Advantages and Disadvantages of Keto Diet
Advantages and Disadvantages of Keto Diet
Advantages and Disadvantages of Keto Diet
1. Internal Medicine, Orange Park Medical Center, Orange Park, USA 2. Radiology, University of Florida
Health Jacksonville, Jacksonville, USA 3. Pharmacy, University of Florida, Gainesville, USA 4.
Endocrinology, Orange Park Medical Center, Orange Park, USA 5. Pharmacy, University of Florida Health
Jacksonville, Jacksonville, USA
Abstract
The ketogenic diet (KD) has gained immense popularity during the last decade, primarily
because of its successful short-term effect on weight loss. In the United States, KD is utilized in
a variety of patient populations for weight management, despite limited evidence regarding its
efficacy and risks. This literature review provides an evaluation of data on the benefits and risks
associated with the chronic use of KD, including its metabolic, endocrinological, and
cardiovascular effects.
Following CHO deprivation and depletion of glycogen stores, the body undergoes metabolic
changes to provide an energy source for the body through gluconeogenesis and ketogenesis.
Gluconeogenesis can be sustained for three days with adherence to an LCD, and subsequently,
additional energy sources are necessary to meet the metabolic requirements of the body and
brain. This is where the process of ketogenesis becomes indispensable, and the formation of
ketone bodies is then used as the primary energy source by cells with mitochondria and, most
importantly, the brain [6].
KD has been shown to effectively lead to weight loss, reduction in hyperinsulinemia, and
improvement in insulin sensitivity. However, patients diagnosed with diabetes on insulin or
oral hypoglycemic agents may suffer severe hypoglycemia if their medication regimen is not
properly managed during the initiation of KD. Furthermore, the diet is limited and/or
contraindicated in patients with liver failure, pancreatitis, inborn disorders of fat metabolism,
primary carnitine deficiency, carnitine palmitoyltransferase deficiency, carnitine translocase
deficiency, porphyria, and pyruvate kinase deficiency [6]. Common short-term side effects
resulting from the initiation of KD have been referred to as “keto flu,” which encompasses
symptoms including fatigue, headache, dizziness, nausea, vomiting, constipation, and low
exercise tolerance [6]. Symptoms typically resolve after a few days to weeks as the body adjusts
to the low CHO, ketogenic state. Long-term side effects include hepatic steatosis, kidney
stones, hypoproteinemia, and vitamin deficiency. While the benefits of following KD have been
extensively reported, long-term compliance with KD is a limiting factor. The sustainability of
the diet has been called into question, and the prognosis of the diet’s effects after
discontinuation must be examined.
Review
1. Ketogenic diet and cardiovascular risk factors
Dyslipidemia
In a systematic review and meta-analysis of clinical trials performed by Santos et al., a total of
23 randomized controlled trials corresponding to 17 clinical investigations were analyzed. The
authors concluded that LCD has positive effects on body weight, BMI, abdominal
circumference, blood pressure, high-density lipoprotein cholesterol (HDL-C), triglycerides,
glycemia, hemoglobin A1c (HbA1c), insulin, and C-reactive protein (CRP) [2]. However, despite
the positive impact on cardiovascular risk factors, there is insufficient data to support KD in the
long term as the studies were of relatively shorter duration, ranging from three to 36 months
only.
The lack of evidence regarding long-term cardiovascular implications indicates that making
Interestingly, multiple studies mention a “favorable” lipid profile associated with KD because it
increases HDL-C and decreases triglyceride levels. Distinguishably, increases are observed with
LDL-C and total cholesterol. A review article analyzing five randomized controlled trials
concluded that, after six months, individuals assigned to an LCD lost more weight than
individuals assigned to an LFD with a weight difference of -3.3 kg (95% CI: -5.3 to -1.4 kg).
Nevertheless, this significant difference was not identified after one year of intervention (95%
CI: -3.5 to 1.5 kg). Triglyceride levels had a significant decrease [-22.1 mg/dl (95% CI: -38.1 to -
5.3 mg/dl)], and HDL-C levels underwent a significant increase [4.6 mg/dl (95% CI: 1.5 to -8.1
mg/dl)] in the LCD group when compared to the LFD group. Conversely, LDL-C and total
cholesterol changed more favorably in the LFD group after six months of the intervention [9].
The mechanism postulated for this is mediated through lower CHO intake, inducing suppressed
insulin production. Concomitantly, decreased insulin production inhibits 3-hydroxy-3-methyl-
glutaryl-coenzyme A (HMG-CoA) reductase activation and stimulates HMG-CoA lyase involved
in ketone production. Thus, following a low CHO diet inadvertently leads to increased
production of LDL-C and hypothetically promotes atherosclerotic properties.
As reported by Seidelmann et al. in a prospective cohort study and meta-analysis, it is not only
a matter of CHO restriction but also the quality of food ingested. The study’s primary outcome
measure was all-cause mortality. After multivariable adjustment and a median follow-up period
of 25 years, a U-shape association was observed between the percentage of energy consumed
from CHO and mortality [pooled hazard ratio (HR): 1.20 (95% CI: 1.09 to 1.32 for low CHO
consumption); pooled HR: 1.23 (95% CI: 1.11 to 1.36 for high CHO consumption)] in the
Atherosclerosis Risk in Communities (ARIC) cohort. The authors emphasized that both low
(<40%) and high CHO consumption (>70%) conferred higher mortality when compared with
moderate CHO intake. Further analysis of the results demonstrated that mortality was worse
when fat and protein sources were animal-derived instead of plant-derived. A relationship may
exist between decreasing mortality rates and long-term approach considerations in the
replacement of CHO with plant-based fats and proteins such as vegetables, nuts, and whole
grains [10].
Hypertension
KD has been postulated to positively impact women diagnosed with polycystic ovarian
syndrome (PCOS). Women with PCOS experience symptoms of irregular/absent menses,
infertility, obesity, and other phenotypical effects of hyperandrogenism such as hirsutism.
PCOS is closely associated with other metabolic and endocrinological irregularities, which
include insulin resistance, hyperinsulinemia, type 2 diabetes mellitus, dyslipidemia, and
hyperandrogenism [12]. PCOS is accompanied by key features such as insulin resistance,
androgen excess, and abnormal gonadotropin dynamics. In turn, treatment is targeted towards
improving insulin resistance, weight loss, decreasing luteinizing hormone (LH) and follicular
stimulating hormone (FSH) ratios, and excess androgens. A study by Mavropoulos et al.
implemented KD for women between the ages of 18-45 years diagnosed with PCOS, with a BMI
greater than 27 kg/m2, and no other serious medical conditions. Participants adhered to a six-
month period of strict KD consisting of less than 20 g of CHO per day with unlimited
consumption of animal-based foods. After 24 weeks, the results of the study (pre- and post-
design) showed a statistically significant decrease in fasting serum insulin (23.5 to 8.2,
p=0.002), LH-to-FSH ratio (2.23 to 1.21, p≤0.05), and free testosterone (2.19 to 1.70,
p≤0.05). Furthermore, the study subjects had an overall mean body weight change from baseline
of -12.1% and a mean decrease in BMI of 4.0 kg/m2 (p=0.0006) [12]. Despite the results of the
pilot study demonstrating a positive impact, there are limitations in generalization due to the
small sample sizes of the study.
A crossover study by Gower et al. included participants with PCOS who were randomly assigned
to either a standard diet or an LCD. The results demonstrated that LCD can lead to decreases in
glycemia, fasting insulin, testosterone, and insulin sensitivity. However, the study had
limitations due to the broad age range of participants and the small sample size, thereby
rendering it inadequate in terms of generalizability [13]. Similar results were reported by Paoli
et al., with significant reductions in BMI, glycemia, insulin, LDL-C, HDL-C, triglycerides, LH,
testosterone, and dehydroepiandrosterone sulfate (DHEAS). Even though a reversal of the LH-
to-FSH ratio was observed initially, it was not reported after 12 weeks. Limitations of this study
include small sample size, single-arm design, lack of infertility measurements, and a short
intervention time interval [14].
The term “Ketogenic Diet” may lead to apprehension in diabetic patients given its association
with the well-known, life-threatening condition of ketoacidosis. It is important to note that
In an outpatient clinic study by Yancy et al., overweight patients diagnosed with type 2 diabetes
were made to follow a VLCKD throughout 16 weeks with the primary outcome measure of
monitoring blood glucose control through HbA1c levels. The 28 participants enrolled were
restricted to less than 20 g of CHO per day. At the end of the 16-week timeframe, HbA1c
decreased from 7.5 ±1.4% to 6.3 ±1.0% (p<0.001). The absolute decrease in HgA1c was
approximately 1.0% in 11 participants (52%). The relative decrease in HgA1c from baseline was
>10% in 14 participants, and >20% in six participants. Furthermore, seven participants had
their baseline diabetic medications discontinued, 10 participants had their baseline
medications decreased, while four participants had unchanged requirements regarding baseline
medications [15].
A similar observational study was performed by Leow et al. to evaluate the glycemic benefits of
a VLCKD in patients diagnosed with type 1 diabetes. The study had a total of 11 eligible
participants based on the study inclusion criteria, which included type 1 diabetes of ≥2 years,
not taking any medications other than insulin, fasting blood beta-hydroxybutyrate levels of
≥0.4 mmol/l, and C-peptide levels of <0.05. Participants were required to follow a VLCKD with
ingestion of less than 55 g of CHO a day for more than six months. The median duration of
intervention was 1.5 years (range: 0.6-3 years). All participants had their HbA1c, C-peptide,
beta-hydroxybutyrate levels, lipoprotein profile, markers of liver and kidney function, height,
body mass, and blood pressure measurements taken after overnight fasting. The participants
were found to have a mean HbA1c of 5.3% ±0.4%; mean and median blood glucose levels
determined from continuous glucose monitoring were 5.8 ±1.2 and 5.5 (3.1-8.4) mmol/l,
respectively. Daily blood glucose variability, expressed as standard deviation (SD) and
coefficient of variation, was 1.5 ±0.7 mmol/l and 26.4% ±8.0%, respectively. The mean and
median magnitude of postprandial blood glucose excursions were 0.8 ±1.5 and 0.5 (0-2.2)
mmol/l, respectively. Hypoglycemic events were detected with continuous glucose monitoring;
patients experienced 0.9 (0.0-2.0) episodes of hypoglycemia per day, defined as blood glucose
levels of <3.0 mmol/l [5]. The results of this study indicate that adherence to KD in type 1
diabetics is associated with well-controlled HbA1c levels and minimal glycemic
variability. Although this shows some evidence regarding the normalization of HbA1c, the diet
comes with increased risks of hypoglycemic episodes. Hence, it is important to emphasize that
insulin regimens, as well as oral hypoglycemic agents, must be closely monitored and adjusted
in any diabetic patient following a VLCKD regimen.
Long-term adherence to KD is a major challenge and that is why this type of diet is considered
non-sustainable. A comparison of different meta-analyses, review articles, and interventional
studies revealed that no uniformity was established in the reported results. The limitations of
most studies are attributed to small sample sizes, short duration of interventions, and high
participant dropout rates. Due to the above-mentioned issues, even though some studies show
positive results, we cannot consider them applicable to the general population; especially given
that patients with diabetes or obesity often have other comorbid conditions such as
dyslipidemia and CVD.
Obesity
The aim of The Diet Intervention Examining the Factors Interacting with Treatment Success
(DIETFITS) randomized clinical trial was to determine the effect of healthy low-fat (HLF) diet
vs a healthy low-carbohydrate (HLC) diet on weight change and if genotype pattern or insulin
secretion were related to the dietary effects on weight loss. The clinical trial, involving 609
overweight adults, did not demonstrate any results of statistical significance regarding its
primary outcome measure, which was weight change with an HLF diet or HLC diet over 12
months. Similarly, neither type of diet showed outcomes of statistical significance in genotype
pattern interaction or baseline insulin secretion interaction with 12-month weight loss. It can
be assumed that it would be difficult to identify which type of diet is better for any individual.
Thus, this leads us to conclude that dietary modifications remain key to successful weight loss
[17].
Conclusions
Based on our review, within the first 6-12 months of initiating KD, transient decreases in blood
pressure, triglycerides, and glycosylated hemoglobin, as well as increases in HDL and weight
loss may be observed. However, the aforementioned effects are generally not seen after 12
months of therapy, as the changes reported in the studies we reviewed are not statistically
significant. Further research is warranted to evaluate the long-term implications of KD. Despite
the diet's favorable effect on HDL-C, the concomitant increases in LDL-C and very-low-density
lipoproteins (VLDL) may lead to increased cardiovascular risks. Additionally, the dietary
restrictions required to sustain ketosis may actually lead to its low sustainability.
Unfortunately, most available studies lack generalizability and validity due to their small
sample sizes and short study durations. Due to the limited amount of robust studies and lack of
strong evidence evaluating the diet’s potential risks, recommendations supporting VLCKD in
patients with no comorbidities, or cardiometabolic and endocrinologic diseases should be
made at the provider’s discretion.
Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors
declare the following: Payment/services info: This research was supported (in whole or in
part) by HCA and/or an HCA-affiliated entity. The views expressed in this publication represent
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