Ketogenic Diet

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1. What Ketogenic Nutrition Is

The ketogenic diet is a therapeutic nutritional procedure characterised by a drastic reduction in carbohydrate intake with a simultaneously high fat content and moderate protein intake. The aim is to induce a metabolic state called ketosis, in which the body uses ketone bodies as the primary energy source. Originally developed in the 1920s for the treatment of epilepsy, the procedure is today applied in various variants, including classic ketogenic diets, modified Atkins diets or very low-carbohydrate diets with a ketogenic orientation.

The implementation varies according to the objective and patient group. Typical macronutrient ratios are 70–80 % fat, 15–25 % protein and 5–10 % carbohydrates. Compliance is often monitored by measuring ketone bodies in blood, urine or breath. Crucial for understanding the evidence base is the diversity of application forms: from short-term interventions for weight reduction to long-term therapies for neurological diseases. In addition, studies differ in the control of food quality – for example whether saturated or unsaturated fats predominate – which limits the comparability of the results.

2. What the Studies Show in Detail

The key human studies and the most important reviews — by application area, with population, duration, preparation, measured variable and result, as the original papers report them. Numbers appear only where the work states them.

Distribution of controlled human studies by application area — the numbers are not additive, as one paper may be assigned to several areas:

Metabolism

The DIETFITS study (2018) compared a carbohydrate-reduced (“healthy low-carbohydrate”, HLC: target < 30 g/day) with a fat-reduced (“healthy low-fat”, HLF: target < 20 g/day) diet over 12 months in 609 overweight adults (BMI 28–40, age 18–50 years, without diabetes). Both groups received 22 behavioural-therapy group sessions. The primary endpoint was weight change. Genetic predisposition (three SNP patterns) or insulin secretion (INS-30) also showed no significant interaction with the diet effect.

The primary endpoint was ad-libitum energy intake under inpatient conditions. The ketogenic group consumed 689 ± 73 kcal more per day than the low-fat group (p < 0.0001); in the final week the difference was 544 ± 68 kcal (p < 0.0001). The study provides an indication that a carbohydrate-reduced diet does not reduce energy intake under controlled conditions. Whether this is associated with clinical effects such as weight loss still stands to be clarified.

The randomised study by Ebbeling et al. (2018) 3 investigated the influence of different carbohydrate proportions (20 %, 40 %, 60 %) on total energy expenditure after 12 % weight loss in 164 adults (BMI ≥ 25, age 18–65 years). A limitation was the short duration of the weight maintenance phase (20 weeks) and the possible underestimation of energy expenditure by the Doubly-Labeled-Water method with high fat intake.

The HbA1c value fell by 1.2 % in the VLCK group (p < 0.05 vs. control), while medication could be reduced more frequently. A limitation was the open design and the lack of long-term observation beyond the 4 months.

In the LCK group, 60 % of participants taking sulfonylureas or DPP-4 inhibitors discontinued these agents (vs. 0 % in the MCCR group, p = 0.005). A limitation was the small sample and the lack of blinding.

A meta-analysis (2017) 6 of 9 randomised studies with 734 T2DM patients showed that carbohydrate-reduced diets (LCD) lowered the HbA1c value by 0.44 % (95 % CI: -0.61 to -0.26, p = 0.00) more than control diets. In addition, HDL cholesterol rose (WMD: +0.07 mmol/l, p = 0.00) and triglycerides fell (WMD: -0.33 mmol/l, p = 0.00). Weight reduction was significant in the short term (WMD: -1.18 kg, p = 0.04) but not in the long term.

A further meta-analysis (2020) 7 with 14 studies and 734 participants (overweight/obese, with or without T2DM) showed that ketogenic diets lowered the HbA1c value more strongly in diabetic patients than low-fat diets (SMD: -0.62, p < 0.001) and reduced weight (SMD: -0.46, p = 0.04). In addition, triglycerides improved (SMD: -0.45, p = 0.01) and HDL cholesterol (SMD: +0.31, p = 0.005). A limitation was the short duration of most studies (median: 12 weeks) and the lack of differentiation by diabetes type.

Hypothesis The studies suggest that ketogenic nutrition leads to a greater short-term improvement in glycaemia and weight in T2DM than low-fat diets. However, long-term data (> 2 years) on the sustainability of the effects and on safety, particularly with regard to cardiovascular risk factors, are lacking. It is also unclear whether the effects are attributable to carbohydrate reduction or the associated calorie restriction.

Inflammatory Processes

The 2-year study (2019) 1 investigated the effect of continuous remote care (CCI) with ketogenic nutrition (target: < 30 g carbohydrates/day) compared with standard therapy (UC, n = 87) in 262 adults with T2DM (age 54 ± 8 years, BMI 40.4 ± 8.8 kg/m²). A limitation was the non-randomised design and the lack of medication control in the UC group.

In an open, controlled study (2018) 5 with 262 T2DM patients (CCI group) and 87 controls (UC), one year of continuous remote care (CCI) with ketogenic nutrition (target: < 30 g carbohydrates/day) led to a significant reduction in small LDL particles (-20.8 %, p = 1.2 × 10⁻¹²) and an increase in LDL particle size (+1.1 %, p = 6.0 × 10⁻¹⁰). Carotid intima-media thickness (cIMT) remained unchanged. A limitation was the absence of randomisation and the possible bias from intensive care in the CCI group.

A randomised study (2022) 10 in 164 adults (BMI 32.4 ± 4.8 kg/m²) compared three diets with different carbohydrate proportions (20 %, 40 %, 60 %) after 10–14 % weight loss over 20 weeks. The lipoprotein insulin resistance score (LPIR) improved in a dose-dependent manner: in the 20 % carbohydrate group, LPIR fell by 15 points (p < 0.001 vs. 60 % group). In addition, HDL cholesterol (+5 mg/dl, p = 0.02) and adiponectin (+1.3 µg/ml, p = 0.02) rose in the 20 % group. A limitation was the short duration and the lack of measurement of specific inflammatory markers such as IL-6 or TNF-α.

Hypothesis The data suggest that ketogenic nutrition can lower preclinical inflammatory markers such as CRP and leukocytes. The lipoprotein insulin resistance score (LPIR) – a surrogate parameter for insulin resistance – showed a dose-dependent improvement in a controlled study, yet studies that specifically examine inflammation-associated endpoints (e.g. cytokines, endothelial function) in non-diabetic populations are lacking.

Cognition and Psyche

Cognitive performance (ACE-III) remained unchanged.

A retrospective analysis (2022) 15 examined 28 inpatients with treatment-resistant depression, bipolar disorder or schizoaffective disorder who received ketogenic nutrition (< 20 g carbohydrates/day) for 6–248 days. A limitation was the absence of a control group and the concurrent medication, which was not controlled.

A pilot study (2024) 14 in 20 patients with bipolar disorder or schizophrenia and metabolic abnormalities showed, after 4 months of ketogenic nutrition (< 20 g carbohydrates/day), a reduction in visceral fat of 36 % (p < 0.001) and in HOMA-IR of 27 % (p < 0.001). In addition, psychiatric scores (CGI: -31 %, p < 0.001) and life satisfaction (+17 %, p = 0.002) improved. A limitation was the absence of a control group and the small sample.

Hypothesis The available controlled studies point to a therapeutic potential of ketogenic nutrition in neurodegenerative and psychiatric disorders, particularly through improvement of metabolic health. However, randomised, controlled studies with adequate power and long-term observation are still required to examine causal relationships.

Gut and Microbiome

A study on ketogenic nutrition showed a significant increase in short-chain fatty acid-producing bacteria such as Roseburia, Ruminococcus and Eubacterium (p < 0.05). In addition, GLP-1 levels rose by 25 % (p < 0.01), while the HbA1c value fell by 1.2 % (p < 0.01). Both values are preclinical surrogate parameters; clinical effects on metabolic diseases were not investigated. A limitation was the lack of ketone body measurement and the short duration.

A narrative review (2021) summarised that ketogenic nutrition can increase microbiome diversity and improve the Bacteroidetes to Firmicutes ratio. However, controlled studies that directly link these effects to clinical endpoints are lacking. It is also unclear whether the observed changes are attributable to carbohydrate reduction or increased fat intake.

An observational study (2021) discussed preclinical evidence from animal and cell models that ketogenic nutrition in NAFLD/NASH could promote short-chain fatty acid production and strengthen the intestinal barrier. Clinical studies in humans examining these mechanisms or their effects on liver disease are still required.

Hypothesis Initial evidence suggests that ketogenic nutrition could modulate the microbiome and increase GLP-1 secretion. Long-term effects on gut health and the clinical relevance of these changes remain to be determined.

Viral Infections

An observational study (2024) 16 compared the effects of a vegan and a ketogenic diet (2 weeks each) on the immune system in 20 healthy adults. The ketogenic diet led to upregulation of adaptive immune cells (e.g. CD8+ T cells) and an increase in ketone bodies (β-hydroxybutyrate: +1.5 mmol/l). The vegan diet, by contrast, activated innate immune pathways (e.g. antiviral genes). A limitation was the short duration and the lack of measurement of clinical endpoints such as infection rates.

Hypothesis The study provides an indication that ketogenic nutrition could alter markers of adaptive immune responses, while vegan nutrition alters markers of innate immune responses. Whether these effects occur in patients with viral infections or immunodeficiency remains to be determined.

Safety and Tolerability

A review (2022) 17 summarised that ketogenic diet appears safe for various indications such as epilepsy and metabolic diseases, provided it is medically supervised. Common side effects are constipation, fatigue and hyperlipidaemia. In T2DM patients, hypoglycaemia may occur if medication is not adjusted. Long-term risks such as kidney stones or liver dysfunction are rare but possible. A limitation was the lack of quantification of risks depending on diet duration.

Hypothesis Ketogenic diet is safe in the short term, yet long-term data on tolerability in non-epileptic indications are still outstanding. It remains unclear how the diet affects bone health or cardiovascular risk.

Oncology

A review (2021) 18 discussed that ketogenic diet could inhibit tumour growth by reducing glucose availability (Warburg effect). In preclinical studies (animal and cell models) a slowing of tumour growth and an increased sensitivity to chemotherapy were observed. Whether these effects occur in humans has not been investigated. The preclinical data showed heterogeneity and lack of standardisation of the diet.

Hypothesis Ketogenic diet could be effective as an adjuvant therapy in oncology, but clinical studies with sufficient power and long-term observation are still outstanding to examine safety and efficacy.

Overall Picture

Some of the controlled studies show that ketogenic diet leads to greater short-term weight loss and improvement in glycaemia than low-fat diets in metabolic diseases such as T2DM and obesity. There are also indications of changes in inflammatory markers, cognitive functions and psychiatric disorders. However, most studies are of short duration (< 12 months) and do not examine the long-term safety or sustainability of the effects. In addition, there is no clear differentiation between the effects of carbohydrate reduction and the associated calorie restriction.

The data situation on non-metabolic indications such as oncology or viral infections consists predominantly of preclinical studies, while some observational studies are also available on gut health. Randomised controlled studies with sufficient power and long-term observation are still outstanding here to examine causal relationships and derive clinical recommendations.

3. How Reliable the Research Is

Research on ketogenic diet focuses predominantly on metabolic diseases. A considerable proportion of the controlled studies in humans examine weight loss, type 2 diabetes mellitus or cardiometabolic parameters. Further focal points lie on inflammatory processes, cognitive functions and oncological questions, although with a markedly lower number of studies. The distribution shows a clear dominance of short- to medium-term interventions (mostly 3–12 months), while long-term data are rare. Observational studies are more numerous than controlled studies in humans, yet the methodologically most robust works are randomised controlled trials that mainly compare metabolic markers such as HbA1c, triglycerides or body weight.

The reliability of the data differs according to area of application. For metabolic parameters (e.g. weight loss, blood glucose control) numerous controlled studies exist that show consistent effects. However, many of these works are small, heterogeneous in execution and often industry-sponsored. In neurological or oncological applications the number of controlled studies is markedly lower: here many statements are based on case series, uncontrolled studies or preclinical models. In addition, long-term data on safety and sustainability are frequently lacking, especially with extreme variants of ketogenic diet. The mechanistic reviews provide plausible explanatory models but show no clinical efficacy for these areas of application.

4. What Is Frequently Claimed — and What the Data Provide

5. The Most Reliable Works

Ordered by strength of evidence, not by familiarity. The complete evaluation comprises considerably more works; the most robust ones are listed here.

Controlled Studies in Humans

• Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association With Genotype Pattern or Insulin Secretion (2018)
• 1 Long-Term Effects of a Novel Continuous Remote Care Intervention Including Nutritional Ketosis for the Management of Type 2 Diabetes: A 2-Year Non-ran (2019)
• 2 Effect of a plant-based, low-fat diet versus an animal-based, ketogenic diet on ad libitum energy intake (2021)
• 3 Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial (2018)
• Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patien (2016)
• Randomized crossover trial of a modified ketogenic diet in Alzheimer's disease (2021)
• 4 Twelve-month outcomes of a randomized trial of a moderate-carbohydrate versus very low-carbohydrate diet in overweight adults with type 2 diabetes mel (2017)
• The Potential Health Benefits of the Ketogenic Diet: A Narrative Review (2021)
• 5 Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restricti (2018)
• The Role of Ketogenic Diet in the Treatment of Neurological Diseases (2022)
• 6 Efficacy of low carbohydrate diet for type 2 diabetes mellitus management: A systematic review and meta-analysis of randomized controlled trials (2017)
• 7 Impact of a Ketogenic Diet on Metabolic Parameters in Patients with Obesity or Overweight and with or without Type 2 Diabetes: A Meta-Analysis of Rand (2020)
• 8 Effect of a ketogenic diet versus Mediterranean diet on glycated hemoglobin in individuals with prediabetes and type 2 diabetes mellitus: The interven (2022)
• An Almond-Based Low Carbohydrate Diet Improves Depression and Glycometabolism in Patients with Type 2 Diabetes through Modulating Gut Microbiota and G (2020)
• Ketogenic Diet Benefits to Weight Loss, Glycemic Control, and Lipid Profiles in Overweight Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of (2022)
• A Novel Intervention Including Individualized Nutritional Recommendations Reduces Hemoglobin A1c Level, Medication Use, and Weight in Type 2 Diabetes (2017)
• 9 Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials (2023)
• 10 Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial (2022)
• Low-Carbohydrate Nutrition in the Treatment of Obesity and Type 2 Diabetes: An Overview by Clinicians Who Use This Approach in Practice (2020)
• 11 Effects of Low-Fat, Mediterranean, or Low-Carbohydrate Weight Loss Diets on Serum Urate and Cardiometabolic Risk Factors: A Secondary Analysis of the (2020)
• 12 Short-term effects of a low carbohydrate diet on glycaemic variables and cardiovascular risk markers in patients with type 1 diabetes: A randomized op (2017)
• 13 The effect of a short-term low-carbohydrate, high-fat diet with or without postmeal walks on glycemic control and inflammation in type 2 diabetes: a r (2018)
• The Ketogenic Diet and Alzheimer's Disease (2022)
• Efficacy and Safety of Dietary Therapies for Childhood Drug-Resistant Epilepsy: A Systematic Review and Network Meta-analysis (2023)

6. Summary

The ketogenic diet is well studied in metabolic diseases such as T2DM and obesity: Controlled studies demonstrate short-term improvements in HbA1c, weight loss, triglycerides and HDL cholesterol. The effects are consistent, yet often of short duration (mostly < 12 months) and associated with methodological limitations such as lack of blinding or industry sponsorship. For metabolic parameters such as LPIR or lipoprotein composition there are indications of dose-dependent improvements, however without targeted analysis of specific cytokines or endothelial function.

Hypothesis A therapeutic potential appears plausible in psychiatric disorders (e.g. depression, bipolar disorder) through metabolic improvements, as well as in neurodegenerative processes. For oncological applications the diet could act as an adjuvant therapy by reducing glucose availability for tumour cells (Warburg effect). However, clinical studies with sufficient power are lacking here. In addition, ketogenic nutrition could modulate the microbiome (e.g. increase in short-chain fatty acids) and activate the adaptive immune system, yet the clinical relevance of these effects is unclear. Hypothesis: The observed effects could be partly attributable to weight loss or calorie restriction, not exclusively to carbohydrate reduction.

Future studies would need to clarify the following questions: 1) Long-term safety and sustainability of the effects (> 2 years) in metabolic and non-metabolic indications, 2) Differentiation of the mechanisms of action (carbohydrate reduction vs. fat quality vs. calorie restriction), 3) Targeted analysis of inflammation-associated endpoints (e.g. cytokines, endothelial function) in non-diabetic populations, 4) Randomised, controlled studies with sufficient power for psychiatric and oncological applications, 5) Standardisation of diet definitions (e.g. carbohydrate proportion, fat quality) to improve comparability. In addition, blinded study designs would be desirable to minimise bias.

7. What Remains Open

• Long-term safety: It is unclear whether a permanent ketogenic diet impairs kidney function, bone health or micronutrient supply.
• Individualisation: Which patient groups (e.g. according to genotype or metabolic type) benefit particularly or carry risks is scarcely researched.
• Combination therapies: Whether ketogenic nutrition acts synergistically with medications (e.g. in oncology or neurology) remains open.