their HbA1c was > 6.5% and dropped to
5.6% with diabetes reversal. Another case study by Lichtash et al. [99] involved a women
patient with T2D and normal weight. After failed glycemic control with standard care,
she voluntarily began a KD with intermittent fasting. Her HbA1c dropped from 9.3% to
5.8% after 14 months while maintaining her weight. Similarly, Wong et al. [100] examined
type 1 and type 2 diabetics who opted to do a KD for >3 months. Participants reported
better glycemic control, decreased medicine use, weight loss, and satiety. Most of these
patients expressed the KD as a normal way of eating and plan to continue for the rest of
their lives. A similar T2D cohort was recruited [55] for a retrospective study on 49 patients
who followed KD for >3 months and compared their outcomes to 75 patients who followed
usual care (UC). 100% of the KD cohort either discontinued or reduced insulin dosage
while only 23% of UC did. The KD cohort had a greater reduction in fasting plasma glucose,
weight loss, as well as a superior reduction in HbA1c compared to UC. Thus, it seems that
those patients who opt to follow the diet are having positive outcomes.
Please refer to Table S2 in the Supplementary Materials for a comparison of studies
evaluating the KD in relation to diabetic outcomes.

6. The Effect of the Ketogenic Diet on Lipidology and Cardiovascular Risk

Cardiovascular disease (CVD) and its risk factors are a major health issue in indus-
trialized nations. Moreover, large epidemiological studies are starting to show that CVD
is becoming a larger problem in developing or low-income countries as well [101]. There
has been a long-standing viewpoint that a diet high in saturated fat is unhealthy and will
eventually lead to cardiovascular disease. Many hypothesized that a diet rich in saturated
fat will increase LDL, and thus more fat in the blood leads to fat deposits in the vessels,
resulting in increased risk of cardiovascular disease [102]. This idea was fortified by Ancel
Keys in his 7-country study and eventually led to the diet-heart hypothesis [102]. More-
over, the United States accepted the idea proposed by Keys and adopted the low-fat diet
(LFD) as the optimal diet to fight the increasing levels of CVD in the U.S. Additionally, the
mainstream view for decades was that high total cholesterol also leads to atherosclerosis
and cardiovascular disease [103]. As a result, the prescription of the LFD that consisted of
~60% energy from carbohydrates became the standard of care for physicians starting in
the 1980s [98]. According to the 2015 Dietary Guidelines for Americans, people are still
recommended to consume a diet that limits saturated fat intake to less than 10%, with some
organizations placing even stricter limitations and advising around 7% [104]. However,
randomized controlled trials have started to question the validity that saturated fat intake
and a single blood marker, LDL, can accurately predict risk. Many scientists now argue for
the need to analyze specifically how different types of macronutrients that replace saturated
fat in the diet are impacting risk [105]. It is also important to consider the data regarding
LDL as the single biomarker chosen to monitor and determine cardiovascular risk [105].
New research is also starting to question that mindset set forth by Ancel Keys, and many
scientists have argued that the global dietary recommendations should be revisited and up-
dated [106]. For example, a recent analysis of the literature done by Ravnskov et al. [103] com-
piled all the data on PubMed from initial to 2015 on over 68,000 patients. Ravnskov et al. [103]
argued that that if the main goal of prevention of disease is prolonging life, then all-cause
mortality should be the measurement used for determining health outcomes. Interestingly,
they found that 30% of patients showed no association between LDL and all-cause mor-
tality, while 70% showed a statistically significant inverse relationship. Contradicting the
diet-heart hypothesis, they also found that the 4-year mortality among patients with the
highest levels of LDL were almost 36% lower than those patients with the lowest LDL
Nutrients 2021, 13, 1654 14 of 29

levels. Furthermore, the patients placed on statins had higher rates of mortality risk than
those with the highest LDL. The results of these studies question the standardized method
of using total cholesterol and LDL as the biomarkers of coronary heart disease.
Thus, if total cholesterol and LDL are not true indicators of cardiovascular risk, then
one must ask what other blood markers could serve as better indicators of coronary heart
disease. In a review by Feinman et al. [88] they argue that the best indicators of CVD
risk are ApoB [107], the ratio of TC/HDL, increased levels of small dense LDL particles
(sdLDL) [108,109], and the ratio of ApoB to ApoA1 [88]. If these markers are, in fact, a better
indicator of disease risk, then understanding the effect of diet on these other biomarkers is
of great importance. One study by Krauss et al. [110] compared patients who consumed
diets of varying carbohydrate intake (54%, 39% or 26%) with the amount of saturated fat
varying between 7% or 15%. This study showed that a high saturated fat intake, combined
with carbohydrate restriction (26%) did raise total LDL. However, the higher total LDL
levels were due to an increase in the larger sized LDL particles, which are less atherogenic
than the sdLDL, and the patients saw a subsequent lowering of the sdLDL particles [9,110].
A large prospective study called the European and Prospective Investigation into
Cancer and Nutrition Study (EPIC) also found that diets high in glycemic load (GL) and
glycemic index (GI) were associated with a greater risk in Cardiovascular Heart Disease
(CHD) [111]. Glycemic index is a measurement of the ability of carbohydrates to increase
blood glucose levels. The glycemic load is the product of the GI of a particular food and its
available carbohydrate. This study included around 520,000 men and women between the
ages of 35 and 70 over a period of 8 years [111]. The study found a greater risk of CHD
with higher sugar consumption. Their findings supported other observational studies that
suggest that replacing saturated fat with sugar or refined carbohydrates might increase
cardiovascular risk, rather than lower it [112,113]. Additionally, the very large PURE study
recently showed that a diet higher in saturated fat did increase LDL, but also increased HDL,
lowered triglycerides (TG), lowered the TC/HDL ratio, and lowered the ApoB/ApoA1
ratio [106]. They also found that the diets high in carbohydrate intake had the complete
opposite effect on these atherogenic biomarkers. The benefit of the PURE study is that it
revealed the risk associated with varying macronutrient composition in diets from over
5 continents in 18 countries, regardless of cultural food trends. Thus, it was a global look
at the effect of dietary patterns on health regardless of background and ethnicity. The
PURE study concluded their findings do not support the current recommendations to limit
total fat intake to 30% of energy and saturated fat to less than 10%, and the recommended
amount of <7% saturated fat might even be harmful. Instead, they argue that individuals
who eat a diet high in carbohydrates might benefit by replacing some of those carbs with
fat [106]. According to the PURE study, the ApoB to ApoA1 ratio was the strongest lipid
predictor of myocardial infarction and ischemic stroke. Since this biomarker has been
found to increase with carbohydrate intake, they concluded that this factor could provide
the mechanistic explanation for higher risks seen in people with the highest carbohydrate
intake [106]. This idea was supported by a recent article on Medscape, which argued that
the predictive power of the ApoB to ApoA1 ratio was superior to other biomarkers to
assess CV risk [114]. It also mentioned adding other lipid parameters to the ApoB/ApoA1
ratio did not improve the predictive power.
A study done by Lu et al. [115] compared the ability of either the ApoB/ApoA1 ratio
or LDL to predict coronary heart disease (CHD) in normal and overweight patients. They
found every quartile increase in the ApoB/ApoA1 ratio showed an increase in CHD preva-
lence. Meanwhile, the increases in LDL quartiles did not predict the highest percentages of
CHD [115]. The ratio had an even stronger predictive capability in the overweight subjects.
Furthermore, other studies have also supported the findings of the PURE study. One study
conducted on postmenopausal women found an inverse relationship between dietary
saturated fat intake and atherogenic disease progression [116]. Another study previously
mentioned even found a positive association between plasma phospholipids and CHD
mortality [117]. According to another study conducted by Dreon et al. [108], a decrease
Nutrients 2021, 13, 1654 15 of 29

in saturated fat intake did lower total LDL, but it appeared to only reduce the amount of
the large, buoyant LDL particles. They argue that more emphasis on CVD risk should be
placed on high levels of triglycerides (TG), decreased concentration of HDL, and increased
amounts of sdLDL particles. If these biomarkers are potentially more effective predictors
of coronary heart disease, then the analysis of a diet’s effect on these lipid markers is of
great importance [109].
Only a few studies have looked at the health impact of very high fat consumption
(VLCKD) on overall health (which could include analysis of weight maintenance, lipid
profiles, and inflammation markers [69]. To accurately determine the effect of a KD
on cardiovascular risk markers, it is important to only look at studies that restricted
carbohydrates below 50 g/day to ensure the patients would be in a state of nutritional
ketosis. One study compared a KD to the standard American diet (SAD) and the SAD plus
exercise. Not only did the KD outperform the other groups in multiple health outcomes,
but it also showed a much more significant decline in triglycerides [69]. Another study
compared a LC diet group (<30 g/day) to a LF diet in obese patients after 6 months [61].
Once again, the LC group had a drastic decrease in TG, while no significant difference was
seen in total cholesterol (TC), HDL or LDL. This led investigators to conclude that the LC
diet did not have adverse effects on serum lipid levels.
The impact of the prescribed low-fat diet versus diets higher in fat on cardiovascular
lipids levels are beginning to emerge. One 2-year diet study compared the effect of a low-fat
diet (LFD), low carbohydrate diet (LC), and a Mediterranean diet (MD) on lipid profiles
of overweight patients [59]. The LC group had a significant decrease in triglycerides and
the total cholesterol/HDL ratio decreased the most in the LC group. Their ratio decreased
by 20% compared to a 12% decrease in the LF group [59]. The beneficial biomarker, HDL,
increased in all groups, while the LDL changes were similar in all groups, which has also
been noted in other studies [118]. A metabolic ward study of shorter duration conducted by
Hall et al. [77] also found that triglycerides decreased in the reduced carbohydrate group.
However, they saw the LDL levels increase in the LC group. Meanwhile, the Choi et al. [73]
study mentioned earlier did not find an increase in LDL. It was conducted on obese patients
with tightly controlled nutrition drinks, which had similar calorie reduction. Only the
KD groups improved blood lipid profiles while reducing appetite. The KD groups saw a
decrease in triglycerides and LDL, and no significant change in HDL [73].
Another 6-month study compared a low-calorie KD to a low-calorie diet in obese
patients; some were diabetic. They found that both the diabetic and non-diabetic patients
in the KD group showed the best lipid outcomes [87]. They found a significant decrease in
triglycerides, a decrease in total cholesterol, a decrease in LDL, and an increase in HDL. A
study conducted by Walton et al. [64] followed 11 women with type 2 diabetes for 90 days
on a KD. The women in this study had increased HDL, a significant decrease in TG, and
a significant decrease in the TG: HDL ratio, although LDL levels were not significantly
changed. Another cardiovascular benefit was the lowering of the patient’s systolic and
diastolic blood pressure. When evaluating type 1 diabetic patients who self-selected to be
on a LCD, they found that these patients showed a decrease in TG, while having increases
in HDL, TC, and LDL [98]. The researchers hypothesized that the total LDL elevation on the
KD, if associated with a low TG, may reflect an increase in the large, buoyant lipoprotein
particles which are considered a lower risk subtype. When the KD was followed for one
year in type 2 diabetics and adherence was confirmed with BHB, it was noted that TG
decreased by 24%, HDL increased 18%, LDL increased 10%, while ApoB was unchanged [2].
Although these lipid changes are considered favorable, the increase in LDL seen in some
groups is still an area of concern. One analysis suggested that the risk from a slight increase
in LDL might be offset by emphasizing the consumption of unsaturated fatty acids rather
than saturated fatty acids [9].
The DIETFITS study also concluded that the increase in saturated fat intake may
improve overall lipid profiles if they are adhering to a high-quality, whole-food based,
low carbohydrate diet [104]. One major area of concern would be whether the KD would
Nutrients 2021, 13, 1654 16 of 29

have these same beneficial changes in patients with dyslipidemia. A 56-week study tested
the effect of the KD on obese patients with and without high cholesterol levels [119]. It
is important to note that these patients were instructed to include 5 tablespoons of olive
oil into the diet, which is a form of unsaturated fatty acids. Throughout the experiment,
the patients saw continuous improvements in their lipid markers. Not only did both
groups have decreased LDL, decreased TG, and increased HDL levels, but the patients
with high cholesterol levels also ended the study with blood profiles that were more like
normal subjects.
A more recently published case study on a young man who used a Mediterranean
KD diet for treating his IBS had some interesting findings [120]. The doctors looked
at more detailed lipid subfractions to determine the lipid outcomes of cardiovascular
risk, which was unique. First, the authors mention that a typical lipid profile analysis
would suggest the diet was having adverse effects on the patient. His total cholesterol
changed from 160 to 450 mg/dL, even though a portion of that was due to increased HDL
levels. Many argue that HDL-P is a superior predictive measure of good cardiovascular
health. The HLD-P in this patient increased from 5699 nmol/L to 12,080 nmol/L. The
current association between LDL-C and cardiovascular risk is driven by atherogenic small
dense and/or oxidized LDL. It is believed that these two components can penetrate the
endothelium of blood vessels and contribute to plaque formation [121,122]. Yet, large
LDL are not associated with cardiovascular risk and may provide a protective effect. This
patient saw an increase of LDL from 90 to 321 mg/dL. The LDL subfraction revealed that
almost the entire increase in his LDL-C was caused by an increase in large LDL, while his
small and medium LDL decreased by almost 10%. Thus, these authors argued that the
typical analysis of lipid profiles from patients on ketogenic diets may not accurately reveal
risk unless more detailed lipid subfraction tests are conducted.
Please refer to Table S3 in the Supplementary Materials for a comparison of studies
evaluating the KD in relation to lipidology outcomes.

7. The Effect of the Ketogenic Diet on Cancer

Cancer currently remains the second leading cause of death (~22%) in the United
States and is second only to heart disease [123]. Typically, cancer occurs in adults because
of multiple mutations in numerous genes, genes that usually regulate cell growth and
proliferation [124–126]. Today it is the accepted model that as many as six mutations need
to occur to produce cancer (usually to oncogenes and tumor suppressor genes). Oncogenes
are genes that regulate cellular pathways that can increase cellular growth, while tumor
suppressor genes regulate pathways that inhibit abnormal cell growth. As the mutated
cell population expands, it accrues the necessary changes to ignore growth control signals,
avoid apoptosis, escape immune surveillance, and creates an environment to thrive (using
mechanisms like angiogenesis and tolerance for anoxic environments) and eventually the
capability to metastasize [124]. These mutations can result from many causes, such as
DNA replication errors, failed DNA repair mechanisms, mutagen exposures, or increased
reactive oxygen species [127].
Consequently, preventative mechanisms that could lower cancer incidence would be
related to reducing these external causes or activating internal pathways to reduce cellular
error. Additionally, epidemiologic evidence linking obesity to elevated cancer incidence
found that 14% and 20% of all cancer deaths in men and women, respectively, are due
to being overweight and obese [128]. As a result, the Annual Report to the Nation on
Cancer emphasized the increasing contribution of obesity on cancer incidence [129]. One
mechanism believed to contribute to obesity’s role in cancer is the increase in adipocytes in
the body, which can increase circulating levels of insulin and Insulin Growth Factor 1 (IGF1)
hormones. These hormones bind receptors in many cell types and activate P13K/AKT
signaling pathways that increase cell survival and upregulate transcription factors that
promote cell proliferation [130]. Both hormones also increase glucose uptake into cells,
resulting in increased energy molecules being available for cell growth. Insulin is an
Nutrients 2021, 13, 1654 17 of 29

anabolic hormone that promotes glucose uptake into cells, reduces the release of fatty acids
from adipocytes, prevents ketone production in the liver, and stimulates fat and glycogen
storage [131]. Additionally, many recent publications support the idea that prolonged,
increased levels of serum insulin is likely to promote cancer growth [132–134].
The alterations in the metabolism of cancer cells were first described by Warburg et al. in
1927 [135] It was discovered that cancer cells acquire mutations in critical genes that change
the way cancer cells acquire energy. First, cancer cells use glycolysis for ATP production
and reduce their dependency on the oxidative cellular respiration in the mitochondria. This
results in the cancer cells gaining only 2 ATP per glucose molecule instead of the average
36 ATP from typical cellular respiration processes, resulting in an enormous demand
for glucose. Secondly, it allows the cancers cells to rapidly divide even in the absence of
oxygen, since glycolysis is an anaerobic process that occurs in the cytosol. Currently, altered
metabolism has been described as a primary signature of cancer [125,136,137]. Since this
discovery, the use of metabolic therapies for dealing with cancer have been overshadowed
by discoveries in the genetics and molecular signatures of cancer [138].
Therefore, it seems reasonable to hypothesize that diet could have profound effects
on reducing cancer risk, especially if that diet is known to decrease body weight, lower
insulin levels, and target the metabolic weaknesses of cancer cells. Some researchers
hypothesize that the ketogenic diet might reduce cancer risk because it capitalizes on the
reduced expression of ketolytic enzymes in cancer cells [48]. The diet would starve the
cancer cells by reducing their ability to utilize glucose, while normal cells can adapt and
begin utilizing ketone bodies for their energy demands. Another potential benefit could be
the decrease in insulin that results from being in nutritional ketosis, which would reduce
insulin-like growth factors that support cancer proliferation [48]. Especially given the fact
that 20% of all cancer cases in North America can be attributed to obesity and 38% of all
attributable cancer cases are linked to the increase in BMI since 1982 [139]. There have
also been numerous studies that have linked cancer risk to hyperinsulinemia [140–144].
It is suggested that insulin resistance leads to hyperinsulinemia, and insulin has both
pro-mitotic and antiapoptotic activity that may assist in tumor progression. Thus, any diet
that can reduce obesity and lower insulin levels, such as the ketogenic diet, might reduce
cancer risk.
Support for a KD as a mono-therapeutic approach for treating cancer is demonstrated
in many mouse models. However, due to the heterogeneity of these studies (types of
cancers, KD protocol, length of study, etc.), we discuss them separately. Poff et al. [145]
tested a KD on systematic metastatic cancer in mice. They found that KD alone significantly
decreased blood glucose levels, reduced tumor growth, and improved mean survival time
by 56.7%. A similar study looked at the effect of the KD on mice with gastric tumor
cells. Both tumor growth and mean survival time were improved [146]. In one study,
Allen et al. [147] found that a KD reduced tumor growth in lung cancer xenografts.
In another study, they tested the use of a calorie-restricted KD on the growth and vas-
cularity of malignant mouse astrocytoma (CT-2A) and human malignant glioma (U87-MG).
When compared to an unrestricted high carbohydrate standard diet, they found that tumor
growth decreased by 65% for CT-2A and 35% for U87-MG tumors [148]. They also found
that signs of angiogenesis were reduced in the calorie restricted KD group. It is important
to note that the mice in this study were fed KetoCal, a new nutritionally balanced high
fat/low carbohydrate ketogenic diet for children with epilepsy. This finding suggests
that the use of KetoCal should be considered not only for epilepsy, but as an alternative
therapeutic option for malignant brain cancer. Another study found that a KetoCal KD
diet also increased mean survival time and slowed tumor growth in mice with brain can-
cer [149]. Additionally, one study on mice by Morsher et al. [150] compared a KD and SD
on neuroblastoma, with or without calorie restriction. It was found that the best results
were in the calorie restricted KD group, with reduced tumor growth and survival time.
Meanwhile, a few studies have tried to compare the effect of a KD (with varying
levels of carbohydrate amounts) on prostate cancer, with differing results. Caso et al. [151]
Nutrients 2021, 13, 1654 18 of 29

studied mice that were either randomized into a standard Western diet, non-carbohydrate
KD (NCKD) with 0% carbs, 10% carbohydrate KD, or 20% carbohydrate KD. The group
with the slowest tumor growth was the 20% carbohydrate KD, while the WD had the
most rapid growth. However, they did not find a significant improvement in survival
among any of the carbohydrate restricted groups when compared to the WD. This result is
different than a similar study done by Masko et al. [152], which compared a NCKD, 10%
carbohydrate, and 20% carbohydrate diet in mice with prostate cancer. They concluded
that none of these diet groups differed greatly in their tumor size throughout most of the
study, and the diet did not affect survival. However, another study conducted on mice with
prostate cancer compared a WD with a NCKD and found that the NCKD was significantly
associated with lower tumor volumes at the end of the 53-day experiment [153]. Regardless
of the varying results, a meta-analysis done by Klement et al. [154] analyzed a total of
29 animal studies and found that the majority (72%) found evidence of reduced tumor
growth because of KDs.
The data of the effect of KD in human patients is limited mostly to case studies and
cohort studies. A meta-analysis of 24 human studies, found that 42% found that the KD can
reduce tumor growth [154]. In addition, it has been found that most human studies had
positive impacts [154,155], with many other studies found it stabilized disease [154,155]
and one study found a pro-tumorigenic effect of the KD [154,155]. However, another
review of 14 studies of the use of KD in cancer found mixed results [154]. It was found
that people responded differently to the diet, with some cancers being reduced, some
neutral in effect, and some cancers getting progressively worse. This finding could be
related to a recent publication by Chang et al. [156] that tested relative expression of several
key enzymes in ketolytic and glycolytic metabolism in human anaplastic glioma and
glioblastoma. They found genetically heterogeneous tumors with varying expressions
of key enzymes. However, they found most cells had an enzyme profile with decreased
levels of mitochondrial ketolytic enzymes and increased expression of glycolytic enzymes,
suggesting that human brain tumors are more dependent on glucose and have defects in
ketone metabolism.
The prognosis of patients with gliomas is extremely poor, with an average survival
duration of 1.5 years [138]. Due to the poor outcomes with brain cancer, many studies
using KD have been aimed at helping brain cancer patients. A small study by van der
Louw et al. [157] followed three patients with recurrent diffuse intrinsic pontine glioma
(DIPG). Although all three patients succumbed to the disease, it was determined that the
use of KD is safe and feasible, but its effect on survival was not clear. Another 12-week
randomized, controlled study also found that the use of KD in women with ovarian and
endometrial cancer had favorable effects on physical function, perceived energy, and
diminished food cravings for starchy and fast-food fats [158].
One of the most intriguing studies was a case study of a 38-year-old man with glioblas-
toma multiforme was treated with standard of care (SOC) along with a calorie-restricted ke-
togenic metabolic therapy, hyperbaric oxygen therapy, and other metabolic therapies [159].
The patient remains in excellent health with no neurological issues after 24 months of
treatment. Thus, it seems that the ketogenic diet might be best utilized as an adjuvant
therapy and should be started when the disease is first diagnosed. Recently the KEAT-
ING study [160] used either the modified ketogenic diet (MKD) or the medium chain
triglyceride ketogenic diet (MCTKD) as an adjuvant therapy for glioblastoma. The Global
Health Status (GHS) increased for patients in MKD cohort and decreased for the MCTKD
patients. They had a low retainment with only 3 of 12 patients completing the 12-month
intervention. The three patients who did complete the study chose to continue doing the
KD. The researchers of the KEATING study suggested that the KD intervention should be
reduced to six weeks and only be utilized during the time of chemo and radiation therapy.
Yet, another study by Panhans et al. [161] had greater compliance. This study recruited
patients with a diversity of CNS malignancies (GBM, astrocytoma, and oligodendroglioma).
These patients were asked to do a more standard KD of 3:1 for 120 days and aimed to
Nutrients 2021, 13, 1654 19 of 29

keep carbohydrates under 20 g/day. One cohort was provided KD meals by Epigenix
Foundation for the first 30 days, while the others were given only meal plans. Adherence
to the diet was confirmed with ketone and glucose levels measured with Precision Xtra
meters. The six patients with the highest ketones were alive at the end of the study. The
two patients with the lowest ketones succumbed to their disease. Five patients were able
to maintain 100% adherence for the duration of the study. Overall, patients’ symptoms
improved, which included higher energy levels, increased physical activity, increased
cognitive function, decreased appetite, and reduced seizure. It is important to note that
one patient had increased seizures. The researchers stated that the KD was well tolerated
and discussed its feasibility for future experiments. This cancer clinic also stated that as
interest in the KD grows, they now openly discuss the risks and potential benefits on a
regular basis with patients and emphasize the lack of robust clinical evidence.
The ketogenic diet is also now being tested as an adjuvant therapy for other cancers as
well. For example, Clinicaltrials.gov currently lists over 100 trials looking at the ketogenic
diet and 12 of those were related to CNS malignancies [161]. Therefore, data is starting to
emerge on the impacts of KD on other cancer types. For instance, a study compared the
typical diet with 55% of calories from carbohydrate (CHO) against a KD with around 6%
from CHO in breast cancer patients in a 6-week trial [162]. The KD group’s global quality
of life was higher at the 6-week mark and no adverse effects were seen in either group.
Interestingly, the KD group lowered caloric intake without any restrictions, which may
have been due to the satiating effects of fat. The KD diet was found to have no adverse
effects on thyroid hormones, electrolytes, LDH, urea, or albumin. Yet, the KD diet was
found to have potential beneficial effects, such as significantly reduced levels of lactate
and ALP. Decreased lactate levels might slow metastases by reducing the acidity of the
tumor microenvironment while reducing its ability to use it as a substrate for increasing
biomass. Furthermore, it is believed that increased levels of ALP in breast cancer is a
negative prognostic marker.
Another 12-week study in ovarian and endometrial cancer patients found an adher-
ence level of 57–80% [163]. The focus of this study was to determine if the diet negatively
affected lipid profiles since that is a current concern of many doctors and may restrict their
decision on whether to suggest the KD diet for their cancer patients. They compared the KD
versus the American Cancer Society (ACS) high-fiber, low fat diet. No changes were seen in
lipid profiles to TC, TG, HDL-C, LDL-C, TC:HDL-C ratio or TG:HDL-C ratio after adjusting
for baseline levels and weight loss. Another recent study looked at the effects of the diet on
the body composition of KD patients while receiving radiation therapy. Klement et al. [164]
compared a nonKD vs a KD with supplemental essential amino acids (KETOCOMP study).
The KD had significantly associated with loss of 0.5 kg of fat mass and 0.4 kg of body
weight per week, while showing no change in fat free mass or skeletal muscle mass. Thus,
KD with ample amino acid intake could improve body composition during radiotherapy.
Finally, a recent study conducted by Hagihara et al. [165] analyzed the effects of a 3-month
KD as an adjuvant therapy for patients with advanced cancers of many types. They found
that the diet was well tolerated, did not have any major negative outcomes, and improved
life expectancy. Researchers were also able to stratify survival outcomes with three factors:
albumin, blood sugar, and CRP levels. Thus, it was argued that stable adherence and
highly reproducible results should be in favor of using the ketogenic diet as a standard for
therapeutic treatment during chemotherapy with advanced cancer diagnoses.
Please refer to Table S4 in the Supplementary Materials for a comparison of studies
evaluating the KD in relation to cancer outcomes.

8. Discussion
A well-formulated ketogenic diet can provide low carbohydrate intake, while pro-
viding adequate fiber sources such as seeds, nuts, coconut, avocado, spinach, broccoli,
cauliflower, and berries. Together, all these rich pre-biotic foods would lead to an increase
in Bacteroides and Bifidobacterium and a subsequent decrease in Firmicutes. With disease
Nutrients 2021, 13, 1654 20 of 29

rates increasing rapidly in the United States and other modern nations, it is increasingly
important that we determine the safety, efficacy, and potential life-saving benefits of alter-
native diets. What might be discovered is that patients should be given individualized
diets based on the species comprising their microbiome. This might enable patients to
eat certain foods that maximize their ability to remain in a state of nutritional ketosis and
optimize their overall health outcomes. The regular monitoring of the microbiome might
be necessary to continually moderate and change dietary needs for diversity. It might
also be determined that fecal microbiota transplants might be necessary to fully alter and
change the microbiome at the onset of a new diet which could then be further modified and
enhanced through diet. Regardless, much more research is needed in this area to determine
the effect of the ketogenic diet on the microbiome.
Even though the ketogenic diet shows promise in helping patients lose weight, obesity
is more than excess adipose tissue being stored on the body. It has been linked to many
other metabolic issues, such as diabetes, cardiovascular disease, neurological disorders, and
cancer. The ability to improve glycemic control in diabetics is critical for long-term health
especially since some would argue that the biggest indicator of cardiovascular disease risk
was HbA1c [88]. Surprisingly, the United Kingdom Prospective Diabetes Study (UKPDS)
examined 5102 newly diagnosed type 2 diabetics and found that patients showed a 14%
decrease in myocardial infarction for every 1% reduction in their HbA1c [166–168]. The
ability to have tight glycemic control is even more challenging in type 1 diabetics since they
are unable to make insulin and must inject it in response to glucose spikes induced by diet.
Thus, their greatest challenge is controlling postprandial glycemia [98]. Some scientists
argue that reducing carbohydrate intake is the easiest way for a type 1 diabetic to control
their blood sugar levels since it will reduce the error in determining the insulin amount
needed to match their increased blood glucose levels [88]. However, the benefits from
the low carbohydrate diet might also improve other health markers in diabetics, such as
abdominal fat and health-related quality of life factors as shown in other studies [169,170].
Type 2 diabetics have also improved or eliminated their diabetic state through diet, specif-
ically a diet that restricts carbohydrate consumption. Type 2 diabetes results in insulin
resistant cells and this has been linked to other complications and atherosclerotic processes
such as inflammation, decreased size of LDL particles, and endothelial dysfunction [171].
Thus, the benefits of a healthy, low carbohydrate diet on diabetes might also improve the
markers for cardiovascular disease as well.
Although the debate about diet and heart health continues, many new studies are re-
vealing that the picture is much more complicated than the diet-heart hypothesis suggested.
The need for more randomized, controlled studies of long-term duration are necessary
to determine the true effect of dietary macronutrients on cardiovascular risks. It appears
from preliminary studies that a ketogenic diet might have favorable outcomes on CVD,
but some still view the idea with great skepticism. In medicine, randomized controlled
trials are considered the gold standard and many physicians feel that there is not enough
of these studies to consider changing their medical advice. It is interesting that while
current scientists are unwilling to consider these dietary recommendations due to the lack
of long-term evidence, the entire United States adopted the current dietary guidelines
based mainly on an epidemiological study done by Ancel Keys [102]. Additionally, when
the available randomized controlled studies and prospective cohort studies of that time
were analyzed, they did not support the recommendation of dietary fat and coronary heart
disease [172,173]. Regardless, the necessity in discovering a healthy diet for most people is
an important endeavor, especially since we are currently seeing an epidemic of diabetes
and obesity, both of which are linked to cardiovascular disease risk.
The potential of the ketogenic diet to aid in cancer treatment is still up for debate.
However, the positive results seen in mice warrant that this metabolic therapy should
be evaluated further. From the studies presented, it appears that in mice and humans,
the diet seems to be most beneficial when used as an adjuvant with other therapies and
when administered as soon as possible. It might also be critical to genetically analyze
Nutrients 2021, 13, 1654 21 of 29

each tumor and determine its metabolic profile to determine if it is exhibiting the Warburg
effect. If so, then the KD diet might be a useful addition to the treatment protocol. In
summary, a ketogenic diet may have positive impacts on the pathogenesis of cancer,
although the determination of its use as a monotherapy or adjuvant therapy in humans
need further study.
In conclusion, it is becoming more and more apparent that a “systems biology” ap-
proach to human health might be the way of the future. Future studies might need to
consider numerous factors such as lifestyle, dietary intake, genotype, gut microbiome
composition, and genome-wide information on the epigenome to create a successful plan
for maximizing good health. According to Gerhauser et al. [20], “this ambitious goal can
only be reached in large interdisciplinary research projects, combining expertise of food
technologists, nutritionists, food chemists, molecular biologists, epigeneticists, clinicians,
nutritional epidemiologists, bioinformaticians, and statisticians to achieve an integrated
view of the influence of diet on human health.” Others argue that a diagnosis of high-risk
epigenetic states may lead to a better understanding of the links between nutrition, the
epigenome, and cancer risk [32]. If these markers can be identified and better understood,
then new interventions can be created. New research suggests that long-term dietary
choices affect diversity and gene expression of the gut microbiome. One such path might
be the use of the ketogenic diet to increase beneficial metabolites which can have positive
impacts on the genome. Additionally, a recent study analyzed the genetic variants for
personalized management of ketogenic diets [174] and it suggested that certain genetic and
dynamic markers of KD response may help identify individuals that will benefit the most
from a KD diet. Thus, the use of the ketogenic diet might have a multitude of therapeutic
effects, including but not limited to, helping with weight loss, improving lipid markers
for cardiovascular health, healing a disrupted microbiome, improving epigenetic markers,
reversing diabetes, or reducing the need for medication, and improving responses to cancer
treatments. However, if a high fat/low carbohydrate KD diet seems too restrictive, then
the use of personalized nutritional advice using microbiome sequencing might be the way
of the future for stabilizing many of these diseases and improving metabolic health.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/

10.3390/nu13051654/s1, Table S1: Main studies reporting the effects of low-carbohydrate diets,
including ketogenic diets, on weight loss, Table S2: Main studies reporting the effects of low-
carbohydrate diets, including ketogenic diets, on diabetes health markers, Table S3: Main studies
reporting the effects of low-carbohydrate diets, including ketogenic diets, on lipidology health
markers, Table S4: Main studies reporting the effects of low-carbohydrate diets, including ketogenic
diets, on cancer.
Author Contributions: Both authors contributed to conceptualization, writing, and editing of this
review. Both authors have read and agreed to the published version of the manuscript.
Funding: No funding was utilized in writing this review.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: We thank Rozanne Wille and Charles Larssen for critical reading of the manuscript.
This work is supported by the Office of Research & Creative Activity and the Department of Biology,
Western Kentucky University.
Conflicts of Interest: The authors declare no conflict of interest.
Nutrients 2021, 13, 1654 22 of 29

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