ketogenic diet thesis statement

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• Published: 30 November 2020

Effect of the ketogenic diet on glycemic control, insulin resistance, and lipid metabolism in patients with T2DM: a systematic review and meta-analysis

• Xiaojie Yuan 1   na1 ,
• Jiping Wang 1   na1 ,
• Shuo Yang 2   na1 ,
• Mei Gao 2 ,
• Lingxia Cao 2 ,
• Xumei Li 1 ,
• Dongxu Hong 1 ,
• Suyan Tian 3 &
• Chenglin Sun   ORCID: orcid.org/0000-0003-3570-1918 1 , 2  

Nutrition & Diabetes volume  10 , Article number:  38 ( 2020 ) Cite this article

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• Type 2 diabetes

At present, the beneficial effect of the ketogenic diet (KD) on weight loss in obese patients is generally recognized. However, a systematic research on the role of KD in the improvement of glycemic and lipid metabolism of patients with diabetes is still found scarce.

This meta-study employed the meta-analysis model of random effects or of fixed effects to analyze the average difference before and after KD and the corresponding 95% CI, thereby evaluating the effect of KD on T2DM.

After KD intervention, in terms of glycemic control, the level of fasting blood glucose decreased by 1.29 mmol/L (95% CI: −1.78 to −0.79) on average, and glycated hemoglobin A1c by 1.07 (95% CI: −1.37 to −0.78). As for lipid metabolism, triglyceride was decreased by 0.72 (95% CI: −1.01 to −0.43) on average, total cholesterol by 0.33 (95% CI: −0.66 to −0.01), and low-density lipoprotein by 0.05 (95% CI: −0.25 to −0.15); yet, high-density lipoprotein increased by 0.14 (95% CI: 0.03−0.25). In addition, patients’ weight decreased by 8.66 (95% CI: −11.40 to −5.92), waist circumference by 9.17 (95% CI: −10.67 to −7.66), and BMI by 3.13 (95% CI: −3.31 to −2.95).

KD not only has a therapeutic effect on glycemic and lipid control among patients with T2DM but also significantly contributes to their weight loss.

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Introduction.

Diabetes mellitus (DM) is the world’s leading cause for motility and morbidity, and the disease has become a major public health burden worldwide. It is estimated that the prevalence of diabetes in adults worldwide is over 300 million, and it will increase by 55% by 2035 1 . Obesity or overweight is one of the essential risk factors for diabetes and contributes to a twice-higher risk to develop DM 2 , 3 . Thus, dietary therapy aiming at weight loss is typically recommended in clinical practice 4 . Due to the fact that diabetes and its complications affect many aspects of physiology, the benefits of weight reduction are not limited to glycemic control but are also related to many cardiovascular risk factors such as blood pressure, high-density lipoprotein (HDL), total cholesterol (TC) and triglyceride (TG) 2 .

Medical nutrition, as part of the comprehensive treatment of DM with obesity with a primary goal of weight reduction, is the most simple, effective and economical choice of intervention. The dietary approach for body weight reduction can be obtained from many strategies, including a low-calorie diet, a very low-calorie diet, high-protein diet, and so on. Ketogenic diet (KD), which contains a very low level of carbohydrates (<55 g/d) with the main energy sources of lipid and protein, and which causes ketosis and simulates the physiological state of fasting, has been well reported to be effective for weight loss and glycemic control 4 , 5 , 6 , 7 , 8 , 9 . Previous meta-analyses have proved the efficacy of KD in body weight reduction 2 , 10 , 11 ; however, systemic reviews on the effect of KD on weight reduction and glycolipid metabolism in patients with DM are still limited. Westman et al. 12 and Partsalaki et al. 13 demonstrated that KD improved type 2 diabetes mellitus (T2DM) by reducing the glycemic response caused by carbohydrate and improving potential insulin resistance. Leonetti et al. 14 and Walton et al. 15 reported reduced TG and TC with increased HDL levels after KD consumption for a lipid profile. However, controversies are still existing; studies revealed that a low-carbohydrate, high-fat diet may exacerbate the lipid profile in patients with diabetes, although glycemic control improved with hypoglycemic medications 16 , 17 , 18 . Therefore, the purpose of the current review was to conduct a meta-analysis on the effects of a KD in patients with diabetes.

Considering the potential benefits of KD in diabetes management and weight reduction, and considering fasting blood glucose and glycated hemoglobin A1c (HbA1c) as common biomarkers for long-term glycemic control, HDL, LDL, TC, and TG levels are included in the current analysis to determine the changes of metabolic disorders in glucose and lipid metabolism. In addition, the homeostatic model assessment of insulin resistance (HOMA-IR) is considered as a reflection of insulin resistance reversal.

Materials and methods

Literature search.

In this meta-analysis, only studies published in English were considered, which were identified by searching the PubMed and MEDLINE databases. The keywords used for this literature search are T2DM or diabetes mellitus, ketogenic diet, obesity, and human. The search was finished on September 20, 2019. This meta-analysis was planned and performed according to the Preferred Reporting Items for Systemic Reviews (PRISM) guideline (Fig. 1 ).

Only studies published in English were considered, which were identified by searching the PubMed and MEDLINE databases. The keywords used for this literature search are T2DM or diabetes mellitus, ketogenic diet, obesity, and human. The search was finished on September 20, 2019.

Inclusive/exclusive criteria

Studies that met the following inclusive criteria were included: (1) the disease of interest is type II diabetes; (2) the therapeutic diet under consideration is KD; (3) the study was carried out on humans; animal experiments are not included; and (4) the summary statistics of the mean difference between before and after KD (if both means for before and after measurements are available, then we took the difference of these two statistics to obtain the desired mean difference), their corresponding standard error or 95% CI (according to this, the standard error was calculated) or p values (according to this, the corresponding t statistics and subsequently the standard error were calculated) are available.

Exclusive criteria: (1) case report studies were excluded; (2) meta-analysis or review studies were excluded; (3) studies on other diseases rather than type II diabetes were excluded; and (4) if only the respective mean and standard errors were available, such studies were excluded given it is hard to get an accurate estimation for the standard error of mean difference (since both measurements were on the same patient, they should be correlated to each other, and hence it is impossible to estimate this correlation).

Statistical analysis

The effects of KD on type II diabetes were estimated by the mean difference after KD versus before KD and their corresponding 95% CIs in random-effects meta-analysis models or fixed-effect meta-analysis models. To determine which model should be used, heterogeneity among studies was evaluated by the Cochrane’s Q statistic corresponding p values and the I 2 statistics. If the p value was <0.05 and I 2  > 0.5, a random-effect meta-analysis model was used. Otherwise, a fixed-effect meta-analysis model was chosen. Additionally, potential bias was assessed by using funnel plots, in which effect sizes versus standard errors were diagrammed. All statistical analysis was carried out in the R software, version 3.5 ( www.r-project.org ) 19 , 20 , 21 .

There are 13 studies included in this meta-analysis; the details of these 13 studies are presented in Table 1 . In total, 567 subjects were included in the final meta-analysis. From the perspective of glucose metabolism, lipid metabolism, and weight control, the effects of KD on T2DM were systemically reviewed by comparing the after-intervention measures with before-intervention measures of several biomarkers for the same patient. The variables used to surrogate for carbohydrate metabolism are included fasting glucose level and HbA1c; for lipid metabolism TC, TG, HDL and LDL; and for weight loss body weight, BMI and waist circumference. For all variables except BMI and waist, random-effect models were adopted according to the Q statistic p value and I 2 statistics.

Using the meta-analysis method, we found that the fasting blood glucose level was decreased 1.29 mmol/l (95% CI: −1.78 to −0.79) after the intervention of KD, compared to before such an intervention (based on ten articles that have the summary statistics for the difference between after- and before-intervention measures). As far as HbA1c is concerned, we found that the reduced proportion of HbA1c is more significant after the KD implementation, with a difference of −1.07% (95% CI: −1.37 to −0.78), which is regarded as the ideal therapeutic effect of drugs that is possible to be achieved on HbA1c. The forest plots for these two carbohydrates metabolism indices are given in Fig. 2 .

The reduced proportion of HbA1c is more significant after the KD implementation, which is regarded as the ideal therapeutic effect of drugs that is possible to be achieved on HbA1c.

In this study, eight articles investigated the effect of KD on the lipid metabolism of diabetic patients, but only five papers analyzed total cholesterol. It can be seen that after KD consumption, TG decreased by 0.72 mmol/L (95% CI: −1.01 to −0.43), TC decreased by 0.33 mmol/L (95% CI: −0.66 to −0.01), and LDL decreased by 0.05 mmol/L (95% CI: −0.25 to −0.15). On the other hand, HDL increased by 0.14 mmol/L (95% CI: 0.03−0.25). The forest plots for these four biomarkers are shown in Fig. 3 .

It can be seen that after KD consumption, TG, TC, and LDL decreased. On the other hand, HDL increased.

Regarding weight loss, many studies have demonstrated that KD has a positive effect by providing effective control over obesity. The results of our meta-analysis are consistent with previous results. Specifically, the average weight decreased by 8.66 kg (95% CI: −11.40 to −5.92), waist circumference reduced by 9.17 cm (95% CI: −10.67 to −7.66) and BMI reduced by 3.13 kg/m 2 (95% CI: −3.31 to −2.95), as shown in Fig. 4 .

Many studies have demonstrated that KD has a positive effect by providing effective control over obesity; our findings were consistent with the previous reports.

The American Diabetes Society (ADA) recommended physical activity, dietary management, and medical intake and other approaches should be applied simultaneously to manage blood glucose levels, and other abnormal metabolic factors. KD showed numerous health benefits to patients with T2DM 22 , 23 . KD provides energy through fat oxidation. When the human body experienced extreme hunger or very limited carbohydrate, the ketone body was produced and released to circulation by hepatic transformation of fatty acids 24 , 25 . Nutritional ketosis is different from severe pathological diabetic ketosis; the blood ketone body remained at 0.5−3.0 mmol/L with reduced blood glucose and normal blood pH, with no symptoms in nutritional ketosis 26 .

The possible mechanism for the health benefit of KD on patients with T2DM is that the extreme restriction of carbohydrate reduces the intestinal absorption of mono-saccharide, which leads to lower blood glucose level and reduces the fluctuation of blood glucose, and its effectiveness on regulating glucose metabolism was confirmed by a large body of evidence 27 , 28 . The current study analyzed 13 studies from literature focusing on diabetic patients; the results showed that the reduction of blood glucose ranges from 0.62 to 5.61 mmol/L. Higher reduction amplitudes were reported by Dashti 29 and Leonetti et al. 14 of 5.61 mmol/L (weight random 3.0%) and 3.87 mmol/L (weight random 1.2%), respectively; other reductions in blood glucose were all lower than 1.8 mmol/L. The possible reason for the higher reduction found in these two studies could be the higher blood glucose level included in the studies, and also that the average blood glucose concentration was above 10.0 mmol/L, leading to the possibility of a larger reduction; however, their contribution to the overall effect estimations in the meta-analysis was low. The average changes in fasting blood glucose after the KD consumption among the selected studies were −1.29 mmol/L, indicating the effectiveness of the KD in lowering fasting blood glucose.

No studies included in this meta-analysis evaluated the effect of KD on postprandial glucose level; unlike medications, dietetic therapy showed a long-term effect on glucose regulation 4 , 16 , and HbA1c was analyzed to evaluate the long-term effect of KD. HbA1c effectively reflects the blood glucose control in the past 2−3 months in patients with diabetes. It is reported that the risk of cardiac infarction and micro-vascular complications reduced by 14% and 37%, respectively, when HbA1c reduced by 1%. Therefore, the HbA1c level showed essential clinical significance in evaluating the blood glucose control, revealing the potential problems in the treatment and thereby guiding the therapeutic schedule 30 , 31 . Eight of the selected studies showed a reduction of HbA1c after KD consumption, the changes ranging from −0.6% to −3.3%; HbA1c reduced <1.5% in the majority of the studies included in the current analysis besides the study conducted by Walton (−3.3%; weight random 5.1%) 15 . The possible explanation for such strong improvement of HbA1c could be that Walton’s study had enrolled a limited number of patients and thus the compliance of patients to KD therapy can be guaranteed. Moreover, the studied subjects were newly diagnosed diabetic patients who were under dietary management without taking glucose-lowering medications; newly diagnosed subjects persist well in the study. Considering the causal factors comprehensively, the above study showed an ideal reduction in HbA1c. The average reduction of HbA1c was 1.07 in the current analysis of the selected eight studies, indicating that dietary management may also achieve the ideal therapeutic effects of medication.

HOMA-IR is considered as an indicator to evaluate the status of insulin resistance. Insulin resistance as a clinical characteristic of T2DM is closely related to obesity. Improving insulin resistance is one of the major targets in diabetes treatment 32 , 33 , 34 . However, studies focusing on the role of KD in the improvement of insulin resistance in patients with diabetes are very limited; most of the studies focused on the effect in obese subjects 35 , 36 . For instance, a controlled clinical trial aiming at the effects of KD consumption in obese people without diabetes revealed that HOMA-IR decreased by about 2.0 after KD consumption for 6 weeks 37 . The current analysis showed consistent changes in the studies that included HOMA-IR evaluation, with reduction ranging from −0.4 to −3.4; the reason for the significant reduction of 3.4 in the study by Tay et al. 38 is that the population included was obese diabetic patients with BMI higher than 30 kg/m 2 . Obesity is closely related to insulin resistance; KD consumption is confirmed to be effective in reducing body weight, and it is expected that KD may improve insulin resistance in obese diabetic patients 39 . During the ketogenesis, the sensitivity of the insulin receptor is promoted; therefore, KD not only ensures the supply of basic nutrients but also maintains a negative balance of energy, and reduces the fluctuation and reduction of insulin secretion caused by reduced carbohydrate intake as well, which eventually leads to improved insulin sensitivity 40 , 41 , 42 , 43 .

Consumption of KD not only improved glucose metabolism, but a large body of evidence has reported that KD improved lipid metabolism as well. Hussain et al. 4 reported that KD reduced TG and TC, and increased HDL level, thus ameliorating the status of dyslipidemia. In the present study, eight studies included showed results of lipid metabolism in diabetic patients after KD consumption; however, only five analyzed the TC levels. The current results showed the mean reduction of TG was 0.72 mmol/L, TC was 0.33 mmol/L, and LDL was 0.05 mmol/L, while the increase of HDL was 0.14 mmol/L. The higher amplitude of variation occurred in the Dashti et al. study 29 . This study reported that TG reduced by 3.67 mmol/L, TC reduced by 1.88 mmol/L, and LDL reduced by 1.78 mmol/L, while HDL increased by 0.14 mmol/L. Changes in the amplitude of the lipid biomarkers were all at the higher end in the above study. Both glucose and lipid metabolism showed great improvement after KD consumption in such a study; the characteristics of subjects recruited were closely correlated. The study recruited 31 obese subjects with hyperglycemia, dyslipidemia, and BMI over 30 kg/m 2 . The baseline TG, TC, and LDL were higher than those of typical patients with T2DM, which may contribute to the significant changes after the intervention. Consumption of KD showed a significant therapeutic effect in common patients with T2DM, including the Dashti 29 study. Disorders of lipid metabolism are particularly strong among patients with insulin resistance in T2DM. Dyslipidemia is lipotoxic to cells, leading to and/or aggravating insulin resistance. Its typical manifestation is the increase of TG and free fatty acid (FFA) 44 , 45 , 46 , 47 . Increased FFA is an independent pathogenic factor for insulin resistance and can possibly increase the risk for cardiovascular diseases 48 , 49 . Therefore, the improvement of dyslipidemia is beneficial for not only regulating insulin sensitivity but also controlling the occurrence and progression of diabetic complications 50 , 51 .

Numerous studies have confirmed the role of KD consumption in weight reduction in obese patients 35 , 36 , 37 , 40 , 41 , 42 , 43 , 52 ; the current meta-analysis focused on the effect of KD on weight reduction in obese diabetic patients. The results showed the average reduction of body weight was 8.66 kg, waist circumference was 9.17 cm, and BMI was 3.22 kg/m 2 , which were consistent with previous studies in nondiabetic patients. We also found that KD reduced systolic blood pressure by 4.30 (95% CI: −7.02 to 1.58) and diastolic blood pressure by 5.14 (95% CI: −10.18 to 0.10) in patients with T2DM, which possibly benefit from the improvement of body weight 51 .

Besides the mediation of glucose and lipid metabolism, KD may also benefit other clinical symptoms in diabetic patients, including insomnia, chills, constipation, pruritus, numbness of limbs, hypopsia, fatty liver, hypertension, and reduced cardiac function.

The potential side effects of KD were only mentioned in two of the studies 14 , 41 included in the meta-analysis; thus it is impossible to perform a systematic review in terms of the risks associated with KD consumption. Specifically, Goday and Leonetti’s 14 , 41 study investigated the adverse reactions of KD. Goday et al. 41 mentioned that fatigue, headache, nausea and vomiting were more common in the KD diet group after a 2-week intervention, while constipation and orthostatic hypotension were more common after 10 weeks. It was revealed by Leonetti et al. 14 that in the early stages of applying the KD, patients reported a sense of hunger, but it could be significantly alleviated with the progress of the intervention. Even though headache, nausea, vomiting, constipation, diarrhea, and other symptoms were reported during the study, the symptoms were mild and lasted for a short time, not relating to clinical practice.

Limitations

Only 13 studies were included in the current analysis, with limited studies focusing on the effect of KD in patients with T2DM worldwide. For instance, no analysis was conducted on HOMA-IR even though there was a trend of improvement; also, very limited literature was available. All studies included in this meta-analysis were carried out among Caucasian diabetic patients (no East Asians included); however, the majority of East Asian diabetic patients showed insulin resistance with central obesity and defect in insulin secretion. Therefore, clinical trials conducted among East Asians are highly desirable to confirm whether there is an improvement in the secretion function of islet cells other than improved regulation of glucose and lipid metabolism. Moreover, the current study analyzed the data without assigning studies into time duration due to the limited number of studies and the missing data of insulin and lipid biomarkers; in addition, the duration of the follow-up was decentralized into days, months, and years. The available studies concerning the effects of ketogenic diet in patients with diabetes are very limited; it is impossible to summarize a similar follow-up interval for statistical analysis of time points. However, the current results suggested that ketogenic diet consumption contributed to therapeutic effects despite the length of the term of intervention. The analysis of the difference before and after the intervention may also give credit to the clinical efficacy of the diet therapy. In current clinical practice, a majority of the patients have to use a combination of multiple drugs to improve their glycolipid metabolism. Drug therapy is a heavy mental and economical burden to patients. Given the fact that most of the patients are confused regarding a proper dietary therapy plan, it is essential to recommend a feasible dietary therapy plan to transmit a positive message to both patients with diabetes and physicians majored in the area of diabetes.

Based on a meta-analysis that systematically reviewed 13 relevant studies, we found that ketogenic diet can not only control fasting blood glucose and reduce glycosylated hemoglobin, but also improve lipid metabolism. Additionally, ketogenic diet can reduce BMI and body weight. Therefore, ketogenic diet may be used as part of the integrated management of type 2 diabetes.

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Acknowledgements

This study was supported by the Science Technology Department of Jilin Province (20180623006TC and 20200404213YY) and the Interdisciplinary Project of First Hospital of Jilin University (JDYYJC010) and Transformation Project of First Hospital of Jilin University (JDYYZH-1902019) and Education Department of Jilin Province (JJKH20190032KJ and JJKH20201081KJ).

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These authors contributed equally: Xiaojie Yuan, Jiping Wang, Shuo Yang

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Department of Clinical Nutrition, First Hospital of Jilin University, 1 Xinmin Street, 130021, Changchun, Jilin, China

Xiaojie Yuan, Jiping Wang, Xumei Li, Dongxu Hong & Chenglin Sun

Department of Endocrinology and Metabolism, First Hospital of Jilin University, 1 Xinmin Street, 130021, Changchun, Jilin, China

Shuo Yang, Mei Gao, Lingxia Cao & Chenglin Sun

Division of Clinical Research, First Hospital of Jilin University, 1 Xinmin Street, 130021, Changchun, Jilin, China

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X.Y., J.W., S.Y., S.T. and C.S. were responsible for writing, M.G., L.C., X.L. and S.Y. were responsible for the literature collection and data management, D.H. and S.T. for statistical analysis, C.S. and S.T. are in charge of the overall research design and supervision.

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Yuan, X., Wang, J., Yang, S. et al. Effect of the ketogenic diet on glycemic control, insulin resistance, and lipid metabolism in patients with T2DM: a systematic review and meta-analysis. Nutr. Diabetes 10 , 38 (2020). https://doi.org/10.1038/s41387-020-00142-z

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Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials

• Chanthawat Patikorn 1 , 2 ,
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Systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported the benefits of ketogenic diets (KD) in various participants such as patients with epilepsy and adults with overweight or obesity . Nevertheless, there has been little synthesis of the strength and quality of this evidence in aggregate.

To grade the evidence from published meta-analyses of RCTs that assessed the association of KD, ketogenic low-carbohydrate high-fat diet (K-LCHF), and very low-calorie KD (VLCKD) with health outcomes, PubMed, EMBASE, Epistemonikos, and Cochrane database of systematic reviews were searched up to February 15, 2023. Meta-analyses of RCTs of KD were included. Meta-analyses were re-performed using a random-effects model. The quality of evidence per association provided in meta-analyses was rated by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) criteria as high, moderate, low, and very low.

We included 17 meta-analyses comprising 68 RCTs (median [interquartile range, IQR] sample size of 42 [20–104] participants and follow-up period of 13 [8–36] weeks) and 115 unique associations. There were 51 statistically significant associations (44%) of which four associations were supported by high-quality evidence (reduced triglyceride ( n  = 2), seizure frequency ( n  = 1) and increased low-density lipoprotein cholesterol (LDL-C) ( n  = 1)) and four associations supported by moderate-quality evidence (decrease in body weight, respiratory exchange ratio (RER), hemoglobin A 1c , and increased total cholesterol). The remaining associations were supported by very low (26 associations) to low (17 associations) quality evidence. In overweight or obese adults, VLCKD was significantly associated with improvement in anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, and total cholesterol. K-LCHF was associated with reduced body weight and body fat percentage, but also reduced muscle mass in healthy participants.

Conclusions

This umbrella review found beneficial associations of KD supported by moderate to high-quality evidence on seizure and several cardiometabolic parameters. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether the short-term effects of KD will translate to beneficial effects on clinical outcomes such as cardiovascular events and mortality.

Peer Review reports

Ketogenic diets (KD) have received substantial attention from the public primarily due to their ability to produce rapid weight loss in the short run [ 1 , 2 ]. The KD eating pattern severely restricts carbohydrate intake to less than 50 g/day while increasing protein and fat intake [ 3 , 4 , 5 , 6 ]. Carbohydrate deprivation leads to an increase in circulating ketone bodies by breaking down fatty acids and ketogenic amino acids. Ketones are an alternative energy source from carbohydrates that alter physiological adaptations. These adaptions have been shown to produce weight loss with beneficial health effects by improving glycemic and lipid profiles [ 7 , 8 ]. KD has also been recommended as a nonpharmacological treatment for medication-refractory epilepsy in children and adults [ 8 , 9 ]. Evidence suggests that KD has reduced seizure frequency in patients with medication-refractory epilepsy, and even allowing some patients to reach complete and sustained remission. 11 However, the exact anticonvulsive mechanism of KD remains unclear [ 10 , 11 ].

Several systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported on the use of KD in patients with obesity or type 2 diabetes mellitus (T2DM) to control weight and improve cardiometabolic parameters [ 1 , 12 , 13 , 14 , 15 ], in patients with refractory epilepsy to reduce seizure frequency [ 16 ], and in athletes to control weight and improve performance [ 17 ]. To date, there has been little synthesis of the strength and quality of this evidence in aggregate. This umbrella review therefore aims to systematically identify relevant meta-analyses of RCTs of KD, summarize their findings, and assess the strength of evidence of the effects of KD on health outcomes.

The protocol of this study was registered with PROSPERO (CRD42022334717). We reported following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (Additional file 1 ) [ 18 ]. Difference from the original review protocol is described with rationale in Additional file 2 : Table S1.

Search strategy and eligibility criteria

We searched PubMed, EMBASE, Epistemonikos, and the Cochrane database of systematic reviews (CDSR) from the database inception to February 15, 2023 (Additional file 2 : Table S2). No language restriction was applied. Study selection was independently performed in EndNote by two reviewers (C.P. and PS). After removing duplicates, the identified articles' titles and abstracts were screened for relevance. Full-text articles of the potentially eligible articles were retrieved and selected against the eligibility criteria. Any discrepancies were resolved by discussion with the third reviewer (SKV).

We included studies that met the following eligibility criteria: systematic reviews and meta-analyses of RCTs investigating the effects of any type of KD on any health outcomes in participants with or without any medical conditions compared with any comparators. When more than 1 meta-analysis was available for the same research question, we selected the meta-analysis with the largest data set [ 19 , 20 , 21 ]. Articles without full-text and meta-analyses that provided insufficient or inadequate data for quantitative synthesis were excluded.

Data extraction and quality assessment

Two reviewers (CP and PS) independently performed data extraction and quality assessment (Additional file 2 : Method S1). Discrepancies were resolved with consensus by discussing with the third reviewer (SKV). We used AMSTAR- 2 -A Measurement Tool to Assess Systematic Reviews- to grade the quality of meta-analyses as high, moderate, low, or critically low by assessing the following elements, research question, a priori protocol, search, study selection, data extraction, quality assessment, data analysis, interpretation, heterogeneity, publication bias, source of funding, conflict of interest [ 22 ].

Data synthesis

For each association, we extracted effect sizes (mean difference [MD], the standardized mean difference [SMD], and risk ratio [RR]) of individual studies included in each meta-analysis and performed the meta-analyses to calculate the pooled effect sizes and 95% CIs using a random-effects model under DerSimonian and Laird [ 23 ], or the Hartung-Knapp- Sidik-Jonkman approach for meta-analyses with less than five studies [ 24 ].  p  < 0.05 was considered statistically significant in 2-sided tests. Heterogeneity was evaluated using the I 2 statistic. The evidence for small-study effects was assessed by the Egger regression asymmetry test [ 25 ]. Statistical analyses were conducted using Stata version 16.0 (StataCorp). We presented effect sizes of statistically significant associations with the known or estimated minimally clinically important difference (MCID) thresholds for health outcomes [ 14 , 26 , 27 , 28 , 29 , 30 ].

We assessed the quality of evidence per association by applying the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluations) in five domains, including (1) risk of bias in the individual studies, (2) inconsistency, (3) indirectness, (4) imprecision, and (5) publication bias [ 31 ]. We graded the strength of evidence (high, moderate, low, and very low) using GRADEpro version 3.6.1 (McMaster University).

Sensitivity analyses

Sensitivity analyses were performed by excluding small-size studies (< 25 th percentile) [ 32 ] and excluding primary studies having a high risk of bias rated by the Cochrane’s risk of bias 2 tool (RoB 2) for RCTs from the identified associations [ 19 , 20 , 21 , 33 ].

Seventeen meta-analyses were included (Fig.  1 and Additional file 2 : Table S3) [ 1 , 2 , 15 , 16 , 17 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. These meta-analyses comprised 68 unique RCTs with a median (interquartile range, IQR) sample size per RCT of 42 (20–104) participants and a median (IQR) follow-up period of 13 (8–36) weeks. The quality of meta-analyses assessed using AMSTAR-2 found that none were rated as high confidence, 2 (12%) as moderate confidence, 2 (12%) as low confidence, and 13 (76.0%) as critically low confidence (Table 1 and Additional file 2 : Table S4).

Study selection flow of meta-analyses. Abbreviation: CDSR, Cochrane database of systematic review

Types of KD identified in this umbrella review were categorized as (1) KD, which limits carbohydrate intake to < 50 g/day or < 10% of the total energy intake (TEI) [ 35 ], (2) ketogenic low-carbohydrate, high-fat diet (K-LCHF), which limits carbohydrate intake to < 50 g/day or < 10% of TEI with high amount of fat intake (60–80% of TEI) [ 38 , 46 ], (3) very low-calorie KD (VLCKD), which limits carbohydrate intake to < 30–50 g/day or 13–25% of TEI with TEI < 700–800 kcal/day, and (4) modified Atkins diet (MAD), which generally limits carbohydrate intake to < 10 g/day while encouraging high-fat foods [ 15 , 47 ]. Meta-analyses of long-chain triglyceride KD, medium-chain triglyceride KD, and low glycemic index treatment were not identified.

Description and summary of associations

We identified 115 unique associations of KD with health outcomes (Additional file 2 : Table S5). The median (IQR) number of studies per association was 3 [ 4 , 5 , 6 ], and the median (IQR) sample size was 244 (127–430) participants. Outcomes were associated with KD types, including 40 (35%) KD, 18 (16%) K-LCHF, 13 (11%) VLCKD, 25 (22%) KD or K-LCHF, 5 (4%) KD or VLCKD, 1 (1%) KD or MAD, and 13 (11%) KD, K-LCHF, or VLCKD.

The associations involved 40 (35%) anthropometric measures (i.e., body weight, body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], waist circumference, muscle mass, fat mass, body fat percentage, and visceral adipose tissue), 37 (32%) lipid profile outcomes (i.e., triglyceride, total cholesterol, high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]), 22 (19%) glycemic profile outcomes (i.e., hemoglobin A 1c [HbA 1c ], fasting plasma glucose, fasting insulin, and homeostatic model assessment of insulin resistance [HOMA-IR]), 6 (5%) exercise performance (i.e., maximal heart rate, respiratory exchange ratio [RER], maximal oxygen consumption (VO 2 max), 5 (4%) blood pressure outcomes (i.e., systolic blood pressure [SBP], diastolic blood pressure [DBP], and heart rate), 1 (1%) outcome associated with seizure frequency reduction ≥ 50% from baseline, and 3 other outcomes (i.e., serum creatinine, C-peptide, and C-reactive protein). In addition, there is 1 association (1%) of adverse events.

Participants in the identified associations included 68 (59%) associations in adults with overweight or obesity with or without T2DM or dyslipidemia, 15 (13%) athletes or resistance-trained adults, 12 (10%) adults with T2DM, 11 (10%) healthy participants ≥ 16 years old, 8 (7%) cancer patients, and 1 (1%) in children and adolescents with epilepsy.

Using GRADE, 115 associations were supported by very low strength of evidence ( n  = 66, 57%), with the remaining being low ( n  = 36, 31%), moderate ( n  = 9, 8%), and high quality of evidence ( n  = 4, 3%) (Additional file 2 : Table S5). Almost half, or 44% (51 associations), were statistically significant based on a random-effects model, of which 51% (26 associations) were supported by a very low level of evidence, followed by low (17 associations [33%]), moderate (4 associations [8%]), and high (4 associations [8%]) levels of evidence. Overall beneficial outcomes associated with KD were BMI [ 37 , 42 ], body weight [ 1 , 2 , 35 , 36 , 37 , 41 ], waist circumference [ 37 , 42 ], fat mass [ 37 , 42 ], body fat percentage [ 38 , 40 ], visceral adipose tissue [ 37 ], triglyceride [ 1 , 2 , 36 , 42 ], HDL-C [ 1 , 2 , 42 ], HbA 1c  [ 2 , 34 , 35 ],  HOMA-IR [ 2 , 42 ], DBP [ 1 ], seizure frequency reduction ≥ 50% from baseline [ 16 ], and respiratory exchange ratio [ 17 , 39 ]. Adverse outcomes associated with KD were reduced muscle mass [ 37 , 38 ], and increased LDL-C [ 2 , 35 ], and total cholesterol [ 2 , 17 ]. In terms of safety, one association showed no significant increase in adverse events (e.g., constipation, abdominal pain, and nausea) with KD [ 44 ].

Eight out of 13 associations supported by moderate to high-quality evidence were statistically significant (Table 2 ). There were 4 statistically significant associations supported by high-quality evidence, including the following: (1) KD or MAD for 3–16 months was associated with a higher proportion of children and adolescents with refractory epilepsy achieving seizure frequency reduction ≥ 50% from baseline compared with regular diet (RR, 5.11; 95% CI, 3.18 to 8.21) [ 16 ], (2) KD for 3 months was associated with reduced triglyceride in adults with T2DM compared with regular diet (MD, -18.36 mg/dL; 95% CI, -24.24 to -12.49, MCID threshold 7.96 mg/dL) [ 14 , 35 ], (3) KD for 12 months was associated with reduced triglyceride in adults with T2DM compared with regular diet (MD, -24.10 mg/dL; 95% CI, -33.93 to -14.27, MCID threshold 7.96 mg/dL) [ 14 , 35 ], and (4) KD for 12 months was associated with increased LDL-C in adults with T2DM compared with regular diet (MD, 6.35 mg/dL; 95% CI, 2.02 to 10.69, MCID threshold 3.87 mg/dL) [ 14 , 35 ]. In addition, there were 4 statistically significant associations supported by moderate-quality evidence: (1) KD for 3 months was associated with reduced HbA 1c in adults with T2DM compared with regular diet (MD, -0.61%; 95% CI, -0.82 to -0.40, MCID threshold 0.5%) [ 14 , 35 ], (2) VLCKD for 4–6 weeks was associated with reduced body weight in T2DM adults with overweight or obesity compared with a low-fat diet or regular diet (MD, -9.33 kg; 95% CI, -15.45 to -3.22, MCID threshold 4.40 kg) [ 14 , 15 ], (3) K-LCHF for 4–6 weeks was associated with reduced respiratory exchange ratio in athletes compared with a high-carbohydrate diet (SMD, -2.66; 95% CI, -3.77 to -1.54) [ 39 ], and (4) K-LCHF for 11–24 weeks was associated with increased total cholesterol in athletes compared with regular diet (MD, 1.32 mg/dL; 95% CI, 0.64 to 1.99) [ 14 , 17 ].

Types of KD showed different effects on health outcomes with changes more than the MCID thresholds in different populations (Fig.  2 ). KD or MAD for 3–16 months was associated with a 5-times higher proportion of children and adolescents with refractory epilepsy achieving seizure frequency reduction ≥ 50% from baseline compared with a regular diet (RR, 5.11; 95% CI, 3.18 to 8.21) [ 16 ]. In healthy participants, K-LCHF for 3–12 weeks could reduce body weight by 3.68 kg (95% CI, -4.45 to -2.90) but also significantly reduced muscle mass by 1.27 kg (95% CI, -1.83 to -0.70, MCID threshold 1.10 kg) [ 14 , 26 , 38 ]. In adults with T2DM, KD for 3–12 months was found to have significant associations with changes more than the MCID thresholds, including reduction of triglyceride and HbA 1c ; however, KD for 12 months led to a clinically meaningful increase in LDL-C by 6.35 mg/dL (95% CI, 2.02 to 10.69, MCID threshold 3.87 mg/dL) [ 14 , 35 ]. In adults with overweight or obesity and/or metabolic syndrome, VLCKD for 4–6 weeks demonstrated a clinically meaningful weight loss of 9.33 kg (95% CI, -15.45 to -3.22, MCID threshold 4.40 kg) [ 14 , 15 ]. VLCKD for 3–96 weeks led to a clinically meaningful improvement in BMI, body weight, waist circumference, triglyceride, fat mass, and insulin resistance, while preserving muscle mass [ 42 ].

Associations of Types of Ketogenic Diet with Health Outcomes. Abbreviations: BMI, body mass index, DBP, diastolic blood pressure; GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; HbA 1c , hemoglobin A 1c ; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model of insulin resistance; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TEI, total energy intake

Excluding RCTs with small sizes in 7 associations found that the strength of evidence of one association was downgraded to very low quality, i.e., KD for 12 months, and the increase of LDL-C in adults with T2DM compared with a control diet. Another association was downgraded to low quality, i.e., KD for 12 months and the reduction of triglyceride in adults with T2DM compared with the control diet (Additional file 2 : Table S6). The remaining associations retained the same rank.

This umbrella review was performed to systematically assess the potential associations of KD and health outcomes by summarizing the evidence from meta-analyses of RCTs. Sensitivity analyses were performed to provide additional evidence from high-quality RCTs, which further increased the reliability of results. We identified 115 associations of KD with a wide range of outcomes. Most associations were rated as low and very low evidence according to the GRADE criteria because of serious imprecision and large heterogeneity in findings, and indirectness due to a mix of different interventions and comparators.

Our findings showed that KD or MAD resulted in better seizure control in children and adolescents with medication-refractory epilepsy (approximately a third of cases) for up to 16 months [ 10 , 11 , 16 ]. Anti-epileptic mechanisms of KD remain unknown but are likely multifactorial. Enhanced mitochondrial metabolism and an increase in ketone bodies or reduction in glucose across the blood–brain barrier resulted in synaptic stabilization [ 48 , 49 , 50 ]. Other mechanisms include an increase in gamma-aminobutyric acid (GABA) [ 51 ], more beneficial gut microbiome [ 52 ], less pro-inflammatory markers [ 53 ], and epigenetic modifications (e.g. beta-hydroxybutyrate [beta-OHB]) [ 54 ].

In adults, KD was associated with improved anthropometric measures, cardiometabolic parameters, and exercise performance. Our findings, however, demonstrated differences in the level of associations with type of KD. On the one hand, VLCKD is very effective in producing weight loss while preserving muscle mass in adults with overweight or obesity, with specific benefits on anthropometric and cardiometabolic parameters [ 15 , 42 ]. On the other hand, a significant portion of the weight loss seen in K-LCHF was due to muscle mass loss [ 17 , 38 ]. Overall KD was negatively associated with reduced muscle mass and increased LDL-C and total cholesterol.

Our findings demonstrated that KD could induce a rapid weight loss in the initial phase of 6 months, after which time further weight loss was hardly achieved [ 35 ]. Furthermore, weight loss induced by KD is relatively modest and appears comparable to other dietary interventions that are effective for short-term weight loss, e.g., intermittent fastingand Mediterranean diet [ 55 , 56 , 57 ].

KD is one of the dietary interventions employed by individuals to achieve rapid weight loss, which usually comes with reduced muscle mass [ 58 ]. However, KD has been hypothesized to preserve muscle mass following weight loss based on several mechanisms, including the protective effect of ketones and its precursors on muscle tissue [ 59 , 60 , 61 ], and increased growth hormone secretion stimulated by low blood glucose to increase muscle protein synthesis [ 58 , 62 , 63 ].

With regards to KD effects on lipid profiles, our results demonstrate an effective reduction in serum triglyceride levels with 3 months of lowered dietary carbohydrate intake, with even further reduction by month 12 [ 35 ]. Triglyceride levels are consistently shown to decrease after KD. Acute ketosis (beta-OHB ≈ 3 mM) due to ketone supplementation also shows decreases in triglycerides, indicating a potential effect of ketones on triglycerides independent of weight loss. One possible mechanism is the decreased very low-density lipoprotein content in the plasma due to low insulin levels. Due to a lack of insulin, lipolysis increases in fat cells [ 2 , 13 , 15 ]. Of note, the converse has also been observed as a phenomenon known as carbohydrate-induced hypertriglyceridemia, whereby higher dietary carbohydrate intake leads to higher serum triglycerides levels, potentially mediated by changes in triglyceride clearance and hepatic de novo lipogenesis rates [ 64 ]. Though our aggregate results also confirm an increase in LDL-C and total cholesterol with KD and K-LCHF, respectively, it is important to note that an increase in either of these levels does not necessarily signify a potentially deleterious cardiovascular end-point. This qualification derives from the fact that LDL particles are widely heterogeneous in composition and size, with small dense LDL particles being significantly more atherogenic than larger LDL particles [ 65 ]. Our observed aggregate effect of KD on cholesterol levels does not account for the difference in LDL particle size, nor does it distinguish the sources of dietary fat, which can also be a significant effector of LDL particle size distribution and metabolism [ 66 ].

Most RCTs of KD were conducted in patients with a limited group of participants, such as those with overweight, obesity, metabolic syndrome, cancer, and refractory epilepsy. In addition, most outcomes measured were limited to only surrogate outcomes. Thus, more clinical trials with a broader scope in populations and outcomes associated with KD would expand the role of KD in a clinical setting. For example, participant selection could be expanded from previous trials to include elderly patients, nonalcoholic fatty live disease (NAFLD) patients, and polycystic ovarian syndrome patients. Outcomes of interest of could be expanded to include (1) clinical outcomes such as cardiovascular events and liver outcomes, (2) short- and long-term safety outcomes such as adverse events (e.g., gastrointestinal, neurological, hepatic, and renal), eating disorder syndrome, sleep parameters, lipid profiles, and thyroid function and (3) other outcomes such as adherence and quality of life. More importantly, long-term studies are needed to investigate the sustainability of the clinical benefits of KD.

Our findings are useful to support the generation of evidence-based recommendations for clinicians contemplating use of KD in their patients, as well as for the general population. We further emphasize the importance of consultation with healthcare professionals before utilizing KD and any other dietary interventions. We demonstrated the benefits of KD on various outcomes in the short term. However, these improvements may prove difficult to sustain in the long term because of challenges in adherence. As for any diet interventions to achieve sustainable weight loss, factors of success include adherence, negative energy balance, and high-quality foods. Thus, communication and education with KD practitioners are important to ensure their adherence to the diet. Some individuals might benefit from switching from KD to other dietary interventions to maintain long-term weight loss.

Limitations

This umbrella review has several limitations. Firstly, we focused on published meta-analyses which confined us from assessing the associations of KD on outcomes and populations that were not included in existing meta-analyses. Secondly, most of the included meta-analyses were rated with AMSTAR-2 as critically low confidence, mainly due to a lack of study exclusion reasons, unexplained study heterogeneity, and unassessed publication bias. However, these domains unlikely affected our findings. Thirdly, we could not perform a dose–response analysis to understand the effects of different levels of carbohydrate intake on health outcomes because of insufficient details of carbohydrate intake reported in the meta-analyses. Fourthly, most RCTs of KD were limited to a relatively small number of participants with a short-term follow-up period, which limited our assessment of sustained beneficial effects after stopping KD. Lastly, due to decreased adherence, carbohydrate intake most likely increased across the course of the trials. For example, subjects in the KD arm of the A TO Z Weight Loss Study [ 67 ], started with a carbohydrate intake < 10 g/day but ended at 12 months with a carbohydrate intake accounting for 34% of TEI. In the DIRECT trial, subjects in the KD group started with carbohydrate intake of 20 g/day and ended at 12 months with 40% of TEI from carbohydrate intake [ 68 ]. Thus, we cannot be certain how the precise degree of ketosis contributed to the beneficial effects noted.

Beneficial associations of practicing KD were supported by moderate- to high-quality evidence, including weight loss, lower triglyceride levels, decreased HbA 1c , RER, and decreased seizure frequency. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether these short-term effects of KD will translate to beneficial effects on more long-term clinical outcomes such as cardiovascular events and mortality.

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary information files.

Abbreviations

Beta-hydroxybutyrate

Body mass index

Diastolic blood pressure

Gamma-aminobutyric acid

High-density lipoprotein cholesterol

Hemoglobin A 1c

Homeostatic model assessment of insulin resistance

Ketogenic low-carbohydrate high-fat diet

Ketogenic diets

Low-density lipoprotein cholesterol

Modified Atkins diet

Minimally clinically important difference

Nonalcoholic fatty liver disease

Randomized clinical trials

Respiratory exchange ratio

Systolic blood pressure

Type 2 diabetes mellitus

Total energy intake

Very low-calorie ketogenic diet

Maximal oxygen consumption

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Acknowledgements

The authors would like to acknowledge Thunchanok Ingkaprasert and Wachiravit Youngjanin for their editorial assistance.

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Chanthawat Patikorn, Pantakarn Saidoung, Sajesh K. Veettil & Nathorn Chaiyakunapruk

Department of Social and Administrative Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand

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Division of Gastroenterology, Hepatology & Nutrition, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA

Division of Ambulatory Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

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School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia

Yeong Yeh Lee

Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA

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CP, PS, SKV, and NC conceived and designed the study protocol. CP, PS, and SKV performed a literature review and data analysis. CP, PS, TP, PP, YYL, KAV, SKV, and NC interpreted the study findings. CP and PS were major contributors to writing the manuscript. All authors read and approved the final manuscript.

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Additional file 1..

 PRISMA 2020 Main Checklist. 

Additional file 2:

Method S1. Data extraction. Table S1. Difference from original review protocol. Table S2. Search strategy. Table S3. Excluded studies with reasons.  Table S4. Quality assessment. Table S5. Summary of associations. Table S6. Sensitivity analyses. 

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Patikorn, C., Saidoung, P., Pham, T. et al. Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials. BMC Med 21 , 196 (2023). https://doi.org/10.1186/s12916-023-02874-y

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• Ketegenic diet
• Umbrella review
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Ketogenic Diet: Overview Presentation

• To find inspiration for your paper and overcome writer’s block
• As a source of information (ensure proper referencing)
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Diet as the Way to Lose Weight

• Many people want to lose weight.
• Every person has their reasons.
• The issue of weight loss is relevant, but requires careful monitoring.

Often, many people think about losing extra weight. Every person has their reasons for doing so – one wants to lead a healthier life, while others want to attract people. One way or another, the questions of weight loss are acute for humanity; for this reason, quite often among the already known classic methods of weight loss new and radical options that can aggravate human health appear. In order to prevent unnecessary health issues and achieve the desired effect, nutritionists offer patients to use the rules of the popular ketogenic diet.

Everything New is Actually Well-forgotten Old

• In the early twentieth century, ketogenic diet was used to treat epilepsy.
• Carbohydrate deficiency in the diet caused insulin reduction.
• With the advent of drugs, the diet has been relegated to the background.
• It was only thirty years ago that nutritionists rediscovered the ketogenic diet.

Recently, ketogenic diets have been used by a large number of young and adult people, and this method of starvation has become incredibly popular. However, if one looks at the historical context of ketogenic diets, it is clear that the diet has a rather long and mixed history. This diet was first introduced in the early 20th century to treat diseases of the nervous system, particularly epilepsy (Rho 5). A prerequisite for the appearance of the diet was the use of fasting: when food ceased to arrive, insulin stopped being produced in the body, significantly affecting the central nervous system (Rho 5). Such fasting was indeed valid, but it was impossible to use it for a long time. The situation was particularly difficult for children, as deprivation of food posed a serious health hazard (Rho 6). At that time, a diet similar to healing fasting was developed, but it gave the body energy from fats. It showed excellent results – people with epilepsy practically stopped having seizures. Indeed, the success of the ketogenic diet was not celebrated for long: soon, there were specially developed drugs, as a result of which the diet was forgotten for some time. It was only in the 1990s, when the problem of non-universal antiepileptic drugs for patients matured, that such a diet became discussed again. Information about ketogenic diets started to spread in the media, and the “new” weight-loss remedy began to be popularized.

The Mechanism of the Diet

The rule is simple: lack of carbohydrates leads to burning of fats. The body draws energy from burning its own deposits or with food – as a result, the body weight is reduced.

The meaning of the ketogenic diet is that when carbohydrates are stopped when glucose concentration in blood decreases, the body searches for other sources of energy and burns fat. This process involves both fats from food and the body’s supplies. In the reorganization of diet, the liver produces ketone bodies (acetoacetate), which participate in the oxidation of fatty acids and are used as energy by many organs, including the brain. This condition is called ketosis (Yancy, Mitchell, & Westman 1734). As glucose disappears from the blood, the production of insulin, a hormone that prevents fat burning, is reduced.

Scientific Evidence

• There are many scientific proofs of the optimality of this model.
• Zajac et al. confirmed the short-term effect of the diet on athletes.
• Carbohydrate elimination strengthens muscles, normalizes the biochemical composition and helps to quickly lose weight.

The decision to use any diet must be meaningful, and the effectiveness of starvation has been scientifically proven. For example, Zajac et al. found that a ketogenic diet has a positive effect on the performance of athletes (2496). The study determined what changes would result from changing diets to predominantly fatty young cyclists. Scientists concluded that the short-term effect of a ketogenic diet could preserve muscle structures in athletes after exercise, reduce body weight, and improve biochemical composition. An incredible achievement of Zajac et al. is the discovery that a ketogenic diet has a positive effect on a person’s breathing ability (2498).

Who is Ketogenic Diet Good for

• Meat lovers;
• Those who want to save muscle mass;
• Patients with diabetes mellitus.

Despite the complexity of the first days and strict diet restrictions, for some people’s ketogenic diets are ideal. It is worth trying out for the following categories of people who want to lose weight:

• Meat lovers. Many diets offer a drastic reduction in meat-eating or complete rejection, but a ketogenic diet does not restrict it.
• Those who want to save muscle mass. Normally diets can reduce muscle mass, but a ketogenic diet does not destroy muscle fiber structures, which is more suitable for professional athletes.
• Patients with diabetes mellitus. Ketosis can control blood sugar levels (Yancy, Mitchell, & Westman 1734). It is a type of professional diet, so a doctor’s consultation is necessary.

Mistakes that are Made

Lack of education can lead to:

• Carbohydrate consumption.
• Consumption of large quantities of proteins.

Due to their lack of education, beginners often make typical mistakes when using a ketogenic diet. Most of these errors will neutralize the positive effects of the diet, but others can have adverse effects on health. The most common mistake is when a person neglects the basic rule of diet and eats small amounts of carbohydrates. However, it is essential to understand that even a slice of eaten bread delays the start of ketosis. The second error is the opposite: people often completely give up carbohydrates, but in addition, they increase the amount of protein they consume. Protein poisoning leads to the destruction of the liver, kidneys, and digestive system problems.

The most challenging part of the keto diet is getting used to an entirely new way of eating, especially the rejection of most foods with high carbohydrate content and the addition of fat. Large amounts of natural fat can be found in vegetable and animal oils. Low-carbohydrate meat products may include beef, poultry and eggs, and fish. Non-starchy foods such as avocados, tomatoes, cabbage, and broccoli are allowed types of vegetables. On a ketogenic diet, it is possible to eat fruits and berries such as raspberries, kiwi, lemons, and blueberries.

What Does a Person Get: Arguments “For”

• The scientific validity of diet.
• Rapidity of fat burning.
• Comfortable process.
• Long-term result.
• Cholesterol Control.
• Reducing epileptic seizures.
• Improving skin condition.

Those who decide to use ketogenic diet rules for weight loss should understand the benefits that await them. First, the effectiveness of such a diet has been scientifically proven (Zajac et al. 2493). Secondly, with such a diet, a person burns excess fat very quickly. Also, unlike other diets, the patient has no sense of hunger, so fasting is comfortable. Also, it should be noted that the result obtained is quite long term as the person is not hungry, and the body is not stressed. Several scientific studies demonstrate that a ketogenic diet improves cholesterol levels (“Pros and Cons” 1). This reduces the likelihood of cardiovascular disease. In addition, it should be remembered that a diet is right for people with epilepsy – the number of seizures and convulsions decreases (Feldman 36). In the world of cosmetology, there is a belief that a ketogenic diet has a positive effect on skin health by inhibiting the growth of acne and pimples (Feldman 36).

What a Person will Face: Arguments “Against”

• This diet is unbalanced
• Like any diet, it requires willpower.
• It is quite long, can be used for years.
• Side effects are possible.

It is essential to understand that there are no ideal weight loss models. A ketogenic diet is rich in deficiencies that can significantly worsen a person’s condition (Pros and Cons” 2). For this reason, it is necessary to consult a nutritionist before using such a diet.

• First, it should be noted that the ketogenic diet is unbalanced – it excludes the intake of several nutrients, vitamins, and trace elements.
• Secondly, it requires motivation and responsibility – one has to give up favorite dishes and regularly calculate the number of calories.
• The third disadvantage of the diet is duration: a ketogenic diet can last from 3-4 weeks to a year. There is no point in staying on a diet for less than three weeks because, during this time, the body will go through ketogenic adaptation and only begin to get all the benefits of this diet.
• It also has many side effects: constipation, nausea and vomiting, growth disorders, kidney stones, and changes in blood lipids.

What Else Should be Mentioned

What must be said is :

• This diet is not suitable for pregnant and sick patients.
• Long-term effects require careful consideration.
• Each diet is selected individually and requires analysis by a specialist.

The ketogenic diet has another disadvantage, which, however, cannot be unequivocally attributed to the general disadvantages. The fact is that this type of diet is not suitable for all population groups, and is contraindicated for medical reasons to pregnant women and people with kidney and liver diseases (Feldman 34). The effects of a long-term diet on healthy people have not yet been well understood. Dieticians are advised to choose a diet that can be sustained throughout life. Short-term effects may be successful, but the method is not suitable for everyone. Dietary recommendations are tailored to each individual and following the next trend without consulting a doctor is not recommended.

Works Cited

Feldman, Ellen. “Ketogenic Diet for Refractory Pediatric Seizures.” Integrative Medicine Alert , vol. 22, no. 9, 2019, pp. 32-37.

Mawer, Rudy. “ 10 Graphs That Show the Power of a Ketogenic Diet. ” heathline . 2018. Web.

Mawer, Rudy. “ The Ketogenic Diet: A Detailed Beginner’s Guide to Keto. ” heathline . 2018. Web.

“Pros and Cons of Low-Carb/Ketogenic Diets.” Nutrition Letter , vol. 37, no. 10, 2019, pp. 1-2.

Rho, Jong M. “How Does the Ketogenic Diet Induce Anti-Seizure Effects?” Neuroscience letters , vol. 637, no. 1, 2017, pp. 4-10.

Yancy, William S., Nia S. Mitchell, and Eric C. Westman. “Ketogenic Diet for Obesity and Diabetes.” JAMA Internal Medicine , vol. 179, no. 12, 2019, pp. 1734-1735.

Zajac, Adam, et al. “The Effects of a Ketogenic Diet on Exercise Metabolism and Physical Performance in Off-Road Cyclists.” Nutrients , vol. 6, no. 7, 2014, pp. 2493-2508.

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The Ketogenic Diet and Cardiovascular Diseases

Affiliation.

• 1 Institute of Health Sciences, Faculty of Medical and Health Sciences, Siedlce University of Natural Sciences and Humanities, 08-110 Siedlce, Poland.
• PMID: 37571305
• PMCID: PMC10421332
• DOI: 10.3390/nu15153368

The most common and increasing causes of death worldwide are cardiovascular diseases (CVD). Taking into account the fact that diet is a key factor, it is worth exploring this aspect of CVD prevention and therapy. The aim of this article is to assess the potential of the ketogenic diet in the prevention and treatment of CVD. The article is a comprehensive, meticulous analysis of the literature in this area, taking into account the most recent studies currently available. The ketogenic diet has been shown to have a multifaceted effect on the prevention and treatment of CVD. Among other aspects, it has a beneficial effect on the blood lipid profile, even compared to other diets. It shows strong anti-inflammatory and cardioprotective potential, which is due, among other factors, to the anti-inflammatory properties of the state of ketosis, the elimination of simple sugars, the restriction of total carbohydrates and the supply of omega-3 fatty acids. In addition, ketone bodies provide "rescue fuel" for the diseased heart by affecting its metabolism. They also have a beneficial effect on the function of the vascular endothelium, including improving its function and inhibiting premature ageing. The ketogenic diet has a beneficial effect on blood pressure and other CVD risk factors through, among other aspects, weight loss. The evidence cited is often superior to that for standard diets, making it likely that the ketogenic diet shows advantages over other dietary models in the prevention and treatment of cardiovascular diseases. There is a legitimate need for further research in this area.

Keywords: CVD; HDL; KD; LDL; blood pressure; cardiomyocytes; cardiovascular disease; cholesterol; diastolic; diet; endothelium; fatty acids; heart; heart metabolism; high fat; inflammation; ketogenic diet; ketone; ketone bodies; lipid profile; low carb; obesity; prevention; reduction; systolic; treatment; triglyceride; weight loss.

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Conflict of interest statement

The authors declare no conflict of interest.

Four main factors influencing the…

Four main factors influencing the anti-inflammatory, cardioprotective potential of the ketogenic diet. The…

Influence of the ketogenic diet…

Influence of the ketogenic diet on vascular endothelial cells. The above figure was…

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The ketogenic diet and cardiovascular diseases.

Graphical Abstract

1. Introduction

2. the ketogenic diet and blood lipid profile, 2.1. lipid profile and cardiovascular diseases, 2.2. the effect of the ketogenic diet on the blood lipid profile, 3. anti-inflammatory potential of the ketogenic diet in cardiovascular diseases, 3.1. anti-inflammatory, cardioprotective potential of the state of ketosis (ketone bodies), 3.2. anti-inflammatory, cardioprotective effects of elimination of simple sugars, 3.3. anti-inflammatory, cardioprotective effects of total carbohydrate restriction, 3.4. anti-inflammatory, cardioprotective effects of omega-3 fatty acids, 4. ketone bodies and cardiac energy metabolism, 5. the ketogenic diet and the vascular endothelium, 6. the ketogenic diet and blood pressure, 7. the ketogenic diet and weight loss as a factor in cvd prevention and therapy, 8. the effect of the ketogenic diet among patients with cvd and healthy people, 9. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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Dyńka, D.; Kowalcze, K.; Charuta, A.; Paziewska, A. The Ketogenic Diet and Cardiovascular Diseases. Nutrients 2023 , 15 , 3368. https://doi.org/10.3390/nu15153368

Dyńka D, Kowalcze K, Charuta A, Paziewska A. The Ketogenic Diet and Cardiovascular Diseases. Nutrients . 2023; 15(15):3368. https://doi.org/10.3390/nu15153368

Dyńka, Damian, Katarzyna Kowalcze, Anna Charuta, and Agnieszka Paziewska. 2023. "The Ketogenic Diet and Cardiovascular Diseases" Nutrients 15, no. 15: 3368. https://doi.org/10.3390/nu15153368

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• The case for a ketogenic diet in the management of kidney disease
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• http://orcid.org/0000-0001-5427-6748 Shaminie J Athinarayanan 1 ,
• Caroline G P Roberts 1 ,
• Chandan Vangala 2 ,
• Greeshma K Shetty 1 ,
• Amy L McKenzie 3 ,
• Thomas Weimbs 4 ,
• Jeff S Volek 5
• 1 Virta Health , Denver , Colorado , USA
• 2 BCM , Houston , Texas , USA
• 3 Abbott , Wiesbaden , Germany
• 4 Department of Molecular Cellular & Developmental Biology , University of California Santa Barbara , Santa Barbara , California , USA
• 5 Department of Human Sciences , The Ohio State University , Columbus , Ohio , USA
• Correspondence to Dr Shaminie J Athinarayanan; sarassam52{at}gmail.com

Ketogenic diets have been widely used for weight loss and are increasingly used in the management of type 2 diabetes. Despite evidence that ketones have multiple positive effects on kidney function, common misconceptions about ketogenic diets, such as high protein content and acid load, have prevented their widespread use in individuals with impaired kidney function. Clinical trial evidence focusing on major adverse kidney events is sparse. The aim of this review is to explore the effects of a ketogenic diet, with an emphasis on the pleiotropic actions of ketones, on kidney health. Given the minimal concerns in relation to the potential renoprotective effects of a ketogenic diet, future studies should evaluate the safety and efficacy of ketogenic interventions in kidney disease.

• Kidney Diseases

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https://doi.org/10.1136/bmjdrc-2024-004101

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Introduction

Low carbohydrate eating patterns including a very low carbohydrate or ketogenic diet have been successfully used for weight loss and remitting type 2 diabetes (T2D). Among patients with T2D, the prevalence of chronic kidney disease (CKD), whether characterized as a reduced estimated glomerular filtration rate (eGFR) function or albuminuria is almost 40%. 1 Yet, a ketogenic diet is cautioned against in individuals with impaired kidney function, 2 in part, due to concerns about increased protein intake. The effect of protein intake in CKD is controversial, but high protein intake has been associated with hyperfiltration, increased acid excretion, and potentially, a decline in kidney function. 3 4 However, protein intake on a well-formulated ketogenic diet (WFKD) is moderate to effectively permit nutritional ketosis. Dietary analysis of very low carbohydrate studies usually reports daily protein intake ranging from 0.6 g/kg to 1.4 g/kg, 5–7 which is similar to that in the standard American diet and below the high protein threshold (≥2.0 g/kg) believed to be of concern. 8 The Kidney Disease Outcomes Quality Initiative clinical practice guideline for nutrition in CKD not dependent on dialysis recommends a “low-protein diet providing 0.55–0.6 g of dietary protein/kg body weight/day, or a very low-protein diet providing 0.28–0.43 g of dietary protein/kg of body weight/day with additional keto acid/amino acid analogs to meet protein requirements (0.55–0.60 g/kg/day).” 9 In contrast, Kidney Disease Improving Global Outcomes (KDIGO) 2022 CKD guideline recommended a slightly higher daily protein allowance of 0.8 g/kg/day for individuals with advanced CKD with or without T2D. 10 The Modification of Diet in Renal Disease (MDRD) study, a landmark trial examining the effect of protein restriction among 585 patients with non-diabetic CKD, did not demonstrate a significantly slower progression of disease, 11 and in fact a very low protein diet (0.28 g/kg/day) was associated with increased risk of death at a median follow-up of 3.2 years. 12 The null findings from MDRD are one of numerous inconsistent results studying protein restriction in patients with CKD. Taken altogether, systematic reviews have suggested—at best—a modest benefit for patients on a low protein diet 13 14 and given the aforementioned long-term data noting increased risk of death with very low protein diets, most nephrology experts are more comfortable with moderate protein restriction to the degree of 0.8 g/kg/day as recommended by the KDIGO 2022 guideline.

The impact of carbohydrate restriction interventions on kidney function is poorly understood. Existing studies consistently reported improvements in glycemic control, blood pressure, weight, and insulin resistance, all of which have favorable downstream implications for slowing kidney disease progression ( figure 1 ). In addition, ketone bodies themselves have a myriad of physiologic and signaling effects that could elicit renoprotective effects. For example, the renoprotective effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been postulated to be partially mediated by the modest medication-induced ketosis. 15–17 This low-grade ketosis induced by SGLT2i may directly or indirectly benefit the kidney by serving as an energy source during stress and kidney injury, and through its anti-inflammatory, antifibrotic, and antioxidant effects ( figure 1 ). 15 16 Given that SGLT2i-induced ketosis may be beneficial for the kidney, endogenously produced ketones resulting from a WFKD may prove to be another therapeutic option for diabetic nephropathy or kidney disease. 18 19

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Summary of pleiotropic renal protective effect of ketones and carbohydrate restriction. BHB, β-hydroxybutyrate; mTORC1, mammalian target of rapamycin complex 1; NLRP3, NOD-, LRR-, and pyrin domain-containing 3; PGC-1ɑ, peroxisome proliferator-activator receptor γ (PPARγ) coactivator-1-alpha; FFAR-3, free fatty acid receptor-3; HCAR, hydroxycarboxylic acid receptor-2; HDAC-3, Histone deacetylase-3; NRF2, nuclear factor erythroid 2-related factor 2; SIRT1, silent information regulator transcript-1.

In this review, we explore the pleiotropic roles and signaling effects of ketones on kidney physiology, address potential concerns of ketogenic therapy, summarize the available literature on the effect of low carbohydrate diets on kidney function, and discuss future studies that could help address the gaps in knowledge and discrepancies in the literature.

Potential roles of ketones on kidney pathophysiology and disease

Ketones as an alternative energy-efficient fuel.

The human body naturally produces ketones, mostly in the liver, at varying rates that result in circulating ketones that span more than four orders of magnitude (<0.01 to >10 mM) 20 21 depending primarily on a person’s carbohydrate intake and insulin level. Increased lipolysis and ketogenesis are upregulated in response to a low insulin-to-glucagon ratio, which occurs during calorie restriction/fasting, prolonged exercise, consumption of a ketogenic diet, or pathologic insulin deficiency. In the liver, when production of fatty acyl coenzyme A (CoA) increases during low insulin secretion and increased lipolysis, fatty acyl CoA is transported to the mitochondrial matrix, where it is then β-oxidized to produce acetyl-CoA. 22 23 Acetyl-CoA is either converted to malonyl CoA or to acetoacetyl CoA ( figure 2 ). Acetoacetyl CoA and acetyl-CoA are further condensed by a rate-limiting enzyme, 3-hydroxy 3-methylglutaryl-CoA synthase 2 (HMGCS2) to generate hydroxymethylglutaryl CoA (HMG-CoA). HMG-CoA is then converted into acetoacetate (AcAc) by hydroxymethylglutaryl coenzyme A lyase (HMGCL). 22 23 Finally, AcAc is reduced to β-hydroxybutyrate (BHB) by BHB dehydrogenase (BDH) ( figure 2 ). Both AcAc and BHB are released from the liver and transported in the blood circulation to extrahepatic tissues where they can have signaling effects and be metabolized and released or oxidized to produce energy. BHB is a vital energy source for the brain with uptake occurring in proportion to circulating levels. As such, during prolonged starvation, ketones can provide over half the brain’s energy requirements. 24 Generally, glucose is considered the most efficient fuel since it produces more ATP per oxygen consumed with a phosphate/oxygen (P/O) ratio of 2.58. 24 25 However, in a state of insulin resistance where glucose uptake and oxidation are impaired, BHB is an effective alternative dense energy molecule with a P/O ratio of 2.50. In contrast to free fatty acids (FFAs), another form of energy-dense fuel, 25 26 BHB gives better ATP yield per oxygen consumed, is water soluble, and generates fewer reactive oxygen species (ROS).

Ketogenesis pathway. AcAc, acetoacetate; BDH, BHB dehydrogenase; CoA, coenzyme A; HMGCL, hydroxymethylglutaryl coenzyme A lyase; HMG-CoA, hydroxymethylglutaryl CoA; HMGCS2, 3-hydroxy 3-methylglutaryl-CoA synthase 2; CPT1/2, carnitine palmitoyltransferase 1/2; MCT, moncarboxylate transporter.

The kidney is among the most metabolically active organs, with very high oxygen demand and the second-highest mitochondrial density after the myocardium. 27 While oxidative metabolism is the principal source of energy in the kidney, the fuel substrates for metabolism differ across regions of the kidney. In the healthy kidney, both fatty acid oxidation (FAO) in the proximal tubules and glycolysis in the distal tubules support its metabolism. The renal cortex, especially the S1/S2 tubule segments, generates energy primarily from FFAs, lactate, and glutamate versus glucose. 28 The outer medulla uses glucose, lactate, FFAs, and ketones for energy. However, in diseased kidneys, mitochondrial dysfunction has been reported as a key pathologic feature that contributes to disease initiation and progression. 29 30 For example, in diabetic nephropathy (DN), hyperglycemia-induced flux of glycolysis increases oxygen demand with the by-product of amplified ROS. 30 31 Excess glucose use in the kidney shifts the energy reliance from fatty acid metabolism to glycolysis, even in the proximal tubules. 30 31

The renoprotective effect of SGLT2i in diabetic kidney disease is driven by amelioration of the pathologic metabolic shift from FAO to glycolysis. SGLT2i decreases reabsorption of excessive glucose, reduces energy production from glucose in the kidney, and increases fatty acid utilization in the kidney. 32 Furthermore, the glycosuric effect of SGLT2i also augments the BHB level in the kidney mainly through increased production of ketones rather than reduced kidney clearance. 33 The kidney is indeed an avid consumer of ketones. 34 BHB serves as an important alternative source of energy for the kidney during metabolic imbalance. It can be effectively metabolized in all nephron regions, except the S1/S2 proximal tubule segments. 35 During starvation or fasting, the BHB level in the kidney increases 20-fold and is used as a substrate for mitochondrial energy production. 20 In the diabetic kidney disease mouse model, both SGLT2i and exogenous ketone treatment normalized the renal ATP levels by restoring its production and this intervention was also associated with kidney function improvement. 36

Anti-inflammatory effect

Inflammation is critical in both acute kidney disease and CKD, especially through activation of inflammasomes such as NOD-, LRR-, and pyrin domain-containing 3 (NLRP3). 37 Numerous studies highlight the link between DN and NLRP3 inflammasome activation, which negatively impacts podocyte function, escalates the expression of inflammatory markers like IL-1β, and is also linked with albuminuria and tubulointerstitial injury. 38 39 Consequently, targeting NLRP3 inflammasome inhibition emerges as a promising approach for kidney disease treatment, despite concerns over the safety of current experimental drugs. 40 BHB stands out for its wide-ranging anti-inflammatory actions, including its effect on inhibiting NLRP3 inflammasome activation. 41 BHB successfully suppresses NLRP3 inflammasome activation in human monocytes and murine neutrophils in vitro and in animal models of NLRP3-mediated diseases. 42 Likewise, the anti-inflammatory effect of SGLT2i in diabetic rats, characterized by subdued NLRP3 inflammasome activation and lower interleukin (IL)-1β and tumor necrosis factor (TNF)-ɑ levels, correlates with elevated BHB and reduced insulin levels in the bloodstream. 43 BHB’s primary receptor is GPR109A (HCAR2), a G protein coupled receptor (GPCR) that acts by suppressing cyclic adenosine monophosphate (cAMP). 44 Beyond NLRP3 inflammasome suppression, animal studies reveal BHB diminishes other proinflammatory cytokines, including IL-6, chemokine (C–C motif) ligand 2, and monocyte chemoattractant protein-1, through activation of GPR109A, partially influenced by BHB’s effect on nuclear factor kappa B translocation. 45–47 In humans, ketogenic diets consistently reduce inflammation indicators. Individuals with T2D on a ketogenic diet show decreased serum C reactive protein and white cell counts, 48 along with significant reductions in 15 out of 16 inflammatory/immune modulators after 1 and 2 years. 49 This anti-inflammatory benefit aligns with prior findings that observed a greater reduction in 7 out of 14 inflammation/immune modulators with a ketogenic diet compared with a low-fat diet after 12 weeks. 50

Antifibrotic effects

The antifibrotic effect of BHB is mainly mediated through the mammalian target of rapamycin complex 1 (mTORC1) pathway. In diabetic kidney disease, mTORC1 hyperactivation is associated with kidney dysfunction and increased fibrosis. 43 In a mouse model of non-proteinuric diabetic kidney disease, SGLT2i, particularly empagliflozin conferred renal protection by increasing endogenous ketones and suppressing mTORC1 activation in the kidneys. 36 The treatment with empagliflozin mirrored the effect of exogenous ketone supplementation, where both treatments reduced kidney damage as evident through lower plasma cystatin-C levels and decreased interstitial fibrosis. 36 The renoprotective mechanism of SGLT2i hinges on the ketogenesis rate-limiting enzyme HMGCS2 highlighting ketone production’s central role in its antifibrotic effects. 36 51

Antioxidative effects

Ketones, specifically BHB, act as an important signaling molecule influencing gene expression through various regulatory pathways. BHB notably inhibits class I histone deacetylase enzyme activity in kidney tissue, enhancing the expression of genes that respond to oxidative stress, including Foxo3a and Mt2 . 52 This confers protection against oxidative stress in human kidney cells and various animal models. Studies also show that a ketogenic diet or BHB treatment can activate the major detoxification and oxidative stress nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. 53 In a spontaneous mouse model of T2D (db/db mice) treated with dapagliflozin, there was a noticeable reduction in the expression of genes related to oxidative stress compared with those treated with a standard vehicle or glimepiride. 54 This reduction is associated with increased levels of BHB and NRF2 protein expression. 54 Similarly, BHB treatment in human proximal tubular cells (HK-2) led to increased NRF2 expression and induced NRF2 nuclear translocation. 55 Furthermore, a ketogenic diet has been reported to increase the expression of other antioxidants such as NAD(P)H dehydrogenase quinone I (NQO1) and superoxide dismutase (SOD1/2), 56 and ameliorated paraquat (PQ)-induced elevated lipid peroxidation, toxicity, reduced antioxidant activity and decreased Nrf2 expression, 57 highlighting its potential therapeutic role in combating oxidative stress and tissue hypoxia.

Mitochondrial dysfunction

Mitochondrial dysfunction is another key feature of both acute kidney failure and CKD. 58 Ketogenic diet activates the expression of peroxisome proliferator-activator receptor γ (PPARγ) coactivator-1-alpha (PGC-1ɑ) 59 and silent information regulator transcript-1 (SIRT1). 60 61 PGC-1ɑ is the main transcription factor that controls the expression of genes involved in mitochondrial biogenesis and function, while SIRT1 activation protects organelle damage including the mitochondria and reduces oxidative stress. In a recent study on diabetic mice, a ketogenic diet improved mitochondrial function and capacity through its activation of PGC-1ɑ and SIRT1. 62 Further, administration of exogenous BHB was found to increase PGC-1ɑ and mitochondrial copy number in rat kidneys. 63 Human data on mitochondrial function are lacking, but we obtained skeletal muscle biopsies from physically active adults before and after a 12-week ketogenic diet and demonstrated that mitochondrial function and efficiency shifted towards fat oxidation while improving insulin sensitivity. 64

Traditional concerns of a ketogenic diet on kidney function

Common misconceptions about ketogenic diets related to kidney health include potential adverse effects on acid–base and electrolyte balance and risk for kidney stones. The next section briefly discusses the typical renal metabolic response to a ketogenic diet that maintains pH and electrolyte status. Most work in this space has been done in the context of normal kidney function, so we mention how the situation in CKD may differ.

Electrolyte and acid–base imbalance

Ketogenic diets promote a natriuretic and diuretic effect similar to that demonstrated during starvation. 65 66 This in part accounts for the typical rapid weight loss that occurs during the initiation of a ketogenic diet. If sodium intake is not commensurate with the additional loss of sodium, two deleterious outcomes are more likely to manifest: (1) Individuals may develop common signs and symptoms of hypovolemia, colloquially referred to as “Keto-Flu,” which include dizziness when standing, lethargy, and muscle spasms/cramps. (2) Counter-regulatory mechanisms are activated that include sympathetic and aldosterone stimulation that act to preserve plasma volume by increasing sodium reabsorption and a concomitant excretion of potassium and magnesium. These side effects can be eliminated with attention to proper electrolyte intake. For most individuals with normal kidney function consuming a ketogenic diet, it should be emphasized to ingest an additional 1–2 g sodium/day (4–5 g sodium/day total), a maintenance of 3–4 g/day potassium, and sufficient fluid intake.

In CKD, a decrease in viable nephrons and reduction in glomerular filtration rate (GFR) change the kidney’s normal physiology and sodium balance. 67 68 Even though an adaptive fractional increase in sodium excretion per individual nephron unit compensates for the reduced number of working nephrons, the kidney’s inability to excrete sufficient amounts of sodium results in sodium retention, extracellular fluid expansion, and blood pressure increase. 68 69 Likewise, the renin–angiotensin–aldosterone system is activated in CKD, further exacerbating sodium retention and causing vasoconstriction which could significantly raise blood pressure. 69 Sodium retention and its association with blood pressure in CKD are often referred to as “sodium-sensitive hypertension.” 70 Therefore, reducing salt intake is recommended to manage hypertension in patients with CKD. 68 The natriuretic and diuretic effect of the ketogenic diet may help alleviate sodium retention and improve systemic and glomerular blood pressure. Low carbohydrate and ketogenic diet studies often report a reduction in systolic and diastolic blood pressure 71 72 and blood pressure medication requirements. 73 However, the current recommendation of sodium intake in a WFKD is based on individuals with normal kidney function. 74 Recommendations for sodium and electrolyte intake for patients with CKD following a ketogenic diet should be individualized by a healthcare professional based on the patient’s renal function and electrolyte status. Future studies should assess the relationship between ketosis, sodium balance, and blood pressure.

Another misconception associated with ketogenic diets relates to promotion of acidosis owing to specific food items and the weakly acidifying effects of ketones, which could worsen kidney function, bone health, and kidney disease-associated endocrinopathies. 75 76 In healthy subjects provided a carefully prepared ketogenic diet with mean BHB levels >2 mM, serum bicarbonate was modestly reduced but well within normal ranges. 77 A ketogenic diet with mild ketosis (~1 mM) in individuals with normal kidney function has no significant impact on blood pH, serum bicarbonate level, and anion gap over 21 days 78 and 4 months. 79

When faced with an increased acid load, normal kidney function affords compensatory increases in ammonium excretion. In a somewhat mirrored perspective where the acid load is stable and the kidney function is reduced, the fewer working nephrons compensate with increased ammoniagenesis and excretion. This adaptation results in high intrarenal ammonia, which is thought to activate the alternative complement pathway eventually leading to tubulointerstitial fibrosis. Decreases in GFR to levels below 40–50 mL/min diminish the kidney’s ability to excrete more ammonium and overall acid 80 ; hence, metabolic acidosis is more commonly encountered at this level of disease. In patients with kidney disease, clinicians commonly monitor steady-state serum bicarbonate levels to assess overall acid load. However, decreases in serum bicarbonate are often reported at a later stage of the disease and it is considered inadequate to reflect the overall acid load. Eubicarbonatemic hydrogen ion retention among patients with earlier CKD is increasingly an area of focus 81 ; thus, studying ketogenic diet in all stages of CKD requires longer term study of acid excretion and the rate of kidney function decline.

Urinary acid excretion is favored as the gold standard for estimating acid load, and the prevailing wisdom was that an increased dietary acid load would burden the kidneys further and lead to more dysfunction. However, recent observations from the rich data collected in the Chronic Renal Insufficiency Cohort Study have demonstrated pitfalls to that simplistic view. 82 83 Among patients with diabetes, higher levels of net acid excretion were associated with a lower risk of CKD progression. These studies suggested that the changes in acid excretion were diet-independent and may be elicited by changes in energy metabolism and endogenous acid production from insulin resistance. 82 83 Currently, the effect of ketogenic diet on net acid excretion is unknown and this would be worthwhile exploring in patients with T2D and varying stages of CKD.

Kidney stones

Kidney stones, especially genetically driven stones, are associated with an increased risk of CKD. 84 A recent meta-analysis reported a pooled kidney stone incidence of 5.9% among patients on a ketogenic diet followed for a median of 3.7 years, 85 compared with a historical incidence rate of <0.3% per year in the general population. 86 Most studies reporting risk of kidney stones were in children receiving a ketogenic diet therapy for epilepsy 85 87–91 with higher incidence during long-term exposure (ie, 25% over 6 years, 91 which is complicated by concurrent use of antiseizure medications (eg, carbonic anhydrase inhibitors) and other risk factors in this population. In adults with obesity, who are at higher kidney stone risk based on their higher adiposity, 92 consuming a ketogenic diet over 2 years revealed no harmful effects on GFR, albuminuria, or fluid and electrolyte balance compared with a low-fat diet 93 ; and there was one possible, but not confirmed, case of kidney stones out of 153 subjects. 94

Uric acid stones are the most frequently reported by individuals on a ketogenic diet, followed by calcium oxalate stones or mixed stones with calcium and uric acid. 85 A ketogenic diet transiently increases uric acid concentration 25%–50%, which usually peaks at 2–4 weeks, and gradually returns to prediet levels by 8 weeks. 95–97 The initial rise in uric acid is concomitant with the rise in ketones, and it was postulated that the reason for this may be competition between uric acid and ketones for the same organic acid transporters, which are required for renal excretion. 98–101 After several weeks, the kidney conserves ketones, 102 presumably allowing for return of normal renal uric acid excretion and serum levels.

There may be effective strategies to mitigate the kidney stone risk in patients following a ketogenic diet. Increasing fluid intake to maintain dilute urine limits the possibility of mineral crystallization. 103 Urine alkalinization, particularly addressing hypocitraturia, may inhibit supersaturation of calcium salts and aggregation. 104 105 Moreover, studies of kidney stones have largely precluded patients with CKD where their urine parameters change alongside diminishing kidney function. A retrospective study of 811 patients with kidney stones noted that advancing kidney disease afforded reduced calcium stone formation, presumably due to reduced calciuria 106 and increased uric acid stone formation. 107 Metabolic acidosis resulting in acidic urine pH is common among individuals with CKD. 108 Low urine pH is a well-known risk factor for forming uric acid kidney stones due to the low solubility of uric acidic in acidic conditions. 109 110 At the same time, low urine pH leads to hypocitraturia which increases the risk of forming calcium oxalate kidney stones. 111 Hence, future examination of how a ketogenic diet impacts the incidence of kidney stones among patients with T2D and CKD is paramount. Being aware of and addressing the potential kidney stone risk with well-established measures—such as urine alkalization, correcting hypocitraturia, and increasing fluid intake—is prudent. Additionally, understanding that diet-imposed change in risk through modulation of ammonia excretion, uricosuria, calciuria, citraturia, and other urinary parameters will assist with future guidance.

Current evidence on very low or low carbohydrate diet intervention and its effect on kidney function

Evidence from animal studies.

Several rodent studies have specifically investigated the effects of a ketogenic diet on kidney function and disease. Two mouse studies reported benefit of ketogenic diet on DN, even reversing some of the key molecular features of DN. Poplawski et al assessed the effect of ketogenic diet on DN using both type 1 (Akita) and type 2 (db/db) murine diabetes models. In both models, the mice initially developed albuminuria on chow diet, and after transitioning to the ketogenic diet reversed and normalized urinary albumin/creatinine ratio (UACR) within 8 weeks. 112 Furthermore, the expression of several stress-induced genes involved in oxidative stress and toxicity was completely normalized by ketogenic diet in both models, with an observed effect that was more consistently robust in the type 1 mouse model. Likewise, histopathologic features of glomerular sclerosis were also partially reversed by the ketogenic diet in the T2D mouse model. 112 Jung et al examined db/db DN mice fed normal chow diet (dbNCD), high-fat diet (dbHFD), or ketogenic diet (dbKETO). dbKETO animals had lower UACR and blood urea nitrogen to creatinine ratio levels after 5 weeks compared with the dbNCD and dbHFD mice. 55 Histologic analysis of the kidney showed that dbKETO mice had less fibrotic changes than the dbNCD and dbHCD mice suggesting that the dbKETO mice delayed progression of DN histologic phenotypes. Furthermore, in the same report, treatment of the human proximal tubular cell line (HK-2) with BHB led to activated autophagy by increasing the LC3 I to LC3 II ratio, phosphorylation of adenosine 5 monophosphate-activated protein kinase (AMPK), beclin, p62 degradation, NRF2 expression, and decreased glucose-induced ROS levels. 55 Studies in a rat model of a genetic form of CKD, polycystic kidney disease, showed that a ketogenic diet not only slowed disease progression and preserved renal function in young animals but even partially reversed existing renal cystic disease in older animals. 18 The treatment resulted in improvement of renal fibrosis and inhibition of mTORC1 and epithelial proliferation. Remarkably, the effects could be replicated by administering BHB in the drinking water in a dose-dependent manner, without any food changes. 18 63 These results suggest that the actions of BHB may underlie most of the renoprotective mechanisms of nutritional ketosis, and that exogenous BHB can be effectively supplemented.

Evidence from clinical and observational studies

Clinical and observational studies that examined kidney function in response to low-carbohydrate diets ranging from <20 g/day to 30%–40% of energy expenditure are presented in online supplemental table 1 . Three of the six randomized controlled trials (RCTs) reported no significant changes in kidney function in the low carbohydrate arm compared with the comparison diet group. Two of the three studies followed the participants with normal baseline eGFR for 52 weeks 113 114 and the third study followed subjects with slightly lower baseline eGFR (<80) for 12 weeks. 115 Another two RCTs reported renal benefit in the low carbohydrate arm with improvements in serum creatinine, cystatin C, eGFR, and albumin. 93 116 The study by Tirosh et al reported greater eGFR improvement in those following a low-carbohydrate diet versus both a Mediterranean and low-fat diet. 116

Supplemental material

The use of surrogate markers, especially serum creatinine-derived estimates of kidney function, is less accurate at higher eGFRs and may be mischaracterized amidst dietary intervention, highlighting the importance of studying major adverse kidney events and assessing cystatin C-derived kidney function estimates. Thus far, only one RCT has reported hard kidney endpoints including all-cause mortality that compared a carbohydrate-restricted, low-iron, polyphenol enriched diet (CR-LIPE) with a standard protein restriction diet (SPRD). 117 The 191 participants in this study were followed for approximately 4 years. In this study, CR-LIPE significantly decreased doubling of serum creatinine (relative risk, 0.53, 95% CI 0.33 to 0.86, p<0.01), all-cause mortality (relative risk, 0.5, 95% CI 0.2 to 1.12) and also delayed end-stage renal disease and renal replacement therapy when compared with SPRD. 117 However, the CR-LIPE intervention was a multimodal dietary intervention that included carbohydrate restriction (35% of the energy intake) as one of the dietary modifications along with low-iron availability and polyphenol enrichment in the diet. Future study involving major adverse kidney endpoints is warranted to confirm if a ketogenic diet has beneficial impact on kidney disease.

Presumably because eGFR is less accurate at healthier function (eGFR >80 mL/min), some of these studies have shown that the beneficial effect of low carbohydrate diet is greater in those with lower starting baseline eGFR. For example, the study by Tirosh et al reported that the increase in eGFR was greater in those with CKD stage 3 (a 7.1-point; 10% eGFR increase from baseline) than the whole cohort (+5.3% increase from baseline) in the low carbohydrate arm. 116 While other studies included a range of baseline eGFRs, the subset of patients with more significant kidney dysfunction (eGFR <60 mL/min) exhibited a slower decline in function, and no deterioration was evident in participants with normal baseline eGFR. 118 119 Furthermore, caution is warranted when interpreting creatinine-derived eGFR measurements because any change in skeletal muscle mass during a nutritional study may affect the endogenous production of creatinine independent of actual changes in renal function. Hence, corroboration with cystatin-C measurements would strengthen these observations. The single-arm prospective 12 weeks study on individuals with relatively advanced diabetes nephropathy (eGFR <40 mL/min) reported statistically significant improvements in eGFR, serum creatinine, and cystatin C. 118 Three additional retrospective observational studies reported improvements in kidney function in individuals following a low carbohydrate diet 120–122 ( online supplemental table 1 ). One of these studies reported improvement in eGFR and decrease in UACR at an average follow-up of 30 months 119 while the other two studies reported eGFR improvement in individuals with reduced kidney function at baseline (eGFR <90 in one study and eGFR <70 in the other study). 121 122

In contrast, there were only two observational studies frequently cited when suggesting that a low carbohydrate diet is associated with adverse kidney outcomes. These studies did not focus on individuals adhering to a ketogenic diet or on those limiting their carbohydrate intake. For instance, Farhadnejad et al ’s 2018 study, which was a population-based prospective analysis, investigated the association between different tertiles of low carbohydrate high protein (LCHP) scores and the incidence of CKD. 123 Notably, none of the LCHP score tertiles in the study indicated a carbohydrate-restricted diet. Even in the tertile with the lowest LCHP score, carbohydrates contributed to 51.0% of the total energy, resembling the carbohydrate profile of a standard Western diet where 40%–60% of energy typically comes from carbohydrates. The other retrospective observational study by Li et al reported an association between elevated fasting ketone level with abnormal renal function 124 in people with T2D who were admitted to the hospital, and who were not specifically eating a ketogenic diet. The association of ketones and renal function in this study is not relevant to dietary carbohydrate restriction in an ambulatory population.

Altogether, these clinical and observational studies show no harm from low or very low carbohydrate diets for people with diabetes in the setting of normal renal function, and a possible beneficial effect in the setting of moderately reduced renal function. The kidney function improvement observed in these studies may be an ancillary outcome associated with other improvements seen in these interventions including weight loss, glycemic control, or blood pressure improvement. Interestingly, Unwin et al reported no association between observed kidney function improvement with the magnitude of weight loss, improvement in blood pressure and HbA1c, 120 while another study reported that the increase in eGFR was significantly associated with a decrease in fasting insulin and systolic blood pressure but not with the level of weight loss and protein intake in the intervention. 116 In our previous study on patients with T2D following a very low carbohydrate intervention, there was a marginally significant increase in eGFR at 1 year. 72 A post hoc analysis of these data revealed that a higher mean BHB at 1 year (β=5.04, p=0.005) was significantly associated with a greater increase in mean eGFR (unpublished data). Furthermore, in a subgroup analysis of 22 trial participants with an eGFR <60 mL/min/1.73 m 2 at baseline who remained in the study for 2 years, 72 the mean eGFR progressively increased from 51 mL/min/1.73 m 2 to 60, 63, and 68 mL/min/1.73 m 2 at 10 weeks, 1 year, and 2 years (unpublished data). Notably, the majority of the 22 participants reverted to stage 2 and no one progressed to stage 4 CKD. Evidently, a dose-dependent association exists between ketosis trajectory classes and the increase in total eGFR slope at 2 years. 125 Participants with higher endogenous ketone concentration and longer duration of ketosis maintenance exhibited the greatest rise in the 2-year eGFR slope compared with those with lower endogenous ketone concentration and unsustainable ketosis maintenance. 125 Hence, available evidence suggests that carbohydrate restriction and ketosis afford benefits to kidney function. It will be important to determine in future trials whether the improvement in kidney function translates to a sustained long-term reduction, or even reversal, in the progression of kidney disease.

Evidence from meta-analyses, systematic and narrative review

A recent review discussing the potential negative effect of purported ketogenic diets on kidney health focused on observational studies that compared low protein versus high protein diets that were not ketogenic or low carbohydrate diets, 126 and raised concern about the association of albuminuria with high animal fat but only referred to observational studies that assessed high animal fat intake in the context of a Western diet 126 negating the relevance of the studies cited for concern.

In contrast, systematic reviews and meta-analyses that assessed pooled effects of RCTs reported beneficial effects of low-carbohydrate diets. The meta-analysis by Oyabu et al evaluated nine RCTs with 861 participants in the low carbohydrate arm and 826 participants in the control group. 127 Despite a large variation in the proportion of carbohydrate intake from 4% to 45% in the low carbohydrate arm of the nine studies with a study duration ranging from 6 to 24 months, the review revealed that there was a significant increase in eGFR in the low carbohydrate group versus control group. 127 Another meta-analysis with 12 RCTs that only included patients with T2D reported no significant difference in the pooled eGFR and creatinine mean estimate between the lower carbohydrate diets (14%–45% of calories from carbohydrate) versus control diets over 5 weeks to 24 months. 128 Similarly, another meta-analysis that included five RCTs with the low carbohydrate arm had carbohydrate intake <45%, and the studies ranging from 5 weeks to 24 months reported no difference in the pooled eGFR estimate between the control and low carbohydrate diets. 129 The current evidence from systematic reviews and meta-analyses with a range of carbohydrate intake suggests that carbohydrate restriction is not associated with adverse effects on kidney function, or in some cases might be beneficial.

Evidence from genetically driven kidney disease

Individuals with autosomal dominant polycystic kidney disease (ADPKD) may benefit from calorie restriction or ketogenic diet. 19 130 131 This chronic progressive condition is characterized by hyperproliferation, inflammation, fibrosis, and cyst growth, leading to deterioration of kidney function over time. 19 132 mTOR is one of the main signaling pathways activated in ADPKD. 132 A study of various polycystic kidney disease animal models showed that time-restricted feeding, administration of a ketogenic diet, or supplementation with exogenous BHB prevented kidney cyst disease progression by inhibiting cell proliferation, fibrosis, and cyst growth. 18 63 Furthermore, the mTOR activity was inhibited in these animal models suggesting that blunting the signaling pathway inhibits cell proliferation, growth, and fibrosis in ADPKD. 18 63 133 In humans, a retrospective observational study of ADPKD patients who self-initiated ketosis either using ketogenic or time-restricted diets reported improvement in eGFR after 6 months. 134 A pilot study on 24 patients with ADPKD demonstrated the feasibility of the ketogenic diet, reporting high adherence rates and improvements in blood pressure, eGFR, and kidney pain. 130 In another exploratory RCT, 66 participants with ADPKD were randomized to ketogenic, water fasting, or control diets. The study confirmed the feasibility of the therapy in the ketogenic arm (KD) and revealed significant improvements in eGFR, including both creatinine and cystatin C-derived eGFR in the KD group but no improvements were observed in the water fasting and control diets. 131 Additionally, there were no significant differences in UACR and blood pressure among the three diets. 131

Perspectives and future direction

There is a considerable body of research suggesting that a very low carbohydrate ketogenic diet is safe in individuals with moderately diminished kidney function, even in studies that had higher protein intake than what is recommended for kidney disease and diets that are not plant-based. The diet can be safely prescribed in patients with T2D for treating and remitting diabetes even if they have underlying stage 2 or 3 CKD or reduced kidney function. Beyond safety, mechanistic plausibility, preclinical data, and even some RCT studies suggest that carbohydrate-restricted diets may be beneficial in improving moderate kidney dysfunction and in reducing progression of CKD. The preliminary proof of concept from small and short duration studies in humans and animals suggests a very low carbohydrate diet could be an effective dietary intervention for patients with CKD. Furthermore, there are predeveloped ketogenic nutritional options to consider when we plan a future trial to assess the impact of ketogenic diet on patients with CKD, such as the recently developed program for treating ADPKD known as Ren.Nu. This program is a plant-focused ketogenic medical nutrition therapy, designed to avoid renal stressors like oxalate, inorganic phosphate, and purines/uric acid. It includes a medical food formulation, KetoCitra, containing BHB with alkaline citrate which helps antagonize kidney stone formation. 129 130 Based on the findings from these different studies and currently available ketogenic medical therapy specific for kidney disease, there is a need for future larger and longer follow-up randomized controlled clinical trials on very low carbohydrate diet, including nutritional ketosis in patients with CKD with or without T2D on kidney hard endpoints including major adverse kidney events (a composite event of death, persistent renal decline >25% decline in eGFR, and a new initiation of dialysis) and other kidney-related outcomes to firmly establish the long-term effectiveness. For example, a head-to-head comparison of the safety and efficacy of ketogenic nutritional therapy versus SGLT2i pharmacologic intervention (that involves the same mechanism of raising ketone levels) could be of high interest. Weight loss from the diet can improve filtration and albuminuria. Thus, including other surrogate endpoints like eGFR slope and microalbuminuria in these studies have the potential to elucidate the degree to which weight loss and blood pressure improvement from the diet affects kidney function markers and also to explore if ketone levels independently have an impact on these markers and endpoints. Furthermore, these studies should also assess the diet’s overall safety in patients with T2D and CKD, specifically exploring its effect on net acid excretion, kidney stone formation, and maybe its beneficial effect on sodium retention hypertension. Finally, another important consideration in the clinical trial design for evaluating the efficacy of a very low carbohydrate diet in patients with CKD is understanding the diet’s additive role, especially how the diet interacts with currently available treatment drugs for patients with CKD including renin–angiotensin system blockade (angiotensin-converting enzyme inhibitor, ACEi and angiotensin receptor blockers, ARBs), SGLT2i, glucagon-like peptide-1 receptor agonists (GLP1-RA), and the non-steroidal mineralocorticoid receptor antagonists (finerenone).

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

Contributors SJA, JV, and CGPR conceptualized the review topic and formulated the objectives; SJA conducted the comprehensive literature search, synthesized and interpreted the data from the collected literature; SJA drafted the original manuscript; JSV, TW, CGPR, and CV provided critical revisions and edits to the manuscript; ALM and GKS reviewed and edited the manuscript; All authors have read and agreed to the final version of the manuscript.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests TW is an inventor on issued and pending patents filed by the University of California, Santa Barbara related to the topic of this article. TW is a founder and shareholder of Santa Barbara Nutrients, Inc., holds a managerial position, and has contributed to the development of the Ren.Nu ketogenic dietary program and the medical food KetoCitra. TW received speaker fees from Otsuka, was a scientific advisor of Chinook Therapeutics, and received research funding from Chinook Therapeutics. JSV is a cofounder and shareholder of Virta Health, serves as a science advisor for Simply Good Foods and Nutrishus Brands, and has authored books on ketogenic diets. SJA, CGPR, and GKS are employees and shareholders of Virta Health. ALM is a shareholder of Virta Health.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Ketogenic Diets and Cardio-Metabolic Diseases

Weiyue zhang.

1 Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2 Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China

3 Department of Nutrition and Food Hygiene, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China

Chaodong Wu

4 Department of Nutrition, Texas A&M University, College Station, TX, United States

While the prevalence of cardio-metabolic diseases (CMDs) has become a worldwide epidemic, much attention is paid to managing CMDs effectively. A ketogenic diet (KD) constitutes a high-fat and low-carbohydrate diet with appropriate protein content and calories. KD has drawn the interests of clinicians and scientists regarding its application in the management of metabolic diseases and related disorders; thus, the current review aimed to examine the evidences surrounding KD and the CMDs to draw the clinical implications. Overall, KD appears to play a significant role in the therapy of various CMDs, which is manifested by the effects of KDs on cardio-metabolic outcomes. KD therapy is generally promising in obesity, heart failure, and hypertension, though different voices still exist. In diabetes and dyslipidemia, the performance of KD remains controversial. As for cardiovascular complications of metabolic diseases, current evidence suggests that KD is generally protective to obese related cardiovascular disease (CVD), while remaining contradictory to diabetes and other metabolic disorder related CVDs. Various factors might account for the controversies, including genetic background, duration of therapy, food composition, quality, and sources of KDs. Therefore, it’s crucial to perform more rigorous researches to focus on clinical safety and appropriate treatment duration and plan of KDs.

Introduction

Cardio-metabolic diseases (CMDs) have become a worldwide epidemic, as demonstrated by an increased prevalence of obesity, diabetes mellitus (DM), metabolic syndrome, cardiovascular disease (CVD), and chronic kidney disease (CKD), and culpable to a significant global financial burden ( 1 ). CVDs comprise a wide range of diseases detrimental to cardiac and vascular function ( 2 , 3 ). To decrease cardiovascular (CV) mortality and related economic burden, it’s important to reduce CV risk factors and employ appropriate therapy in developed countries ( 4 ). Various established risk factors such as age, gender, genetic heritage, smoking, high blood pressure, poor eating habits, type 2 diabetes mellitus, dyslipidemia and obesity had been accounted for the development and progression of cardiovascular diseases (CVD).

Dietary factors that profoundly influence human health are linked to cardiovascular disease and other chronic metabolic conditions such as obesity and type 2 diabetes ( 5 ); thus, dietary interventions have become an essential component in managing cardiovascular risks ( 6 ).

A ketogenic diet (KD) is a high-fat, low-carbohydrate diet with appropriate protein content and calories ( 7 ). A traditional KD consists of a 4:1 ratio of fats to carbohydrates and protein, with 90% of the calories from fat, 8% from protein, and only 2% from carbohydrate ( 8 ). In recent years, to improve compliance and imitate the effects of classic KD, alternative protocols with different formulations of KD have been proposed ( 9 ), including 3:1 KD, 2:1 KD, 1:1 KD, the modified Atkins diet (MAD), the medium-chain triglyceride ketogenic diet (MCTKD), the low glycemic index treatment (LGIT) ( 10 , 11 ) ( Table 1 ). With the implementation of KD therapy, a drastic decrease in dietary carbohydrates reduces glucose utilization. In the human body, KD treatment could imitate the metabolic changes of fasting. In addition, some of the beneficial effects of KDs could be attributable to the production of ketones, e.g., β-hydroxybutyrate (BHB), acetoacetate, and acetone in the liver ( 12 ).

Table 1

Formulations of common ketogenic diets (KDs).

MAD, the modified Atkins diet; MCTKD, the medium chain triglyceride ketogenic diet; LGIT, the low glycemic index treatment.

KD was firstly used as a dietary treatment for epilepsy in the 1920s ( 8 ). However, with the progress in antiepileptic drugs (AEDs) development and application, the clinical use of KDs in epilepsy has dramatically decreased. Interestingly, about one-third of patients receiving epilepsy treatment couldn’t gain significant relief from the disease, and the KD regained scientists’ attention and became a choice for application in drug-resistant or difficult-to-treat epilepsies ( 13 , 14 ). Apart from neurological diseases, KD has recently shown promising efficacy in a wide variety of diseases, including various cancers and metabolic diseases. Ovarian cancer, for instance, may reveal significantly better clinical outcomes under KD intervention, as revealed by a systematic review of randomized controlled trials ( 15 ). Furthermore, KD intervention has been found to inhibit tumor progression or mitigate cachexia symptoms ( 16 ).

KD has drawn more interest and gradually become an elective dietary intervention choice for CMDs ( 17 ). Moreover, it is significantly effective in mitigating various metabolic diseases, including obesity ( 18 , 19 ), glucose transporter type 1 deficiency syndrome (GLUT1DS) ( 20 ), and pyruvate dehydrogenase (PDH) deficiency ( 21 ). Meanwhile, due to the uncertainty of dietary interventions, different voices have also occurred regarding the safety issues and drawbacks of employing KD. The clarity on how KD influences cardiovascular and metabolic diseases remains unclear. Therefore, the current review highlighted pertinent information concerning KD and CMDs ( Figure 1 ). Qualified studies reflecting the advantages or disadvantages of KD in CMDs were all equally considered and incorporated without bias.

Graphic abstract.

Effects of Ketogenic Diets on Metabolic Diseases

Various metabolic diseases have been recognized as cardiovascular risk factors, including diabetes mellitus, obesity and other metabolic diseases ( 22 ). The disrupted glucose and lipid metabolism lead to abnormal oxidative stress, inflammatory, vasoactive factors, cardiac and vascular function, and finally elevate the risk of CVD ( 23 ). KD can regulate metabolic profiles and may consequently regulate the risk of CVD.

As for the management of obesity, most studies indicated that KDs were efficient at weight loss ( 24 , 25 ), especially in reducing food intake in humans and elevating energy consumption in animals ( 18 , 19 ). Studies concerning the effects of KDs on body composition changes reported that KD-fed mice had an increased fat mass percentage than regular-chow fed mice ( 26 , 27 ), and reduced ( 28 ) or no differences ( 26 ) in the percentage of lean body mass between diets; whereas in humans, weight loss affects both fat and lean mass ( 29 ). Obesity is commonly connected with insulin resistance and type 2 diabetes mellitus (T2DM), in which systemic ketone body metabolism is perturbed ( 30 , 31 ). As such, the weight-loss effect of KDs is expected to be beneficial for diabetes; although it remains disputable that KD induces insulin resistance. There are studies indicating that KD led to ameliorated glucose homeostasis and reduced antidiabetic medications in T2DM subjects ( 32 , 33 ), even with reduced baseline insulin levels and elevated insulin sensitivity in diabetic rats ( 34 , 35 ). Moreover, the study by Farrés et al. ( 33 ) appeared to offer a plausible explanation of how KDs bring about the anti-diabetic effect, which might be attributable to the anti-inflammatory effect of KD itself and beneficial effects of the altered lipid metabolism on diabetes effector proteins. However, certain studies suggested that KD reduced glucose and insulin levels while inducing insulin resistance and glucose intolerance in rats ( 27 , 36 ). Besides, utilizing KD in adults with type 1 diabetes mellitus (T1DM) is associated with dyslipidaemia and a high number of hypoglycaemic episodes apart from excellent HbA1c levels and little glycaemic variability ( 37 ). Thus, in T1DM, the safety issues are considerable; while in T2DM, more studies are needed to address how KD might impact on insulin resistance and other aspects.

In Polycystic ovarian syndrome (PCOS), KD appears to be a valuable non-pharmacological treatment. A 24-week low-carbohydrate KD ( 38 ) and a 12-week ketogenic Mediterranean diet with phyoextracts ( 39 ) were both reported to lead to remarkable improvement in body weight, percentages of free testosterone, LH/FSH ratios, and insulin levels in women with PCOS and obesity/overweight. Besides, KD has also been proven effective in other metabolic diseases including glucose transporter type 1 deficiency syndrome (GLUT1DS) ( 20 ), pyruvate dehydrogenase (PDH) deficiency ( 40 ), phosphofructokinase (PFK) deficiency and glycogenosis type V (McArdle disease) ( 41 ).

In summary, KDs are recommended in some inherited metabolic diseases and PCOS, while the effects of KDs on diabetes and some other metabolic diseases remain controversial. Rigorously-designed long-term studies are warranted to evaluate the effects and the safety problems of KDs and further evaluate whether the impact of KDs can be maintained.

Cardiometabolic Effects of Ketogenic Diets

The occurrence and development of CMDs are closely related to systemic chronic low-grade inflammation characterized by the continuous increase of circulatory inflammatory factors ( 42 ). Dietary pattern is one of the important factors that affect chronic inflammatory states ( 43 ). Thus, the effects of dietary pattern on CMDs arouse scientists’ interest and a large number of studies have focused on the cardiometabolic effects of KD. Apart from the above-mentioned metabolic diseases, the effects of KD on cardiac function, hypertension, vascular function and lipid profile have also been studied.

Ketogenic Diets Regulate Cardiac Function

The effects of KD on cardiac health have been widely investigated, but researches concerning the effects of KD on cardiac functions provided a few relatively controversial data. Studies generally suggest that KD intake benefited cardiac metabolic efficiency and acted as a cardioprotective antioxidant. Selvaraj et al. ( 44 ) reviewed current evidence surrounding the use of therapeutic ketosis including KD in heart failure (HF) and pointed out its potential benefit in HF, particularly in HF with reduced ejection fraction. Further, Balietti et al. ( 45 ) found that an 8-week supplementation of medium-chain triglycerides KD (MCT-KD) to late-adult rats partly restored age-related decrease of succinic dehydrogenase (SDH) activity and metabolically active mitochondria, which might offset senescent alterations leading to apoptosis-induced myocardial atrophy and failure. Another study with a similar conclusion indicated that a 19-week low carbohydrate KD following global ischemic injury significantly increased the numbers of mitochondria in cardiac muscles and the reperfusion recovery of coronary flow ( 46 ). As such, the two studies demonstrated that KD was cardio-protective in terms of regulating cardiac energy metabolism including mitochondrial capability. However, some studies suggested that KD might be just not harmful to cardiac functions. A study utilizing KD for at least 12 months on cardiac functions in intractable epilepsy patients suggested that the KD used appeared to have no negative impact on ventricular functions in epileptic children in the midterm ( 47 ). Similarly, a 6-month KD therapy didn’t affect electrocardiogram outcomes in the drug-resistant children with epilepsy ( 48 ). The subjects in these two studies are both epileptic children, which cannot represent all the patients who might use KD therapy. Thus, we can still stay optimistic about the effects of KD on cardiac functions.

Studies have also been conducted concerning the mechanism of how KD might affect cardiac health. Abnormal substrate metabolism is one of the major changes of insulin resistance and diabetic myocardium ( 49 ). Given this, changes in the regulation of myocardial ketone body metabolism appear to be a novel diagnostic biomarker of altered ketolytic capacity. Wentz et al. ( 50 ) utilized ketogenic nutritional mouse models (24 h of fasting and a very low carbohydrate ketogenic diet) to demonstrate that cardiac muscle engages a metabolic response that limits ketone body utilization. Specifically, the results revealed that unmetabolized substrate concentrations were higher within the hearts of ketogenic diet-fed mice. Furthermore, a recent study suggested that a KD or a high-fat diet could reverse the structural, metabolic and functional remodeling of non-stressed cMPC1-/- (cardiomyocyte-restricted deletion of subunit 1 of mitochondrial pyruvate carrier) mouse hearts ( 51 ). A KD of 3 weeks before transverse aortic constriction was already enough to rescue cMPC1-/- hearts from rapid decompensation and early mortality after pressure overload. Another study also indicated that a high-fat, low-carbohydrate KD could completely reverse progressively developed cardiac dilation and contractile dysfunction in mice with cardiac-specific deletion of Mpc2 (CS-MPC2-/-) ( 52 ). Accordingly, KD therapy might be promising in improving cardiac fat metabolism to prevent or reverse cardiac dysfunction and remodeling in MPC deficiency.

As mentioned above, KDs are generally cardioprotective, which might be attributable to the effects of KDs on cardiac metabolism, such as ketone body metabolism and energy metabolism including mitochondrial capability ( Figure 2 ). Despite the evidence supporting the cardioprotective effect of KDs, another study utilizing KD on cardiac remodeling in spontaneously hypertensive rats (SHRs) suggested that KD might deteriorate cardiac remodeling in the hypertensive heart and warranted fully evaluation of its reliability before clinical use ( 53 ). The different pathogenesis backgrounds of hypertension might account for the different results. More studies with larger samples, longer follow-up duration, and standardized basic health status can be conducted to further clarify the role of KDs in cardiac functions and other potential mechanisms.

The role and mechanism of ketogenic diets in cardiac function and vascular function. Various pathways might underly the effects of ketogenic diets in cardiomyocytes and endothelial cells in different models. In cardiomyocytes, βHB regulates PI3K/Akt pathway and SDH in mitochondria to finally ameliorate cell apoptosis. However, elevated βHB might also acts through inhibiting HDAC2 and influencing mitochondrial biogenesis, leading to myocardial fibrosis. In endothelial cells, ketone bodies can functions through inhibiting mTOR pathway to regulate the level of eNOS, subsequently dilating blood vessels and enhancing vascular function. Besides, elevated ketone bodies can give rise to mild oxidative/electrophilic stress, activate Nrf2 in cytoplasm and enhance antioxidant gene expression, which lead to lowered ROS level and improved vascular functions. Created with BioRender.com .

Ketogenic Diets and Hypertension

Attention has also been paid to the effects of KD in hypertension. Most studies showed positive effects of KD in hypertension. Castellana et al. ( 54 ) suggested that very-low-calorie ketogenic diet (VLCKD) manifested improvements in hypertension, type 2 diabetes and dyslipidemia, apart from being a promising lifestyle intervention for overweight and obesity. Another study incorporating 377 patients across Italy drew a similar conclusion that VLCKD could significantly lower SBP in three months ( 55 ). Even a short-term 4-week KD with micronutrient supplementation could result in improved hypertension control and in a reduction for the usage of hypertension medications in patients with preoperative T2DM and hypertension ( 56 ). Increasing ketone bodies by nutritional interventions of ketone bodies or their precursors, such as 1,3-Butanediol, was also reported to attenuate hypertension ( 57 ). However, Guo et al. ( 58 ) revealed that subjecting spontaneously hypertensive rats (SHRs) to KD for 4 weeks aggravated hypertension, increased the expression of IL1-β and TNF-α, impaired endothelium-dependent relaxation and decreased CD31 and eNOS expression in mesenteric arteries. This finding is opposite to the previous results; thus, it remind us to be cautious in treating hypertension with KD, and perform more studies to explore the effects of KD on hypertension in human studies and animal models.

The Dietary Approaches to Stop Hypertension (DASH) diet is a classic dietary approach that has been endorsed for patients with elevated blood pressure (BP). Besides, the addition of exercise and weight loss to the DASH diet resulted in even larger BP reductions, greater improvements in vascular and reduced left ventricular mass for obese people with elevated BP ( 59 ). The main drawback of DASH might be the difficulty in long-term adherence to this diet. Considering the different components of DASH and KD, KD might become another choice for those people who love a high-fat diet, although we suggest cautious application since the antihypertensive efficacy and side effects of KD under the background of hypertension remain unclear. Interestingly, a review suggested that intermittent fasting could lower both systolic and diastolic blood pressure in human studies and animal studies, possibly through reducing oxidative stress, syncing with circadian rhythm, and inducing a ketogenic state ( 60 ). The less consumption of fats is assumed as the reason why intermittent fasting appears to be more beneficial than KD in treating hypertension. Thus, the type of fats consumed in KD therapy is crucial to be considered both in treating hypertension and evaluating its effects.

Ketogenic Diets Regulate Vascular Functions and Vascular Blood Flow

A study by Keogh et al. ( 61 ) has indicated that a very-low-carbohydrate, high-saturated-fat weight-loss diet did not impair FMD. How would the actual KD impact on vascular function and vascular blood flow?

In some studies, KD appears to play a protective role in vascular functions. Ischemic tolerance can reduce brain injury and neurological dysfunction after brain ischemia. Additional to the cardiovascular effects such as higher reperfusion recovery of coronary flow, KD also can enhance brain vascular function. As supported by the results from a study upon feeding a KD to young healthy mice, KD intervention enhanced neurovascular function through reducing mTOR protein expression and increasing eNOS levels ( 62 ). Yang et al. ( 63 ) discovered that feeding mice with KD-fed mice could remarkably decrease infarct volume and elevate regional cerebral blood flow in both ischemic and reperfusion phases. Besides, while investigating the effects of KB level on HMEC-1 endothelial cells, one study indicated that KB activated transcription factor Nrf2 and elevated the expression of cell antioxidant defending genes via inducing moderate oxidative stress ( 64 ). Thus, the increased KB level by KD might also lead to these protective effects.

However, as for big vessels such as carotid and aortic artery, the effects of KD remain controversial. For instance, after observing the effect of KD on the vascular structure and functions for at least one year, it was found that KD notably elevated the serum levels of lipids but didn’t significantly affect carotid intima-media thickness, aortic and carotid strain, the stiffness index, distensibility, and elastic modulus ( 65 ). Another study by Doksoz et al. ( 66 ) also demonstrated that a 6-month KD didn’t affect carotid intima-media thickness and elastic properties of the carotid artery and the aorta. In contrast, in the research of Coppola et al. ( 67 ), participants prescribed with KD had higher arterial stiffness parameters, including AIx and beta-index and higher serum levels of cholesterol or triglycerides. Another study revealed that a high-fat KD notably elevated atherogenic apolipoprotein B (apoB)-containing lipoproteins and decreased antiatherogenic HDL cholesterol and urged further researches to investigate whether this diet deteriorates endothelial function and facilitates inflammation and formation of atherosclerotic lesions ( 68 ). However, a clinical study involving 26 children after one year and 13 children after two years of KD suggested that the initial influences on arterial function observed within the first year of KD-treatment were reversible and were no longer significant after 2 years of the therapy ( 69 ). Therefore, the effects of KD on big vessels such as carotid and aortic artery were reversible and were no longer significant after 1-2 years, which might explain the above results.

Ketogenic Diets Regulate Serum Lipids

Apart from the cardiometabolic effects mentioned above, the impact of KD on serum CVD biomarkers has also been investigated. Research on 20 normal-weight, normolipidemic men indicated that a 6-week KD notably decreased fasting serum triglyceride, postprandial lipemia, and fasting serum insulin concentrations, tended to increase HDL cholesterol, while not affecting fasting serum total and LDL cholesterol and oxidized LDL ( 70 ). These results revealed that short-term KD would not deteriorate CVD risk profile and, indeed, appeared to ameliorate lipid disorders that are characteristics of atherogenic dyslipidemia. Another research also indicated that changes in the ratio of protein to carbohydrate toward higher protein proportion could provide beneficial effects on serum lipids apart from lowering body weight ( 71 ).

However, Özdemir et al. ( 65 ) pointed out that prescribing patients with at least 12 months KD could significantly elevate serum total and LDL cholesterol and triglyceride at a median of 12.6 months while not affecting HDL level. Moreover, another research ( 72 ) found that a 6-month KD could notably increase median triglyceride, total cholesterol, LDL, and HDL. They suggested that classic KD was indeed efficient in treating refractory seizures in children but might give rise to hypercholesterolemia and hypertriglyceridemia.

As such, disputable voices concerning the impact of KDs on serum lipids remain to be settled by future work in this field.

Ketogenic Diets and Cardiovascular Complications of Metabolic Diseases

The potential effects of KDs on the prevention or treatment of cardiovascular risk factors or diseases have been significantly studied over the past decades. Moreover, various animal and human studies have investigated the role of KDs in regulating cardiovascular complications of obesity, insulin resistance and type 2 diabetes, dyslipidemia, NAFLD, and/or GLUT1DS. However, whether and how KDs influence the cardiovascular risk factors or complications in metabolic diseases remains undetermined.

Obesity-Associated Cardiovascular Disease

Obesity is closely related to CVD, and complications of CVD are often witnessed in obese patients. Cicero et al. ( 55 ) evaluated the effect of a very low carbohydrate ketogenic diet (VLCKD) on overweight-related risk factors of CVD such as blood pressure, lipid levels, and glucose metabolism, and the study found that VLCKD intervention for 3 months was generally safe and found effective in inducing weight loss and improved CV risk factors levels.

Another study recruited a hundred obese patients and prescribed them a ketogenic diet for over six months showed significant improvement in patients’ cardiovascular status in addition to weight reduction ( 73 ). Moreover, a meta-analysis study by Bueno et al. ( 74 ) assessed the long-term effects of VLCKD on body weight and cardiovascular risk factors. The results indicated that under VLCKD, the participants had a significant reduction in body weight, TAG, and diastolic blood pressure, while increased HDL-C and LDL-C levels were observed. Apart from long-term studies, a study by Ministrini et al. ( 75 ) that treated obese patients with VLCKD for 25 days also concluded that VLCKD had positive effects on cardiovascular risk factors, and such a beneficial outcome in the short term is remarkable.

Other studies investigated the effects of modified KDs on cardiovascular risks in obese participants. Perez-Guisado et al. ( 76 ) carried out a prospective evaluation in 31 obese participants with “Spanish Ketogenic Mediterranean Diet” (incorporating virgin olive oil as a principal source of fat, moderate red wine intake, green vegetables and salads as the primary source of carbohydrates and fish as the main source of protein, SKMD). The SKMD was found safe and effective interventional approach for improving non-atherogenic lipid profiles and lowering blood pressure while lowering body weight. Similarly, Paoli et al. ( 77 ) applied another modified KD that incorporated phytoextracts and ingredients imitating the taste of carbohydrates (ketogenic Mediterranean with phytoextracts, KEMEPHY). The study recruited 106 overweight Rome council employees and revealed a remarkable reduction in body weight, BMI, percentage of fat mass, total cholesterol, LDL-C, TAG and blood glucose while displaying a significant increase in HDL-C after the intervention with KEMEPHY. In addition to good compliance, extra beneficial effects on cardiovascular risk markers and waist circumference were also achieved by the KEMEPHY diet.

Since the beneficial effects of KDs on metabolism and cardiovascular risk factors are similar to those seen after n-3 polyunsaturated fatty acids (omega-3) supplementation, Paoli’s team ( 78 ) modified the ketogenic Mediterranean diet with phytoextracts after their previous research through combining with omega-3 supplementation. The results suggested that this newly modified diet can further enhance the beneficial effects on cardiovascular risk factors and inflammation in overweight participants.

The influence of a multi-step dietary program including different dietary patterns has also been evaluated. In an open-label study by Castaldo et al. ( 79 ), 73 obese patients entered a rehabilitative multi-step dietary program: a 3-week protein-sparing, very low-calorie KD (<500 kcal/day; Oloproteic Diet) and a 6-week hypocaloric (25–30 kcal/kg of ideal body weight/day), low glycemic index, Mediterranean-like diet (hypo-MD). In both phases, improved glucose and lipid metabolism and blood pressure were observed. Based on this, it was concluded that a dietary program consisting of a KD and a subsequent MD could decrease cardiovascular risks efficaciously in obese patients.

CVD During Diabetes Mellitus

Diabetes mellitus is often associated with obesity ( 80 ), and recent estimates showed that 87.5% of T2DM patients are overweight or obese ( 24 ). Moreover, obese subjects are prone to developing hypertension, CVD, and strokes, and the risk is even higher if it co-exists with T2DM ( 81 ).

In patients with both T2DM and obesity, LC diets not only cause weight loss but also improve postprandial plasma glucose levels, glucose variability, serum triglycerides, and HDL-C levels ( 82 ). Similar results were observed by a 2-year randomized clinical trial study ( 39 ) that investigated the effect of an LC diet with high unsaturated fat and low saturated fat on glycemic control and CVD risk factors in overweight or obese patients with T2DM. KD is a low-carbohydrate (LC) and high-fat (HF) diet, which sort of belongs to one type of LC diets. However, one of the potential concerns of KDs is postprandial hyperlipidemia, which leads to significant cardiovascular risks ( 83 ).

Studies have found that individuals with pre-diabetes or diabetes who received an earlier LCHF diet revealed several beneficial outcomes, including weight loss, improved insulin sensitivity, glucose homeostasis, and lower fasting blood glucose levels. These outcome improvements also decreased the risks of cardiovascular diseases development ( 38 , 84 ). Mobbs et al. ( 28 ) analyzed the evidence concerning the treatment of diabetes and diabetic complications with a KD. They revealed that a classic KD significantly reduced blood glucose in animal models of type 1 and 2 diabetes and reversed diabetic nephropathy without producing significant cardiovascular risks. Moreover, a study on db/db mice revealed that KD ameliorates cardiac dysfunction by inhibiting apoptosis via activating the PI3K-Akt pathway in type 2 diabetic mice and suggested KD as a promising lifestyle intervention against diabetic cardiomyopathy ( 85 ).

However, there also are studies with conflicting or controversial findings and opinions. Westman et al. ( 86 ) stated that LCHF diets gave rise to decreased appetite, thus the improved surrogate markers of cardiovascular disease resulted from weight loss but not from low carbohydrate intake itself. In an animal study, Abdurrachim et al. ( 87 ) investigated the effects of long-term KD on cardiac metabolism and diabetic cardiomyopathy status in lean diabetic Goto-Kakizaki (GK) rats. Upon KDs for 62 weeks, diabetic GK rats displayed decreased blood glucose, triglyceride, and insulin levels, revealing increased blood ketone body levels. Additionally, KDs decreased myocardial ketone body and glucose oxidation and induced cardiac hypertrophy. These results suggested that KDs might lead to maladaptive cardiac metabolic modulation and lipotoxicity and deteriorate diabetic cardiomyopathy in GK rats. Given this, the possible role of KDs in cardiovascular risks of DM remains controversial in rodent models and humans, which warrants more studies for elucidation.

Dyslipidemia-Associated CVD

As for patients with dyslipidemia, Westman et al. ( 88 ) investigated the effect of KDs on serum lipoprotein subclasses to address the concern of KDs on cardiovascular risks. The study was a randomized, two-arm clinical trial involving overweight and hyperlipidemic participants motivated to lose weight. After 6 months, the KD group displayed more significant decreases in medium VLDL, small VLDL, and medium LDL, and more significant increases in VLDL particle size, large LDL, and HDL particle size than the control group. Although the KDs did not decrease total LDL cholesterol, they shifted from small, dense LDL to large, buoyant LDL, thus decreasing CVD risks in these participants.

NAFLD-Related CVD

NAFLD contributes to CVD through various mechanisms. Weight loss has been commonly recommended for treating obesity-associated NAFLD; meanwhile, LCKD benefits weight loss. Recent studies have revealed an association between LC diets and NAFLD in both rodents and humans. In the study by Garbow et al. ( 28 ), mice fed a KD for 12 weeks were lean, euglycemic, ketotic, and hypo-insulinemic but were glucose intolerant and with NAFLD. Also, obese subjects on LC diets displayed enhanced weight loss, improved metabolic parameters and decreased intrahepatic triglyceride content. Nevertheless, long-term KDs led to NAFLD and systemic glucose intolerance in mice ( 89 ), negatively impacting CVD. As such, current evidence is insufficient to conclude, and more related studies are warranted to explore how KDs might influence NAFLD-related CVD in the long run.

CVD During GLUT1DS

GLUT1DS is an inherited but treatable disease concerning cerebral energy metabolism ( 90 ). KDs are currently a treatment option for GLUT1DS from infancy into adulthood, raising concerns about long-term cardiovascular risks ( 43 , 60 , 69 ). To address this problem, Heussinger et al. ( 91 ) performed a 10-year follow-up study on cardiovascular risk of KDs in GLUT1DS and revealed that dyslipidemia caused by KDs might be transient; and carotid intimal wall thickness (CIMT), BMI and blood pressure parameters remained normal after 10 years. Because of this, Heussinger et al. suggested that cardiovascular risks of KDs in some previous studies appeared to be attributable to inadequate follow-up. Also, a period of at least five years appears to be necessary for evaluating the effect of KDs on lipid parameters. Moreover, the authors recommended KDs as a treatment of choice for GLUT1DS. Another study by Alter et al. ( 90 ) also characterized the long-term course of GLUT1DS and followed up for an average of 14.2 years (range = 8.9-23.6). The results indicated that earlier introduction of KDs correlated with better long-term outcomes and KDs seemed to be protective of vital organs. However, GLUT1DS is a rare disease, and therefore, the study cohort’s size and external validity are limited. Long-term follow-up studies are warranted to confirm the above findings further.

Potential Safety Concerns on KD

The majority of the studies had found KD to be beneficial, but some studies had shown concerns regarding heart functions, liver inflammation and so on.

The Effects of KD on Heart Functions in Rodents

One study found KD treatment ameliorates cardiac dysfunction by inhibiting apoptosis via activating the PI3K-Akt pathway in type 2 diabetic mice, suggesting that the KD is a promising lifestyle intervention offering protection against diabetic cardiomyopathy ( 85 ). In contrast, a ketogenic diet may lead to adverse effects on the remodeling in the hypertensive heart via mechanisms involving increased mTOR signaling, and they underscore the necessity to evaluate its reliability before clinical use ( 53 ). Preclinical studies results indicate that KD also has a potential safety concern, although much evidence suggests that KD is a promising approach for managing CVD.

The Effects of KD on Hepatic Inflammation in Rodents

As a key factor that triggers or exacerbates CVD risk, liver inflammation is a potential safety concern related to KD. In support of this, a study observed that mice fed with KD sustained unimpaired insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness but ultimately developed hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation ( 28 ).

The Effects of KD on Lipid Profile

KD is enriched in lipid contents, and it’s natural to speculate the potential risk of elevated levels of lipids. Apart from studies indicating the beneficial effects of KD, concerns regarding the elevated level of lipids, including serum total and LDL cholesterol and triglyceride, are subjective while prescribing KD ( 65 , 72 ). It is reported that KDs are likely to deteriorate levels of total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides ( 27 , 34 , 92 ) in rodents while doing the opposite in humans ( 39 ). These contradictory results might be attributable to the different composition of diets since animal researches generally employ diets higher not only in total fat but also in saturated fat ( 93 ). Considering this, it is necessary to compare the fat composition, e.g., content of saturated fat versus unsaturated fat in KDs in long-term studies involving both rodents and humans.

As described above, while considering KD as an exciting approach for managing CMDs, it also is important to be cautious about the potential safety concern associated with KD. While future studies are warranted to confirm and elucidate whether and how KD causes potential safety concerns, it would also be important to consider to modifying KD or combining KD with other healthy diets for managing CMDs.

Despite particular safety concerns, the beneficial and advantageous aspects of KD cannot be denied. Because multiple factors are affecting the results, including using different mouse strains, providing KD with different food compositions, short study duration, etc. In the future, studies essentially need to explore the possible factors influencing the responses to KD and improve KD dietary plan for utilizing KD as a dietary therapy to minimize safety concerns.

Factors Affecting Ketogenic Diets Responses

Genetic control of the responses to a ketogenic diet.

Nutrigenetic research suggested that genetic markers critically regulate nutritional interactions that impact body weight and composition, which lays the foundation for personalized nutrition therapy ( 94 , 95 ).

Barrington et al. ( 96 ) observed that mouse genetic backgrounds determined dietary outcomes on CVD risk. Specifically, the study included mice from four inbred strains (A, B6, FVB, and NOD), which accounted for genetic and phenotypic diversity and examined mice’s metabolic responses to four human-comparable mice diets (American, Mediterranean, Japanese and ketogenic diets). The authors revealed that the effects of these diets on metabolic health were indeed dependent on genetic backgrounds. The outcomes of KD on body composition, glucose metabolism and liver health varied markedly among different strains.

The different diet responses could be partly attributable to the genetic background related to varying dietary therapy compliance. Parnell et al. ( 97 ) analyzed the interactions between single nucleotide polymorphisms (SNP) in various cardiometabolic pathways and the intake of different nutrients. Their results indicated that gene-environment (GxE) genes had better responses to plasma cholesterol-lowering or regression of atherosclerotic plaques, primarily through high-energy diets and fat intake.

As mentioned above, genetic background plays a vital role in individual responses to KDs and may consequently influence the effects of KDs. It is of great importance to take genetic background into account when initiating KD therapy.

Food Composition, Quality and Sources of KDs Influence the Outcome

As KDs are a kind of macronutrient-focused diet, we should fully consider the food composition, quality and sources to avoid potential drawbacks when starting a KD. As indicated in the research by Seidelmann et al. ( 98 ), there was a U-shaped association between the percentage of energy consumed from carbohydrates and mortality: 50–55% carbohydrate intake was associated with minimal mortality risk. In comparison, a percentage of <40% or >70% led to greater mortality risk. Besides, different types of dietary fatty acids have different effects on CVD risk and replacing saturated fatty acid (SFA) with unsaturated fats especially polyunsaturated fatty acids can lead to a significant reduction in CVD risk ( 99 ). Moreover, diets that favored plant-derived protein and fat intake were associated with lower mortality than animal-derived protein and fat sources. Thus, the nutrient composition, types and sources should be taken into consideration when prescribing a KD therapy; the diversity in these nutrient details could affect the effects of KD and should be relatively standardized to compare the results.

Duration of KD Therapy Affects the Responses

Interestingly, increasing the therapeutic duration of KDs appears to reduce some safety-related problems ( 34 , 35 ). For instance, long-term follow-up research has demonstrated that dyslipidemia caused by KDs is transient. Moreover, over 10 years, KD therapy has ended with normal vascular function as indicated by carotid artery ultrasound ( 91 ).

Modified KD Dietary Plan

Because of the irreconcilable options on the therapeutic use of KD, several studies concerning modified KD and cardiovascular risks have been performed. The “Spanish Ketogenic Mediterranean Diet” carried out by Perez-Guisado et al. ( 76 ) and two modified KDs (KEMEPHY ( 77 ) and KEMEPHY with omega-3 supplementation ( 78 )) employed by Paoli et al. have all displayed beneficial effects on cardiovascular risk factors. A combined diet consisting of KD and a subsequent Mediterranean-like diet has been proven to decrease cardiovascular risks in patients ( 79 ). Therefore, a modified KD or multi-step dietary program including different diet patterns is promising in resolving the safety concerns associated with KDs.

Based on the currently available evidence, KD appears to play a significant role in treating various cardio-metabolic diseases and reveals remarkable effects on cardiovascular function. KD therapy is generally promising in obesity, heart failure, and hypertension, though different voices still exist. In diabetes and dyslipidemia, the performance of KD remains controversial. As for cardiovascular complications of metabolic diseases, current evidence suggests that KD is generally protective to obese related cardiovascular disease (CVD), while remaining contradictory to diabetes and other metabolic disorder related CVDs. Various factors might account for the controversies, including genetic background, duration of therapy, food composition, quality and sources of KDs. Therefore, further studies are warranted to provide concrete and more conclusive opinions. Also, it is vital to monitor safety-related signs and biomarkers during the KD intervention, although most are reversible or transient. In addition, modified KD could be adequately designed and utilized to enhance compliance as a therapeutic approach. Overall, there is a critical need to conduct more rigorous research focusing on the clinical implication and safety issues of KD.

Author Contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication. WYZ: designing, conceptualization, writing, figure plotting, revising; JZ and CDW: designing, funding acquisition, review & editing; XG: funding acquisition, review & editing; LLC: supervision, editing, revising; TC and JYY: figure plotting.

The development of this review was supported in whole or in part by grants from the National Natural Science Foundation of China (81770772 to JZ), the Hubei Province Natural Science Foundation (2019CFB701 to JZ), National Natural Science Foundation of China (81803224 to XG) and Young Scholars Program of Shandong University (2018WLJH33 to XG).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

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AcknowleDgments

We especially express our appreciation to Mohammad Ishraq Zafar for his assistance with the English language of our review.