The Ketogenic Diet: The Ke(y) - to Success? A Review of Weight Loss, Lipids, and Cardiovascular Risk

Background: Obesity remains a global epidemic with over 2.8 million people dying due to complications of being overweight or obese every year. The low-carbohydrate and high-fat ketogenic diet has a rising popularity for its rapid weight loss potential. However, most studies have a maximal 2-year follow-up, and therefore long-term adverse events remain unclear including the risk of Atherosclerotic Cardiovascular Disease (ASCVD).

Results: Based on current evidence on PubMed and Google Scholar, there is no strong indication ketogenic diet is advantageous for weight loss, lipid profile, and mortality. When comparing a hypocaloric ketogenic diet with a low-fat diet, there may be faster weight loss until 6 months, however, this then appears equivalent. Ketogenic diets have shown inconsistent Low-Density Lipoprotein (LDL) changes; perhaps from different saturated fat intake, dietary adherence, and genetics. Case reports have shown a 2-4-fold elevation in LDL in Familial hypercholesterolaemic patients which has mostly reversed upon dietary discontinuation. There is also concern about possible increased ASCVD and mortality: low (< 40%) carbohydrate intake has been associated with increased mortality, high LDL from saturated fats, high animal product consumption can increase trimethylamine N-oxide, and cardioprotective foods are likely minimally ingested.

Conclusion: Ketogenic diets have been associated with short-term positive effects including larger weight reductions. However, by 2 years there appears no significant differences for most cardiometabolic risk markers. Therefore, this raises the question, excluding those who have a critical need to lose weight fast, is this diet worth the potentially higher risks of ASCVD and mortality while further long-term studies are awaited?

Obesity remains a global epidemic with over 2.8 million people dying due to complications of being overweight (body mass index (BMI) 25 - 29.9 kg/m2) or obese (BMI > = 30 kg/m2) every year [1]. Despite public health strategies to combat obesity, the worldwide prevalence has tripled between 1975 and 2016 and not only is there an increasing number of adults becoming obese but also 39 million children under the age of five were reported as BMI > = 25 in 2020 [1]. It is well known that obesity is not only a major risk factor for multiple chronic diseases including ischaemic heart disease, stroke, diabetes mellitus [2], and certain cancers including breast, colorectal, and liver [3] but can also be a debilitating condition in isolation.

In the Obesity Society 2018 Position Statement, they describe obesity as a “multi-causal chronic disease… distinguished by multiple phenotypes, clinical presentations, and treatment responses” [4]. Various approaches to managing obesity have been implemented over the years including different dietary modifications, exercise regimes, emerging pharmacological treatments, and in severe cases, bariatric surgery. Different proposed diets have often been subject to scrutiny with a limited evidence base of concept or safety profile, often leading to polarising opinions about their appropriateness.

The low-carbohydrate (CHO) and the high-fat ketogenic diet have been utilized for over one hundred years; however, we still require further evidence of long-term safety. There are several contraindications including liver failure, pancreatitis, and rarer conditions such as porphyria, disorders of fat metabolism, primary carnitine deficiency, and pyruvate kinase deficiency. A common short-term side effect is “keto flu” including symptoms such as fatigue, headache, nausea, vomiting, and low exercise tolerance which are usually mild and self-limiting. However long-term adverse effects may include hepatic steatosis, nutritional deficiencies, and renal stones. As most studies have only followed up with patients for a maximum of 2 years, long-term adverse events and safety profiles remain unclear including the risk of atherosclerotic cardiovascular disease (ASCVD) [5].

To identify relevant studies and reviews, we used electronic databases including PubMed and Google Scholar and manually searched reference lists to reduce missing records up until 1 February 2024. We used the keywords “keto” and “ketogenic” diet to identify papers in the English language and reviewed guidelines of relevant societies. While there may be an individual set point for where patients become ketotic, we focussed on studies that prescribed reduced CHO intake to < 50 g/day. However clearly with dietary intervention, it can be hard to assure complete adherence.

The basis of the ketogenic diet

The Ketogenic diet was first introduced in 1921 in France as an adjunct treatment for refractory epilepsy in children [6]. During severe CHO restriction, the body’s glucose reserves become insufficient to fuel the central nervous system after approximately 3 days - 4 days. As fatty acids do not cross the blood-brain barrier, the brain requires an alternative source of energy.  Low insulin levels promote lipolysis and fatty acids undergo beta oxidation to form ketone bodies largely in the mitochondrial matrix in the liver, which can then be utilized by the brain as energy. The diet gained mainstream popularity in the 1970s and has recently received more public attention likely due to its rapid short-term weight loss potential [7-9]. In a 2023 survey of 1022 American adults aged 18 to 80 years old, 10% of those following a diet described this as low in CHO [10]. There are now different types of ketogenic diets characterized by their macronutrient content to try and improve adherence to this dietary plan. These include long-chain triglyceride, medium-chain triglyceride, and modified Atkins [5].  

Typically, the fat content in ketogenic diets is over 70-80% of total intake with very low CHO intake of ~20 - 50 g/ day or 5% - 10% total intake [11-13] with moderate protein intake (1.2 - 1.5 g/kg/day) [11,13]. This is almost the opposite of recommendations by the World Health Organisation and the European Societies of Cardiology (ESC) and Atherosclerosis (EAS) which advise total fat should not exceed 30% of total energy with saturated < 10% [14,15]. This advice is also echoed in the Public Health England, United Kingdom Government Dietary Recommendation - the Eatwell Guide [16].

While not focussed in this paper, the European Association of Obesity recently recommended A Very Low-Calorie Ketogenic Diet (VLCKD) as a possible treatment option for obesity. However, they stipulated this was a short-term intervention usually lasting 8 weeks - 12 weeks (or a weight loss target of 80%) under medical supervision in select patients needing immediate and substantial weight loss. Examples of potential patients include those with severe obesity and/or comorbidities such as preoperative period of bariatric surgery and cardiovascular and metabolic diseases. The diet which is split into 3 phases starts with initially a VLCKD characterized by daily 500 - 800 calories, 15 g - 30 g fat, < 50g CHOs, and 1 g - 1.5 g protein/kg of ideal body weight, which is a lower amount of fat consumed than in other ketogenic diets. This is then followed by a low-calorie diet (1200 - 1500 calories/day) where CHOs are reintroduced to the maintenance stage (1500 - 2000 calories/ day). Their meta-analysis of fourteen studies showed VLCKD was advantageous for faster weight loss for up to 1 year, but they expressed concern about possible adverse effects that may be found in the future [17].

Ketogenic diet and lipid profile

Ketogenic diets have shown an increase in High-Density Lipoprotein (HDL), reduction in triglycerides, and inconsistent changes in Low-Density Lipoprotein (LDL) cholesterol in patients with BMI > = 25 in short-term studies [8,12,18-20].

There are many possible explanations for these changes in lipid levels. The variation in LDL results may reflect variations in the CHO and fat quantity, variable dietary adherence, genetics, and different diet macronutrient prescriptions. As ketogenic diets require a high fat intake, they may be rich in saturated fat and/or trans fatty acids and animal protein which can in turn raise LDL [21]. Conversely, weight loss from any method can reduce LDL and triglycerides while increasing HDL [22]. Triglycerides may also be reduced due to low insulin levels as low quantities of CHO are consumed [12]. In addition, gene-nutrient interaction studies have demonstrated that genetics contribute to different responses in blood cholesterol to dietary intervention, however further studies are required to allow this to be applied to personalized nutrition [23]. For example, carriers of APOE4 have been found to have higher serum cholesterol levels after consuming a high-cholesterol diet compared to APOE2 carriers [24].

While dietary studies are usually performed in those with raised BMI, a meta-analysis of 3 randomized control studies investigating ketogenic diet in 42 participants with BMI < 25 kg/m2 was carried out by Joo, et al. While low sample size, results suggest increased total cholesterol, LDL, and HDL. Triglyceride levels were not significantly different with commencing the ketogenic diet; however, the 3 studies had varied results (mean difference -0.29 to 0.13 mmol/L) [25] and as baseline triglyceride levels were 0.6 - 0.86 mmol/L, triglyceride changes in any of these studies likely did not represent a strong clinically significant difference.  

While there is evidence ketogenic diets can increase LDL, there is limited information about the morphology and density of these particles. It is well known that small dense LDL cholesterol particles are significantly more atherogenic than larger particles [26] and therefore we cannot ascertain if there will be a direct elevated ASCVD risk even if LDL is increased.

Ketogenic diet and genetic disorders of lipid metabolism

It is well known that patients with genetic dyslipidaemias are at a higher risk of CVD and prematurely [15]. The basis of treatment for these patients is usually pharmacological and lifestyle management. However, as mentioned above there is further work required to establish if personalized nutrition plans would be indicated in relation to genetic profiles [23]. Currently, dietary advice for non-hyperchylomicronaemic genetic dyslipidaemic patients is similar to the general population with a recommendation for a Mediterranean-style diet, and in the presence of hypercholesterolemia, saturated fat intake should be reduced to < 7% of total energy [15].

The National Lipid Association has expressed considerable concern about the ketogenic diet in patients with hypercholesterolemia, especially Familial Hypercholesterolaemia (FH) as they may be predisposed to increased LDL. They also state ketogenic diets are contraindicated in patients with hyperchylomicronaemia as they must adhere to a very low-fat diet (< 15 – 20 g/ day or 10% - 15% total daily intake) due to their increased risk of acute pancreatitis [21]. 

Familial hypercholesterolaemia: Heterozygous Familial Hypercholesterolaemia (FH) is a common monogenic dyslipidaemia with a prevalence of at least 1 in 200 - 250 [27], caused by loss-of-function mutations in LDLR (95%) or APOB gene or gain-of-function in PCSK9. Patients have an up to ten-fold increased risk of coronary heart disease, many of whom develop premature disease. Therefore, early diagnosis and appropriate management are paramount to reduce this risk. Commonly used criteria to help identify patients with probable FH include the Simone Broome criteria and Dutch Lipid Clinic Network diagnostic criteria [15].

While there are few case reports of known FH patients consuming a ketogenic diet, there are a few showing dramatic elevations in LDL cholesterol ranging from 2-4-fold which returned to near baseline upon discontinuing their diet. Omar, et al. described an over 2-fold increase in LDL in a 45-year-old APOB missense mutation female upon starting a ketogenic diet with LDL rising from 211 mg/dL to 454 mg/dL. Interestingly upon following a “less strict” ketogenic diet, her LDL reduced to 276 mg/dL with no additional intervention [28]. A similar case has been described by Khovidhundkit, et al. with a 49-year-old lady with probable FH who experienced an almost 4-fold increase in LDL: LDL 133 mg/dL rising to 530 mg/dL which again reversed with the implementation of low saturated fat diet and also Ezetimibe [29]. Finally, Houttu, et al. described a 41-year-old APOB mutation male having their stable LDL rise from 2.9 mmol/L to 8.39 mmol/L which reversed to baseline upon discontinuation of this diet [30].

Familial dysbetalipoproteinaemia: Familial dysbetalipoproteinaemia (i.e.type III hyperlipoproteinaemia) is a rare autosomal recessive disorder characterized by raised total cholesterol and triglycerides, usually both approximately 7 - 10 mmol/L. Clinical signs such as tuberoeruptive xanthomas or palmar xanthomata can develop in severe cases and patients can be diagnosed by APOE genotyping [15].  Patients are known to be at an increased risk of Coronary Artery Disease (CAD) and it is known that there is a strongly increased risk of premature familial CAD with elevating triglycerides [31].

Case reports have shown a ketogenic diet in these patients may also exaggerate an increase in LDL levels [28, 32]. Omar, et al. described 2 patients with the ApoE3/4 variant, a 58-year-old male who had an over 3-fold increase in LDL with a baseline 132 mg/dL rising to > 455 mg/dL, and a 53-year-old male whose LDL increased approximately 1.5 fold despite losing 100 pounds on a ketogenic diet: 212 mg/dL to 317 mg/dL [28]. Goldberg, et al. described a 69-year-old female with APOE2 homozygosity who after consuming < 20 grams CHO/day for 6 weeks, developed marked dyslipidaemia with total cholesterol 947 mg/dL, triglycerides 1109 mg/dL and LDL 683 mg/dL [32]. While the patient’s baseline lipid profile was not stated, the patient was only referred for genetic testing with these results and she developed palmar xanthomas upon commencing her diet, and therefore we can assume her baseline lipids were much less severely deranged.  It is well known the majority of APOE2/2 subjects are either normolipidaemic or hypocholesterolaemic and it is thought a genetic, hormonal, or environmental factor can precipitate the dyslipidaemia [33] for which the patient already had many baseline risk factors including sex, obesity and insulin resistance.

Ketogenic diet and weight loss

The National Lipid Association Nutrition and Lifestyle Task Force has stated that personal preference should be considered when selecting a weight loss diet after being presented with the different options [21]. This is mostly due to the wide variation in weight loss achieved in different trials.

When comparing low CHO ketogenic to low-fat diets, studies have suggested low CHO diets may result in faster weight loss in the first 6 months, however, longer-term the weight loss effects appear equivalent in both normoglycaemic [8,12,18] and impaired glycaemic control/ type 2 diabetics patients [12,19,20]. It seems likely the initial weight loss is primarily due to body water loss [5,34,35] which may be due to increased renal sodium and water loss secondary to ketosis and glycogen depletion [35]. Ketogenic diets also cause larger lean body mass loss which may be reduced by an increase in protein intake [12,36,37].

It is well known that adherence to diets can be challenging, especially very low/ low CHO diets [12,18-20]. Rafiullah, et al. performed a meta-analysis of 10 studies encompassing 320 patients on a very low CHO ketogenic diet. However, in only 2 of the studies, patients were able to achieve the desired dietary cut-off for a ketogenic diet [20]. Mansoor, et al. also noted that in their meta-analysis, 7 studies that reported macronutrients at the study end date had varied CHO intake ranging from 9% - 40% of total energy also showing a lack of adherence [18]. Clearly given variable dietary adherence, data should be interpreted with caution and possibly limits its generalisability.

Ketogenic diet and atherosclerotic cardiovascular risk

The 2013 Joint American Heart Association/ American College of Cardiology/ The Obesity Society Guideline for management of overweight and obese adults felt there was insufficient evidence to comment on the cardiovascular risk factor effects of these diets, and there remain gaps in the evidence today due to lack of long-term studies [22].

As previously described, the ESC/EAS recommends a Mediterranean-style diet with CHO intake between 45% - 55% [15]. Siedelmann, et al. performed a meta-analysis of 432,179 participants which showed a U-shaped curve with CHO intake and mortality. They noted marked increases in mortality with low CHO (< 40% of total intake) and high CHO (> 70%) diets. However, they noted food type modified this, with plant-derived protein and fat such as vegetables, nuts, and whole-grain breads associated with lower mortality compared to animal-derived products [38]. There is a potentially increased ASCVD risk and mortality by increased trimethylamine N-oxide exposure (TMAO) in animal products [39] which can be seen in patients consuming ketogenic diets both acutely postprandially and chronically [40].  

In addition, typically there is limited emphasis on the type of fat consumed in ketogenic diets. This may result in high saturated fat intake, higher LDL cholesterol, and increased ASCVD risk [15,21]. There also will likely be a reduction in cardioprotective food intake such as fiber-rich fruits, vegetables, and whole grains [15]. The EAS/ESC promotes low saturated fat intake [15] and the American Heart Association supports omega 6 polyunsaturated intake of at least 5% - 10% of energy intake to help reduce CHD risk [41].

By approximately 2 years, there are no differences in most cardiometabolic risk factors, and therefore with the potential increase in ASCVD and mortality, there is no evidence to routinely recommend this diet [21].

Ketogenic diets have been associated with a positive reduction in multiple cardiovascular risk factors including triglycerides, weight, and an increase in HDL in the short term. However, by 2 years there are no significant differences in most cardiometabolic risk factors and low carbohydrate intake (< 40%) has been associated with increased mortality. Moreover, there has been noted concern regarding the potential increased LDL, especially in those with genetic disorders of lipid metabolism who already have an increased premature ASCVD risk. While it is unclear if the LDL is directly atherogenic given its wide heterogeneous composition, the National Lipid Association and EAS/ESC are not recommending the ketogenic diet for routine use currently.

Long-term studies are required to understand the true effects of a ketogenic diet, especially on ASCVD and mortality, as well as look at patients’ quality of life and adherence. While patient preference is important, currently there is no evidence this diet should be preferentially adopted routinely by the public. However, a short-term ketogenic diet could be an important tool utilized by medical professionals in specific clinical scenarios, but they must weigh up the potential benefits and risks.

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