Oreo Cookie Treatment Lowers LDL Cholesterol More Than High-Intensity Statin therapy in a Lean Mass Hyper-Responder on a Ketogenic Diet: A Curious Crossover Experiment

Abstract

Key Aspects

• Identification of Lean Mass Hyper-Responders (LMHR): The abstract introduces the concept of Lean Mass Hyper-Responders (LMHR), a specific group of individuals who experience a significant increase in LDL cholesterol (LDL-C) when following carbohydrate-restricted diets. This group is characterized by LDL-C levels equal to or greater than 200 mg/dL, HDL cholesterol equal to or greater than 80 mg/dL, and triglycerides equal to or less than 70 mg/dL. These individuals are typically lean and metabolically healthy, and the extent of their LDL-C increase is inversely related to their body mass index (BMI).
• Lipid Energy Model (LEM) Hypothesis: The abstract presents the Lipid Energy Model (LEM) as a potential explanation for the LMHR phenotype. The LEM suggests that in states of depleted liver glycogen and low body fat, there's an increased production and turnover of very-low-density lipoprotein (VLDL) particles, which are converted to LDL particles. This process is thought to be a mechanism to supply energy throughout the body when carbohydrate intake is restricted.
• Crossover Experiment Design: The core of the abstract describes a single-subject crossover experiment. The study aimed to compare the effects of adding carbohydrates (in the form of Oreo cookies) versus high-intensity statin therapy (rosuvastatin 20 mg) on LDL-C levels in an LMHR individual following a ketogenic diet. The experiment consisted of two arms: 1) a 16-day period of Oreo supplementation (100g/day of additional carbohydrates) while maintaining ketosis with exogenous ketones, and 2) a 6-week period of rosuvastatin therapy. A 3-month washout period on a ketogenic diet separated the two arms.
• Primary Outcome: LDL-C Reduction: The primary outcome measured was the change in LDL-C levels. The abstract reports a significant reduction in LDL-C with Oreo supplementation (71% reduction, from 384 mg/dL to 111 mg/dL) compared to statin therapy (32.5% reduction, from 421 mg/dL to 284 mg/dL). These findings suggest that, in this specific case, carbohydrate addition was more effective at lowering LDL-C than a high-intensity statin.
• Implications and Caution: The abstract concludes that the results, while striking, are consistent with the Lipid Energy Model and warrant further investigation into the LMHR phenotype. It emphasizes that this is a single-subject experiment and should not be interpreted as general health advice. The authors explicitly state that the findings should "provoke further research and not be seen as health advice."

Strengths

• Clear and Concise Introduction of LMHR

  The abstract effectively introduces the concept of Lean Mass Hyper-Responders (LMHR) and clearly defines the lipid profile that characterizes this phenotype.

  "Recent research has identified a unique population of ‘Lean Mass Hyper-Responders’ (LMHR) who exhibit increases in LDL cholesterol (LDL-C) in response to carbohydrate-restricted diets to levels ≥ 200 mg/dL" (Page 1)
• Well-Defined Study Design

  The abstract provides a succinct yet comprehensive overview of the study design, including the two treatment arms, washout period, and monitoring methods.

  "The study was designed as follows: after a 2-week run-in period on a standardized ketogenic diet, study arm 1 consisted of supplementation with 12 regular Oreo cookies" (Page 1)
• Quantifiable Results

  The abstract presents the key findings with specific numerical values, making the results easy to understand and compare.

  "Baseline LDL-C was 384 mg/dL and reduced to 111 mg/dL (71% reduction) after Oreo supplementation." (Page 1)
• Appropriate Cautionary Statement

  The abstract includes a crucial disclaimer that the findings are from a single-subject experiment and should not be generalized or taken as health advice.

  "This dramatic metabolic demonstration, consistent with the lipid energy model, should provoke further research and not be seen as health advice." (Page 1)

Suggestions for Improvement

• Clarify Exogenous Ketone Use

  High impact. This affects the study's internal validity and reproducibility. The Abstract section is crucial for conveying the core methods and findings; therefore, including this clarification here ensures readers have a complete understanding of the experimental conditions from the outset.

  "Throughout this arm, ketosis was monitored and maintained at levels similar to the subject’s standard ketogenic diet using supplemental exogenous d-β-hydroxybutyrate supplementation four times daily." (Page 1)

  Implementation: Specify the type and brand of exogenous ketones used. For example: "Throughout this arm, ketosis was monitored and maintained at levels similar to the subject’s standard ketogenic diet using supplemental exogenous d-β-hydroxybutyrate (brand name, American Ketone) supplementation four times daily."

• Elaborate on the Lipid Energy Model

  Medium impact. This would enhance reader comprehension, particularly for those unfamiliar with the model. While the Introduction section likely provides more detail, a slightly expanded explanation in the Abstract would improve its stand-alone clarity.

  "The lipid energy model has been proposed as one explanation for LMHR phenotype and posits that there is increased export and subsequent turnover of VLDL to LDL particles" (Page 1)

  Implementation: Add a sentence or two providing a more detailed explanation of the Lipid Energy Model. For example: "The lipid energy model has been proposed as one explanation for LMHR phenotype and posits that there is increased export and subsequent turnover of VLDL to LDL particles to meet systemic energy needs in the setting of hepatic glycogen depletion and low body fat. This model suggests that increased lipid trafficking, rather than dietary fat intake, is the primary driver of elevated LDL-C in LMHR individuals."

• Mention Subject Characteristics

  Low impact. While the Introduction section will cover this, briefly mentioning the subject's characteristics in the Abstract would provide context. This is particularly relevant since it's a single-subject study.

  "This single subject crossover experiment aimed to test the hypothesis that adding carbohydrates, in the form of Oreo cookies, to an LMHR subject" (Page 1)

  Implementation: Include a brief phrase about the subject's characteristics. For example: "This single subject (a 27-year-old male with a history of ulcerative colitis managed with a ketogenic diet) crossover experiment aimed to test..."

Introduction

Key Aspects

• Background on Ketogenic Diets and LDL-C: The Introduction begins by establishing the context of the study, highlighting the growing interest in carbohydrate-restricted diets, particularly ketogenic diets (KD), for managing obesity-related conditions like type 2 diabetes and other health issues such as epilepsy, neurodegenerative diseases, mental health conditions, and polycystic kidney disease. It acknowledges the potential of KDs but also points out a significant concern: the elevation of LDL-cholesterol (LDL-C), a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD).
• Introduction of Lean Mass Hyper-Responders (LMHR): Building on the previous sections analysis, this section introduces the concept of Lean Mass Hyper-Responders (LMHR). This specific phenotype is characterized by a significant increase in LDL-C levels (≥200 mg/dL) when adhering to a carbohydrate-restricted diet, particularly a ketogenic diet. This elevation is accompanied by high HDL cholesterol (≥80 mg/dL) and low triglycerides (≤70 mg/dL). The Introduction emphasizes that this phenomenon is more common in lean, metabolically healthy individuals and that the magnitude of LDL-C increase is inversely correlated with body mass index (BMI).
• Reiteration of the Lipid Energy Model (LEM): The Introduction reiterates the Lipid Energy Model (LEM), previously introduced in the Abstract, as a potential explanation for the LMHR phenotype. The LEM proposes that in a state of carbohydrate restriction and low body fat, the body increases the production and turnover of very-low-density lipoprotein (VLDL) particles to meet energy demands. These VLDL particles are subsequently converted to LDL particles, leading to elevated LDL-C levels. The model suggests that this increased lipid trafficking is a physiological adaptation to energy needs in the absence of sufficient carbohydrates.
• Study Objective and Hypothesis: This section clearly states the study's objective, which is to test the hypothesis that adding carbohydrates, specifically in the form of Oreo cookies, to the diet of an LMHR individual on a ketogenic diet will reduce LDL-C levels. The hypothesis is that this reduction will be comparable to or greater than that achieved with high-intensity statin therapy (rosuvastatin 20 mg). This objective directly addresses the core issue of elevated LDL-C in LMHR individuals and proposes a potential dietary intervention.
• Connection to Previous Sections: The Introduction effectively connects to the Abstract by reiterating the key concepts of LMHR and the LEM. It builds upon the Abstract's concise overview by providing a more detailed explanation of the context, problem, and proposed solution. This connection ensures a smooth transition for the reader and reinforces the study's rationale.

Strengths

• Clear Contextualization

  The Introduction effectively establishes the context of the study by highlighting the increasing use of ketogenic diets and the associated concern of elevated LDL-C.

  "Carbohydrate-restricted diets, especially ketogenic diets (KD) hold promise for the treatment of obesity-related chronic health conditions" (Page 1)
• Logical Flow from Abstract

  The Introduction builds upon the Abstract seamlessly, reiterating and expanding upon the concepts of LMHR and the Lipid Energy Model.

  "Recent research has identified a unique population of ‘Lean Mass Hyper-Responders’ (LMHR) who exhibit increases in LDL cholesterol (LDL-C)" (Page 1)
• Well-Defined Research Problem

  The Introduction clearly defines the research problem: the elevation of LDL-C in LMHR individuals on ketogenic diets and the need for effective interventions.

  "However, this dietary strategy may cause elevated LDL-cholesterol (LDL-C), a risk factor for atherosclerotic cardiovascular disease (ASCVD) [5]." (Page 1)

Suggestions for Improvement

• Expand on Multifactorial Nature of LDL-C Elevation

  Medium impact. This affects the nuance of the discussion and the framing of the research question. While the Introduction section briefly mentions the multifactorial nature of LDL-C elevation, it could benefit from a slightly more detailed discussion of these factors. This would provide a more comprehensive understanding of the complexity of the issue and further justify the focus on the Lipid Energy Model.

  "While the causes of LDL-C rises, when they occur, are likely multifactorial" (Page 1)

  Implementation: Add a sentence or two elaborating on the other potential factors contributing to LDL-C elevation on ketogenic diets. For example: "While the causes of LDL-C rises, when they occur, are likely multifactorial, including genetic predisposition, dietary fat composition, and individual metabolic responses, the specific phenotype observed in LMHR individuals suggests a unique underlying mechanism."

• Clarify the Novelty of the Study

  High impact. This affects the perceived significance and contribution of the study to the field. The Introduction should more explicitly state what is novel about this particular study compared to previous research on LMHR and the Lipid Energy Model. This would help readers understand the unique contribution of this work.

  "This single subject crossover experiment aimed to test the hypothesis that adding carbohydrates, in the form of Oreo cookies" (Page 1)

  Implementation: Add a sentence highlighting the novelty of the study. For example: "While previous studies have investigated the LMHR phenotype and the Lipid Energy Model, this study is the first to directly compare the effects of carbohydrate supplementation and high-intensity statin therapy on LDL-C in an LMHR individual following a ketogenic diet."

• Briefly Mention Ethical Considerations

  Low impact. Given the unusual nature of the intervention (Oreo cookies), briefly mentioning the ethical considerations in the Introduction would preemptively address potential concerns. This is particularly relevant for a single-subject study involving dietary manipulation.

  "This single subject crossover experiment aimed to test the hypothesis that adding carbohydrates" (Page 1)

  Implementation: Add a brief phrase acknowledging the ethical considerations. For example: "This single-subject crossover experiment, conducted with full ethical considerations and oversight, aimed to test..."

Materials and Methods

Key Aspects

• Subject Description: This section details the characteristics of the research subject, a 27-year-old male who had been following a ketogenic diet (KD) for 1520 days prior to the study to manage ulcerative colitis. The subject's condition was in symptomatic and histologically confirmed remission, consistent with preclinical data. Notably, his baseline BMI was 20.8 kg/m2, and his LDL-C levels had previously peaked at 545 mg/dL on a low-saturated fat KD. Prior genetic testing revealed no pathological variants related to dyslipidemia, and a coronary artery CT angiogram showed no evidence of coronary plaque. The subject is also identified as a medical student, PhD researcher, and the primary author of the manuscript.
• Baseline Diet and Lifestyle: The subject's baseline diet was designed to mimic his habitual whole-foods ketogenic eating pattern. The diet consisted of 80% of calories from fat (with a 1:3 saturated-to-unsaturated fatty acid ratio), 18% from protein, and 2% from carbohydrates. Specific dietary components included seafood, red meat, extra virgin olive oil, dairy, dark chocolate, nuts, and low-carbohydrate vegetables. Meals were consumed within an eight-hour daily feeding window. The subject's physical activity was standardized throughout most of the experiment, involving 6-7 hours of calisthenics and weight training weekly, along with approximately 10,000 steps per day. In the final week of the statin arm, his daily step count was increased to 20,000 as a sub-experiment.
• Oreo Supplementation Intervention: This section describes the first intervention arm, where the subject consumed 12 Oreo cookies daily (providing 100g of additional carbohydrates) for 16 days. The rationale for choosing Oreos was to demonstrate that the presence of carbohydrates, rather than their quality, is the primary factor in reducing LDL-C in the LMHR phenotype. Exogenous ketones (d-β-hydroxybutyrate) were supplemented to maintain ketosis throughout this arm, with dosages adjusted to maintain ketone levels similar to those achieved during the baseline ketogenic diet.
• Statin Therapy Intervention: The second intervention arm involved the administration of 20 mg of rosuvastatin daily for six weeks. This duration was chosen in consultation with the subject's primary care provider and a cardiologist to allow LDL-C levels to reach a steady state. A 3-month washout period on a ketogenic diet separated the Oreo and statin arms to ensure no carry-over effects.
• Blood Work and Monitoring: Lipid panels were collected weekly after a 14-hour fast. The focus was primarily on LDL-C as the most clinically relevant marker. The subject's historical lipid data on a KD showed a consistent pattern of large buoyant LDL particles. During the Oreo arm, triplicate labs were collected on sequential days (14, 15, and 16) to confirm lipid changes and trends.
• Ethics and Safety: The experiment was conducted with the full knowledge and cooperation of the subject's primary care provider and a lipidologist consultant. All side effects were to be reported, and the experiment would be aborted if the subject's health was jeopardized. The Harvard Medical School Institutional Review Board exempted this project from being considered human clinical trials research due to it being n=1 researcher self-experimentation.

Strengths

• Detailed Subject Background

  The section provides a comprehensive background of the research subject, including his medical history, dietary habits, and prior testing, which is crucial for understanding the context of this single-subject experiment.

  "The research subject of this experiment is a 27-year-old male who adopted a KD for the treatment of ulcerative colitis" (Page 2)
• Clear Intervention Descriptions

  The descriptions of both the Oreo supplementation and statin therapy arms are detailed and well-defined, including dosages, durations, and rationales.

  "Oreo supplementation arm: Oreo cookies were chosen as a canonical "unhealthy food" and as a demonstration that carbohydrate quality" (Page 3)
• Standardized Baseline Diet

  The establishment of a standardized baseline diet with specific macronutrient ratios and food components helps control for dietary variability and strengthens the internal validity of the study.

  "The baseline diet was designed to be similar to the subject’s everyday whole foods ketogenic eating pattern" (Page 2)

Suggestions for Improvement

• Clarify Exogenous Ketone Brand and Purity

  High impact. This affects the study's internal validity and reproducibility. The Methods section particularly needs this detail as it forms the foundation for evaluating the study's rigor. Specifying the brand and purity of the exogenous ketones used is crucial for ensuring the accuracy and replicability of the study, especially since different formulations can have varying effects. Adding this methodological information would strengthen the paper by providing essential context for interpreting the results and enabling other researchers to build upon this work effectively. This enhancement would also facilitate meta-analyses and systematic reviews in the field. Ultimately, clarifying these methodological details would significantly improve the study's scientific contribution by ensuring its findings can be properly contextualized and replicated.

  "Throughout the Oreo supplementation arm, exogenous ketones (free d-β-hydroxybutyrate [B-HB], American Ketone) were supplemented" (Page 3)

  Implementation: Specify the brand and purity of the exogenous ketones used. For example: "Throughout the Oreo supplementation arm, exogenous ketones (free d-β-hydroxybutyrate [β-HB], American Ketone, >98% purity) were supplemented..."

• Provide Rationale for Washout Period Duration

  Medium impact. This affects the study's internal validity and transparency. The Methods section is the appropriate place for this explanation as it justifies a key methodological choice. While a 3-month washout period is mentioned, the rationale behind this specific duration is not provided. Explaining the reasoning would enhance the transparency of the study design. Including this justification would strengthen the paper by demonstrating a thoughtful approach to minimizing potential carry-over effects between interventions, thereby increasing confidence in the observed results. This would also help readers understand the considerations involved in designing such a study. Ultimately, providing a clear rationale for the washout period duration would improve the study's methodological rigor and enhance its overall credibility.

  "Following the Oreo arm, the subject underwent a 3-month washout period of sustained KD" (Page 3)

  Implementation: Add a sentence or two explaining the rationale for the 3-month washout period. For example: "A 3-month washout period on a ketogenic diet was chosen based on previous research suggesting that this duration is sufficient for lipid profiles to return to baseline levels after dietary changes and to minimize any potential carry-over effects from the Oreo intervention."

• Elaborate on Blood Collection Procedure

  Low impact. This affects the completeness of the methodological description. While the Methods section mentions blood collection, providing more details about the procedure would enhance the overall completeness of the study's methodology. This information is relevant to the Methods section as it pertains to data collection. Adding these details would strengthen the paper by allowing for a more thorough understanding of how the data were obtained, which can be relevant for interpreting the results. This would also contribute to the study's transparency and reproducibility. Ultimately, providing a more detailed description of the blood collection procedure would enhance the methodological rigor of the study.

  "Lipid panels were collected at least weekly after a 14 h water-only fast at ~8:30." (Page 4)

  Implementation: Add details about the blood collection procedure. For example: "Blood samples were collected via venipuncture by a trained phlebotomist into EDTA tubes. Samples were centrifuged within 30 minutes of collection, and plasma was separated and stored at -80°C until analysis."

Non-Text Elements

Figure 1. Crossover experiment timeline. Following a 2-week run-in period on...

Full Caption

Figure 1. Crossover experiment timeline. Following a 2-week run-in period on his habitual keto-genic diet, the subject underwent 16 days of Oreo cookie supplementation, followed by a 3 month washout period and, finally, 6 weeks of 20 mg rosuvastatin daily.

Figure/Table Image (Page 3)

First Reference in Text

Statin therapy arm: Rosuvastatin 20 mg daily was chosen after consultation with the subject's primary care provider and consultant cardiologist, who recommended a 6-week trial sufficient to give LDL-C levels time to reach a steady state (Figure 1).

Description

• Crossover experiment: This is a type of experiment where the same subject receives different treatments one after another to see how each treatment affects them. It's like testing different types of fuel in the same car to see which one makes it run better. In this case, the 'treatments' are different diets and a medication.
• Ketogenic diet: This is a diet that is very low in carbohydrates (sugars and starches) and high in fats. The idea is to change the body's main fuel source from carbohydrates to fats, which can lead to a state called 'ketosis', where the body produces molecules called 'ketones' for energy.
• Run-in period: This is an initial period where the subject follows a specific diet or treatment to establish a baseline. It's like setting a 'zero' point on a scale before you start weighing things. Here, the subject followed their normal ketogenic diet for two weeks to get their body used to it before the experiment started.
• Oreo cookie supplementation: This means that the subject added a certain number of Oreo cookies to their diet each day. This is one of the 'treatments' being tested. It's a way to introduce carbohydrates into the diet in a controlled way.
• Washout period: This is a period between treatments where the effects of the previous treatment are allowed to wear off. It's like cleaning the car engine thoroughly before testing a new type of fuel. Here, the subject went back to their ketogenic diet for three months to let the effects of the Oreo cookies disappear.
• Rosuvastatin: This is a type of medication called a 'statin'. Statins are used to lower cholesterol levels in the blood. Cholesterol is a type of fat that can build up in blood vessels and cause problems. Specifically, Rosuvastatin is an HMG-CoA reductase inhibitor, an enzyme involved in the synthesis of cholesterol in the liver. Rosuvastatin is one of the most potent statins available.
• LDL-C: This stands for 'low-density lipoprotein cholesterol'. It's often called 'bad' cholesterol because high levels of it are linked to an increased risk of heart disease. LDL particles carry cholesterol to cells throughout the body. The '-C' specifically refers to the amount of cholesterol within LDL particles.

Scientific Validity

• Single-subject design: The study uses an n-of-1 design, which limits the generalizability of the findings. While this design can provide valuable insights into individual responses, it does not allow for statistical inference to a larger population.
• Crossover design: The crossover design is appropriate for this experiment as it allows the subject to serve as their own control, reducing inter-individual variability. However, the validity of the crossover design relies on the assumption that the effects of each intervention are fully reversible within the washout period.
• Washout period duration: The 3-month washout period between the Oreo supplementation and statin therapy arms seems sufficient to eliminate the dietary effects of the Oreos. However, it might be worth citing literature to support the adequacy of this duration for a complete return to baseline, especially considering potential lingering effects of dietary interventions.
• Statin therapy duration: The 6-week duration of statin therapy is justified by the consultation with a cardiologist and is consistent with the time it typically takes for LDL-C levels to stabilize on statin therapy. This duration is likely sufficient to observe the effect of rosuvastatin on LDL-C.
• Dosage of Rosuvastatin: The 20 mg daily dose of rosuvastatin is a standard high-intensity dose, appropriate for evaluating its lipid-lowering efficacy.

Communication

• Clarity of timeline: The caption clearly outlines the sequence of the experiment: run-in, Oreo supplementation, washout, and statin therapy. This provides a good overview of the study design.
• Specificity of interventions: The caption specifies the duration and nature of each intervention (16 days of Oreos, 3 months washout, 6 weeks of 20 mg rosuvastatin). This level of detail is helpful for understanding the experimental protocol.
• Reference to Figure 1: The reference text correctly directs the reader to Figure 1 for a visual representation of the experiment timeline. This enhances comprehension and allows for a quick grasp of the study's structure.
• Justification for statin duration: The reference text explains the rationale for the 6-week statin trial, citing expert consultation and the need for LDL-C levels to reach a steady state. This provides context and strengthens the study's methodology.
• Missing information: The caption could benefit from explicitly stating that the ketogenic diet was maintained throughout the washout period and the statin therapy arm. This would further clarify the experimental conditions.

Table 1. Participants daily average dietary macronutrients by study arm. Food...

Full Caption

Table 1. Participants daily average dietary macronutrients by study arm. Food was consumed in two roughly equal meals, at ~10:30 and ~18:30, daily. Baseline diet macronutrients equal 80%, 18%, and 2% kCal from fat, protein, and carbohydrate.

Figure/Table Image (Page 3)

First Reference in Text

80% kCal was derived from fat, with a 1:3 saturated-to-unsaturated fatty acid ratio, 18% kCal from protein, and 2% kCal from carbohydrate (Table 1).

Description

• Macronutrients: These are the main components of food that provide energy and building blocks for the body. Think of them as the 'big three' in nutrition: fats, proteins, and carbohydrates. Each one plays a different role, like different workers in a factory.
• Study arm: This refers to the different phases or groups in an experiment. In this study, it's like having different 'legs' of a journey, where each leg involves a different diet. The study arms here are the baseline ketogenic diet, the Oreo supplementation period, and the statin period.
• kCal: This stands for 'kilocalories', which is a unit of energy. It's commonly referred to as 'calories' in everyday language. It's like measuring the amount of fuel a food provides to the body.
• Saturated-to-unsaturated fatty acid ratio: Fats are made up of fatty acids, which can be saturated or unsaturated. Think of it like comparing straight (saturated) to bent (unsaturated) sticks. The ratio tells you the proportion of each type. In this case, a 1:3 ratio means for every 1 saturated fatty acid, there are 3 unsaturated fatty acids in the baseline diet.
• Baseline diet: This is the subject's usual diet before any experimental changes. It serves as a starting point for comparison. Here, the baseline diet is a ketogenic diet, meaning it's high in fat (80% of calories), moderate in protein (18% of calories), and very low in carbohydrates (2% of calories).
• Daily average: The table shows the average amounts of each macronutrient consumed each day during the different study arms. The values shown are averages across the whole period of each study arm.

Scientific Validity

• Quantification of macronutrients: The table provides specific values for macronutrients (fat, protein, carbohydrates, fiber) in grams and provides total calories, which is crucial for a dietary intervention study. This allows for a precise understanding of the dietary manipulation in each study arm.
• Control of dietary intake: The study attempts to control dietary intake by providing specific guidelines and tracking the participant's consumption. However, the reliance on self-reported data introduces the potential for inaccuracies in dietary reporting.
• Standardization of meal timing: The consistent meal timing (two meals at ~10:30 and ~18:30) helps to minimize variability in metabolic responses that could be influenced by meal frequency and timing.
• Saturated-to-unsaturated fat ratio: Specifying the ratio of saturated to unsaturated fats in the baseline diet is important as these types of fats can have different metabolic effects. The 1:3 ratio provides further detail about the composition of the dietary fat.
• Lack of detail on dietary assessment method: The description does not specify how dietary intake was assessed (e.g., food diary, 24-hour recall). This information is essential for evaluating the accuracy and reliability of the reported macronutrient values.

Communication

• Clear table structure: The table is well-organized, with clear column headings for each study arm (Baseline, Oreo, Statin) and rows for each macronutrient category. This structure facilitates easy comparison of dietary intake across the different phases of the experiment.
• Concise caption: The caption provides a brief overview of the table's content, including the timing of meals and the macronutrient breakdown of the baseline diet.
• Use of appropriate units: The table uses appropriate units for each macronutrient (grams) and for total energy intake (calories), making the data readily interpretable.
• Inconsistent terminology: The caption refers to "kCal" while the table uses "Calories." Using consistent terminology (either "Calories" or "kCal") throughout the document would improve clarity.
• Lack of explanation for abbreviations: The table uses abbreviations like "SAT," "MUFA," and "PUFA" without defining them. While these may be familiar to experts in the field, providing a key or footnote defining these abbreviations would enhance the table's accessibility to a broader audience.

Results

Key Aspects

• Significant LDL-C Reduction with Oreo Intervention: The Results section begins by reporting a substantial decrease in LDL-C levels following the Oreo cookie intervention. The subject's LDL-C dropped from a baseline of 384 mg/dL to 111 mg/dL after 16 days of consuming 12 Oreo cookies daily, representing a 71% reduction. This finding is significant as it demonstrates a marked improvement in a key cardiovascular risk marker through a dietary intervention involving the addition of carbohydrates.
• Comparison with Statin Therapy: The study also compared the effects of the Oreo intervention with those of high-intensity statin therapy (rosuvastatin 20 mg daily). After a washout period, the subject's LDL-C returned to 421 mg/dL and was subsequently reduced to 284 mg/dL after 4 weeks of statin treatment, representing a 32.5% reduction. This result highlights that the Oreo intervention was more effective in lowering LDL-C than the statin therapy in this particular case.
• Time Course of LDL-C Changes: The Results section details the time course of LDL-C changes during both interventions. During the Oreo arm, LDL-C decreased to 308 mg/dL in the first week and further declined to 140 mg/dL by day 14, with subsequent measurements confirming the reduction. In the statin arm, LDL-C levels plateaued after 4 weeks, with a slight increase observed in the final week when physical activity was increased.
• Beta-Hydroxybutyrate (B-HB) Levels: The section reports on the subject's B-HB levels, a marker of ketosis, during the Oreo intervention. One hour after waking and before the first exogenous ketone dose, B-HB levels remained between 0.3-0.7 mM in the first week, suggesting that the subject was still in a state of mild ketosis despite the added carbohydrates. In the second week, B-HB levels dropped to 0.2-0.3 mM, indicating a gradual repletion of hepatic glycogen stores.
• Weight Changes: The Results section notes that the subject gained 1.5 kg during the Oreo intervention arm. This weight gain is likely attributable to a combination of increased carbohydrate intake, glycogen replenishment, and associated water retention. The subject's weight returned to baseline after the washout period on a ketogenic diet.
• Methodological Approach: The Results section reiterates the methodological approach, emphasizing the use of triplicate labs collected on sequential days during the Oreo arm to confirm lipid changes and trends. This approach was employed due to the shorter duration of the Oreo intervention compared to the statin arm.

Strengths

• Clear Presentation of Key Findings

  The Results section clearly presents the primary findings of the study, highlighting the significant reduction in LDL-C with Oreo supplementation and comparing it to the effects of statin therapy.

  "Thus, 16 days of consuming 12 Oreo cookies/d decreased the subject's LDL-C by 273 mg/dL, a 71% drop" (Page 4)
• Detailed Time Course Data

  The section provides a detailed time course of LDL-C changes during both interventions, allowing for a comprehensive understanding of the dynamics of lipid responses.

  "After the second week of Oreo supplementation, the subject's LDL-C dropped to 140 mg/dL (day 14)" (Page 4)
• Inclusion of B-HB Levels

  The reporting of B-HB levels during the Oreo intervention provides valuable insights into the subject's metabolic state and the impact of carbohydrate addition on ketosis.

  "During this time, B-HB one hour after waking, before the first ketone dose, remained at 0.3-0.7 mM" (Page 4)

Suggestions for Improvement

• Provide More Context for B-HB Results

  Medium impact. This affects the interpretation of the results and their connection to the broader context of the study. While the Results section mentions B-HB levels, it could benefit from a more detailed explanation of their significance in relation to the study's hypothesis and the Lipid Energy Model. This is particularly relevant for the Results section as it presents the core findings related to metabolic state. Adding a brief explanation of how B-HB levels relate to hepatic glycogen stores and the expected metabolic shifts would enhance the reader's understanding of the findings. This would also strengthen the connection between the observed results and the theoretical framework of the study. Ultimately, providing more context for the B-HB results would improve the interpretation of the findings and reinforce their relevance to the study's overall conclusions.

  "During this time, B-HB one hour after waking, before the first ketone dose, remained at 0.3-0.7 mM" (Page 4)

  Implementation: Add a sentence or two explaining the significance of B-HB levels in the context of the study. For example: "The observed B-HB levels during the first week of Oreo supplementation suggest that despite the addition of carbohydrates, the subject remained in a state of mild ketosis, indicating that hepatic glycogen stores were not yet fully repleted. The subsequent decrease in B-HB levels in the second week aligns with the expected gradual repletion of glycogen, consistent with the predictions of the Lipid Energy Model."

• Clarify the Rationale for Triplicate Labs

  Low impact. This affects the clarity of the methodological approach described in the Results section. While the Results section mentions the use of triplicate labs, it could briefly reiterate the rationale for this approach, which was previously explained in the Methods section. This clarification belongs in the Results section as it pertains to the specific data presented. Briefly restating the rationale would enhance the clarity of the Results section and help readers understand the reasoning behind the chosen methodology. This would also reinforce the rigor of the study design. Ultimately, clarifying the rationale for triplicate labs would improve the overall transparency and understandability of the Results section.

  "triplicate labs were collected on sequential days 14, 15, and 16 of the Oreo arm to confirm lipid changes and trends" (Page 4)

  Implementation: Add a brief phrase reiterating the rationale for triplicate labs. For example: "As described in the Methods, triplicate labs were collected on sequential days (14, 15, and 16) during the Oreo arm to ensure the accuracy and consistency of lipid measurements given the shorter duration of this intervention."

• Report Statistical Analyses

  High impact. This affects the rigor and interpretability of the results. The Results section currently lacks any statistical analysis of the data, which is crucial for determining the significance of the observed changes. This is particularly important for a Results section as it forms the basis for drawing conclusions. Including statistical analyses, even simple ones given the single-subject nature of the study, would significantly enhance the rigor of the findings. This would also allow for a more objective assessment of the magnitude and significance of the observed effects. Ultimately, adding statistical analyses would greatly improve the scientific validity and interpretability of the Results section.

  "The subject's baseline BMI was 20.8 kg/m² with LDL-C 384 mg/dL. Oreo supplementation at 12 cookies/d (100 g added carbohydrate) decreased LDL-C to 308 mg/dL during the first week." (Page 4)

  Implementation: Given the single-subject nature of the study, simple descriptive statistics and potentially paired t-tests (if appropriate) could be performed. For example: "Mean LDL-C levels decreased from 384 ± 0 mg/dL at baseline to 111 ± 14.5 mg/dL (mean ± SD of triplicate measurements) after 16 days of Oreo supplementation. This change represents a statistically significant reduction in LDL-C (p < 0.05, paired t-test)."

Non-Text Elements

Figure 2. Effects of Oreo cookies versus Statins on LDL cholesterol (LDL-C). 16...

Full Caption

Figure 2. Effects of Oreo cookies versus Statins on LDL cholesterol (LDL-C). 16 days of Oreo cookie supplementation (Left) lowered the subject's LDL-C from 384 to 111 mg/dl (71% reduc-tion). Following a 3-month washout period, the subject underwent 6 months of 20 mg rosuvastatin therapy daily (Right), which decreased his LDL-C from 421 to 284 mg/dl at nadir (32.5% reduction). The subject's LDL-C on a standard mixed diet, prior to adopting a ketogenic diet 4.5 years ago, was 95 mg/dl.

Figure/Table Image (Page 5)

First Reference in Text

Thus, 16 days of consuming 12 Oreo cookies/d decreased the subject's LDL-C by 273 mg/dL, a 71% drop, and returned his LDL-C into the 'normal' reference range (Figure 2, Table 2), with a continued downtrend towards his pre-KD level of 95 mg/dL.

Description

• LDL cholesterol (LDL-C): LDL stands for Low-Density Lipoprotein. It's a type of fat-like particle that carries cholesterol in the blood. LDL-C is often called "bad cholesterol" because if there's too much of it, it can build up in the walls of your arteries and increase the risk of heart disease. The "-C" in LDL-C refers specifically to the amount of cholesterol within these LDL particles.
• Oreo cookie supplementation: This means the subject added Oreo cookies to their diet for a certain period. In this case, it was 12 cookies per day for 16 days. It's like adding a new ingredient to a recipe to see how it changes the final dish.
• Statins: These are a type of medicine that helps lower cholesterol levels in the blood. They work by blocking a substance your body needs to make cholesterol. It's like putting a roadblock in the cholesterol production line. In this experiment, the statin used was rosuvastatin.
• mg/dl: This stands for milligrams per deciliter. It's a unit used to measure the concentration of a substance in a liquid, in this case, the amount of LDL-C in the blood. It's like measuring how much salt is dissolved in a glass of water.
• Nadir: This refers to the lowest point reached. In this context, it's the lowest level of LDL-C achieved during the statin treatment period.
• Washout period: This is a period between treatments where the effects of the previous treatment are allowed to wear off. It is like taking a break between trying different medications to see the true effect of each one without interference.
• Standard mixed diet: This refers to a regular diet that includes a variety of foods from different food groups, as opposed to a restrictive diet like the ketogenic diet. This was the subject's diet before they started the ketogenic diet 4.5 years prior to the study.
• Pre-KD level: This refers to the subject's LDL-C levels before they started following a ketogenic diet (KD). It serves as a reference point to see how the ketogenic diet and the interventions in the study affected their cholesterol.

Scientific Validity

• Graphical representation of data: The figure presents the primary results graphically, which is appropriate for visualizing changes in LDL-C over time. However, presenting individual data points instead of just connecting lines would provide a more complete picture of the variability in the data.
• Comparison of interventions: The study directly compares the effects of two interventions (Oreo supplementation and statin therapy) on LDL-C levels in the same individual. This head-to-head comparison is a strength of the study design.
• Magnitude of effect: The reported reductions in LDL-C (71% with Oreos and 32.5% with statins) are substantial and clinically meaningful. However, it is important to note that these results are based on a single subject and may not be generalizable to the broader population.
• Lack of statistical analysis: Due to the single-subject design, no statistical tests were performed. While the observed differences are large, the lack of statistical analysis limits the ability to draw firm conclusions about the superiority of one intervention over the other.
• Pre-ketogenic diet LDL-C level: The inclusion of the subject's pre-ketogenic diet LDL-C level (95 mg/dL) provides an important reference point. However, it would be helpful to know more about the subject's diet and lifestyle during that period for a more complete comparison.

Communication

• Clear labeling of axes: The graphs clearly label the x-axis as time (days or weeks) and the y-axis as LDL-C (mg/dL), making the data easy to interpret.
• Visual comparison of interventions: Presenting the results for the Oreo and statin interventions side-by-side allows for a direct visual comparison of their effects on LDL-C.
• Concise summary of results: The caption provides a concise summary of the main findings, including the percentage reductions in LDL-C for each intervention. However, the caption incorrectly states that the statin intervention lasted for 6 months when it was actually 6 weeks.
• Inconsistent time scale: The x-axis scale is different between the two graphs (days for Oreo, weeks for statin), which could make direct visual comparison slightly more difficult. Using a consistent time scale (e.g., days) for both interventions would improve clarity.
• Missing data points: The graphs only show lines connecting the measured LDL-C values, without displaying the individual data points. Including the data points would provide a better sense of the variability in the measurements.
• Overemphasis on visual impact: The dramatic drop in LDL-C with Oreo supplementation is visually striking. However, the caption could further emphasize that this is a single-subject study and that the results may not be generalizable.

Table 2. Lipid changes by study arm. TC, total cholesterol; TG, triglycerides....

Full Caption

Table 2. Lipid changes by study arm. TC, total cholesterol; TG, triglycerides. All units are in mg/dL. * indicates the LDL-C nadir for statin treatment, which was used to represent the statin effect even though it occurred at week 4, not the end of treatment.

Figure/Table Image (Page 4)

First Reference in Text

Thus, 16 days of consuming 12 Oreo cookies/d decreased the subject's LDL-C by 273 mg/dL, a 71% drop, and returned his LDL-C into the 'normal' reference range (Figure 2, Table 2), with a continued downtrend towards his pre-KD level of 95 mg/dL.

Description

• Lipid changes: Lipids are fats in the blood. This table shows how different types of fats in the blood changed during the different parts of the experiment. It's like tracking the levels of different ingredients in a recipe over time.
• Study arm: This refers to the different phases of the experiment: the baseline (normal ketogenic diet), the Oreo cookie period, and the statin treatment period. Each phase is like a different 'treatment' being tested.
• TC, total cholesterol: This is the total amount of cholesterol found in the blood. Cholesterol is a waxy, fat-like substance that's found in all the cells in your body. It includes both 'good' (HDL) and 'bad' (LDL) cholesterol, plus other types of fat. It's like measuring all the different types of flour in a recipe.
• TG, triglycerides: This is another type of fat found in the blood. When you eat, your body converts any calories it doesn't need to use right away into triglycerides. High levels can increase the risk of heart disease. It's like measuring the amount of butter in a recipe.
• mg/dL: This stands for milligrams per deciliter. It's a unit used to measure the concentration of a substance in a liquid, in this case, how much of each type of fat is in the blood. It's like measuring how much salt is dissolved in a glass of water.
• LDL-C nadir: LDL-C, as explained before, stands for Low-Density Lipoprotein Cholesterol, often called 'bad' cholesterol. 'Nadir' means the lowest point. So, this refers to the lowest level of LDL-C reached during the statin treatment. It's like finding the lowest temperature recorded during a cold spell.
• Statin effect: Statins are medicines that lower cholesterol. The 'statin effect' refers to how much the statin treatment lowered the cholesterol levels. In this case, they used the lowest LDL-C level reached during treatment to represent the statin's effect.

Scientific Validity

• Comprehensive lipid panel: The table presents a comprehensive lipid panel, including total cholesterol, LDL-C, HDL-C, and triglycerides. This allows for a thorough assessment of the effects of the interventions on various lipid parameters.
• Multiple time points: The table includes data from multiple time points within each study arm, providing a more detailed picture of the lipid changes over time. However, the selection of specific time points for the table (e.g., day 7 and day 16 for the Oreo arm) could introduce bias if these points were chosen selectively.
• LDL-C nadir as representative of statin effect: Using the LDL-C nadir to represent the statin effect is a reasonable approach, as it captures the maximum lipid-lowering effect of the medication. However, it is important to acknowledge that this occurred at week 4 and not at the end of the 6-week treatment period.
• Lack of statistical comparisons: The table presents the absolute and relative changes in LDL-C but does not include any statistical comparisons between the study arms. Due to the single-subject design, formal statistical testing is not possible. However, the magnitude of the observed changes can still be evaluated for clinical significance.
• Washout period data: Including data from the washout period between the Oreo and statin arms is valuable, as it provides information about the return to baseline lipid levels after the Oreo intervention.

Communication

• Clear table structure: The table is well-organized, with clear column headings for each study arm and time point, and rows for each lipid parameter. This structure facilitates easy comparison of lipid levels across the different phases of the experiment.
• Explanation of abbreviations: The caption defines the abbreviations TC and TG, which is helpful for readers who may not be familiar with these terms.
• Specification of units: The caption clearly states that all units are in mg/dL, ensuring that the data can be interpreted correctly.
• Clarification of LDL-C nadir: The caption explains the use of the asterisk (*) to indicate the LDL-C nadir for the statin treatment and clarifies that this value was used to represent the statin effect.
• Incomplete definition of LDL-C: While the caption defines TC and TG, it does not explicitly define LDL-C or HDL-C. Although these terms were explained previously in the paper, it would be helpful to include their definitions in the caption for completeness.
• Lack of visual aids: The table presents a large amount of numerical data, which can be difficult to process. Including graphical representations of the lipid changes (e.g., bar graphs or line plots) could enhance the visual communication of the results.

Discussion

Key Aspects

• Oreo Intervention and LDL-C Reduction: The Discussion section begins by highlighting the seemingly paradoxical finding that Oreo cookie supplementation led to a significant 71% reduction in LDL-C levels in the study subject. This observation, while unexpected in conventional dietary paradigms, is presented as being consistent with the predictions of the Lipid Energy Model (LEM). The LEM posits that in states of carbohydrate restriction and low adiposity, the body increases the trafficking of lipids via very-low-density lipoprotein (VLDL) particles to meet energy demands. The addition of carbohydrates, even in the form of a processed food like Oreos, is hypothesized to reduce the need for this lipid mobilization, consequently lowering LDL-C levels.
• Lipid Energy Model (LEM) as a Framework: The section elaborates on the Lipid Energy Model (LEM) as a theoretical framework for understanding the observed results. The LEM suggests that under conditions of carbohydrate restriction sufficient to deplete hepatic glycogen stores and in individuals with relatively low levels of adiposity, free fatty acids are packaged into VLDL particles in the liver. These particles are then exported as part of a systemic fuel trafficking system. At peripheral tissues, lipoprotein lipase (LPL) mediates the hydrolysis of triglycerides (TG) in VLDL, leading to the formation of LDL particles. The model proposes that the increased production and turnover of VLDL in this context result in elevated LDL-C, elevated HDL-C (due to the integration of surface components from VLDL into HDL), and low TG, a triad that characterizes the LMHR phenotype.
• Carbohydrate Quality and the Oreo Effect: A key point of discussion is that the LEM does not emphasize the source or quality of carbohydrates in influencing LDL-C levels in LMHR individuals. Thus, the study's use of Oreo cookies is justified as a means to test the hypothesis that carbohydrate repletion, regardless of the source, can reduce LDL-C. The persistence of elevated HDL-C in the subject is attributed to potentially persistent high VLDL turnover, despite reduced hepatic VLDL export, along with other factors like stable or increased enteric ApoA production and differences in particle clearance dynamics.
• Multifactorial Nature of the Oreo Effect: The section acknowledges that while the LEM provides a useful framework, the observed "Oreo effect" may be multifactorial. It mentions that Oreo consumption can increase post-prandial insulin, which in turn can influence LDL receptor pathway activity. However, it argues that insulin-induced changes in LDL receptor activity are unlikely to fully account for the magnitude of the LDL-C reduction observed in this study, particularly given the LMHR context. Additionally, changes in LDL receptor activity alone wouldn't explain the characteristic LMHR lipid triad.
• Saturated Fat and the LMHR Phenotype: The Discussion addresses the common assumption that saturated fat intake is the primary driver of increased LDL-C in individuals on high-fat ketogenic diets. It challenges this notion by pointing out that in this study, saturated fat intake actually increased during the Oreo arm, yet LDL-C levels decreased. Furthermore, it references the subject's previous high LDL-C levels while consuming a diet lower in saturated fat, suggesting that factors like lower body fat, higher activity levels, and greater energy demands, as predicted by the LEM, are more likely explanations.
• Impact of Increased Physical Activity: The section briefly discusses the sub-experiment conducted during the final week of the statin arm, where the subject's physical activity was increased. This resulted in a moderate increase in LDL-C, which is interpreted as being consistent with the LEM's prediction that increased energy demands can lead to increased lipid trafficking and consequently higher LDL-C levels.
• Study Limitations and Future Directions: The Discussion acknowledges the limitations of the study, particularly its single-subject nature and the use of Oreo cookies as an intervention. It suggests that future studies should consider using a macronutrient switch rather than simple carbohydrate addition to enhance clinical translatability. It also highlights the need for larger-scale crossover trials to further investigate interventions for LDL-C lowering among LMHR individuals.
• Ethical Considerations: The section addresses the ethical considerations of self-experimentation and the Citizen Scientist movement. It emphasizes that the Oreo intervention should not be interpreted as health advice and acknowledges the potential risks of long-term consumption of refined carbohydrates. However, it also argues that the subject and primary investigator are the same person and that the interventions used are generally considered safe in the short term. It concludes by suggesting that the ethics of self-experimentation is a topic that deserves further discussion.

Strengths

• Comprehensive Explanation of LEM

  The Discussion provides a thorough explanation of the Lipid Energy Model and how it relates to the study's findings, effectively connecting the theoretical framework to the observed results.

  "The LEM proposes that under conditions of carbohydrate restriction sufficient to deplete hepatic glycogen stores" (Page 5)
• Clear Justification for Oreo Intervention

  The section clearly justifies the use of Oreo cookies as a carbohydrate source, explaining that the LEM does not differentiate between carbohydrate types in the context of LDL-C reduction in LMHR.

  "The model does not emphasize sources or quality of carbohydrates" (Page 5)
• Critical Evaluation of Saturated Fat

  The Discussion critically evaluates the role of saturated fat in the LMHR phenotype, presenting evidence that challenges the conventional view of saturated fat as the primary driver of LDL-C elevation on ketogenic diets.

  "Further consistent with the notion that saturated fat intake is not the main driver of increased LDL-C" (Page 6)

Suggestions for Improvement

• Expand on the Multifactorial Nature of LDL-C Changes

  High impact. This affects the nuance of the discussion, the interpretation of the results, and the framing of future research directions. The Discussion section is the appropriate place for this expansion as it is where the study's findings are interpreted and contextualized within the broader field of knowledge. While the Discussion acknowledges the potential multifactorial nature of the Oreo effect, it could benefit from a more in-depth exploration of these factors and their potential interplay. This would provide a more comprehensive understanding of the complex mechanisms involved in LDL-C regulation in LMHR individuals. Expanding on this aspect would strengthen the paper by acknowledging the limitations of solely attributing the observed effects to the LEM and by highlighting the need for future research to disentangle the contributions of various factors. This would also provide a more balanced perspective on the findings and enhance their interpretation. Ultimately, a more detailed discussion of the multifactorial nature of LDL-C changes would improve the depth and comprehensiveness of the Discussion section, leading to a more nuanced understanding of the study's implications.

  "While the LEM is a helpful framework for understanding lipid dynamics in LMHR, the cause of the Oreo effect may be multifactorial." (Page 6)

  Implementation: Include a dedicated paragraph exploring other potential factors contributing to LDL-C changes, such as alterations in gut microbiota, changes in bile acid metabolism, and the impact of exogenous ketones. Discuss how these factors might interact with the mechanisms proposed by the LEM. For example: "Beyond the mechanisms proposed by the LEM, other factors may contribute to the observed LDL-C reduction during the Oreo intervention. Alterations in gut microbiota composition, which have been shown to influence lipid metabolism, could play a role. Additionally, changes in bile acid metabolism and the enterohepatic circulation of cholesterol may be involved. Furthermore, the use of exogenous ketones during the Oreo arm could have influenced hepatic lipid metabolism, although the specific mechanisms remain to be elucidated. Future research should investigate the interplay between these factors and the LEM to provide a more complete understanding of LDL-C regulation in LMHR individuals."

• Discuss Clinical Implications More Explicitly

  Medium impact. This affects the practical applicability of the study's findings and their relevance to clinical practice. The Discussion section is the ideal location for this discussion as it bridges the gap between research findings and their potential real-world applications. While the Discussion mentions the need for further research, it could more explicitly address the potential clinical implications of the findings, particularly for LMHR individuals on ketogenic diets. Elaborating on the clinical implications would strengthen the paper by highlighting the potential of dietary interventions for managing LDL-C in this specific population. This would also provide a clearer connection between the study's findings and their potential impact on patient care. Ultimately, a more explicit discussion of clinical implications would enhance the paper's relevance to clinicians and researchers interested in the management of dyslipidemia in the context of ketogenic diets.

  "This project's aim was to provoke constructive discussion and inspire a larger-scale crossover trial investigating interventions for LDL-C lowering" (Page 7)

  Implementation: Add a paragraph discussing the potential clinical implications of the findings. For example: "While this study is based on a single subject, the findings suggest that dietary interventions, particularly carbohydrate reintroduction, may be a viable strategy for managing elevated LDL-C in LMHR individuals on ketogenic diets. This approach could potentially offer an alternative or adjunct to pharmacological interventions like statins. However, it is crucial to emphasize that this is a preliminary finding and that individualized approaches are necessary. Clinicians should carefully monitor lipid profiles in LMHR patients on ketogenic diets and consider personalized dietary strategies based on individual responses and overall cardiovascular risk. Further research, including randomized controlled trials, is needed to establish the efficacy and safety of carbohydrate reintroduction as a therapeutic strategy in this population."

• Address Potential Confounding Effects of Exogenous Ketones

  High impact. This affects the internal validity of the study and the interpretation of the results. The Discussion section is the appropriate place to address this limitation as it is where the study's findings are critically evaluated and potential confounding factors are discussed. While the Methods section describes the use of exogenous ketones to maintain ketosis during the Oreo arm, the Discussion section could benefit from a more thorough examination of their potential confounding effects on lipid metabolism. Addressing this limitation would strengthen the paper by acknowledging a potential factor that could have influenced the observed results, thereby providing a more transparent and balanced interpretation of the findings. This would also highlight an important consideration for future research investigating the effects of dietary interventions on lipid profiles in individuals using exogenous ketones. Ultimately, a more detailed discussion of the potential confounding effects of exogenous ketones would improve the rigor and transparency of the Discussion section, leading to a more accurate interpretation of the study's findings.

  "Throughout the Oreo supplementation arm, exogenous ketones (free d-B-hydroxybutyrate [B-HB], American Ketone) were supplemented to maintain ketosis throughout the study." (Page 3)

  Implementation: Add a paragraph discussing the potential impact of exogenous ketones on lipid metabolism. For example: "The use of exogenous ketones during the Oreo arm could have potentially influenced the observed changes in lipid profiles. While the intention was to maintain ketosis at levels similar to the baseline ketogenic diet, exogenous ketones themselves may have independent effects on hepatic lipid metabolism and lipoprotein production. Some studies suggest that B-HB can modulate hepatic fatty acid oxidation and VLDL synthesis. Therefore, it is possible that the exogenous ketones contributed, at least in part, to the observed LDL-C reduction. Future studies should consider including a control arm without exogenous ketone supplementation to isolate their specific effects on lipid metabolism in the context of carbohydrate reintroduction."

Conclusions

Key Aspects

• Summary of Main Findings: The Conclusions section succinctly summarizes the primary finding of the study: Oreo cookie supplementation in a lean mass hyper-responder (LMHR) on a ketogenic diet led to a substantial 71% reduction in LDL-cholesterol (LDL-C) over 16 days. This reduction was significantly greater than the 32.5% decrease observed with 6 weeks of high-intensity statin therapy (rosuvastatin 20 mg). This result is framed as a key takeaway, emphasizing the magnitude of the dietary intervention's effect compared to a standard pharmacological treatment.
• Consistency with the Lipid Energy Model: This section reiterates that the observed results align with the predictions of the Lipid Energy Model (LEM). The LEM, as introduced in earlier sections, is a theoretical framework that explains the elevation of LDL-C in LMHR individuals on ketogenic diets. It posits that increased lipid trafficking via very-low-density lipoprotein (VLDL) particles, driven by carbohydrate restriction and low adiposity, leads to elevated LDL-C. The study's finding that carbohydrate reintroduction via Oreos reduced LDL-C supports this model, suggesting that the added carbohydrates decreased the need for lipid mobilization.
• Implications for the LMHR Phenotype: The Conclusions section highlights the implications of the findings for the understanding and potential management of the LMHR phenotype. It emphasizes that this unique population, characterized by high LDL-C, high HDL-C, and low triglycerides on ketogenic diets, may respond differently to dietary interventions than the general population. The study suggests that carbohydrate reintroduction, even in the form of processed foods, could be a potential strategy for lowering LDL-C in LMHR individuals, although this is not presented as a general recommendation.
• Call for Further Research: A crucial aspect of the Conclusions is the explicit call for further research on the LMHR phenotype. The authors acknowledge the limitations of the single-subject study design and emphasize the need for larger-scale investigations to validate these findings and explore other potential interventions. This call for further research underscores the preliminary nature of the study and positions it as a catalyst for future investigations into this specific area of lipid metabolism and ketogenic diets.
• Reiteration of Study Design and Authorship: The section briefly reiterates the study's design, execution, and authorship, reminding the reader that the primary author was also the research subject. This reiteration serves to reinforce the context of the study as a self-experiment and to acknowledge the potential implications of this unique approach. It also mentions the contributions of the co-author in manuscript revisions.
• Funding and Ethical Considerations: The Conclusions section briefly addresses the funding of the research, stating that it received no external funding. It also mentions the Institutional Review Board (IRB) exemption for the project, reiterating the ethical considerations surrounding the self-experimentation nature of the study, as discussed in more detail in the Discussion section.

Strengths

• Concise Summary of Key Findings

  The Conclusions section effectively summarizes the main findings of the study, highlighting the significant reduction in LDL-C with Oreo supplementation compared to statin therapy in an LMHR individual on a ketogenic diet.

  "Oreo cookie supplementation lowered LDL-C by 273 mg/dL over 16 days, a 71% drop" (Page 8)
• Clear Connection to Lipid Energy Model

  The section clearly connects the findings to the Lipid Energy Model, reinforcing the theoretical framework used to interpret the results.

  "These findings are consistent with the lipid energy model" (Page 8)
• Explicit Call for Further Research

  The Conclusions section appropriately emphasizes the need for further studies on the LMHR population, acknowledging the limitations of the current study and highlighting the importance of future research in this area.

  "highlight the need for further studies on this unique lean mass hyper-responder population" (Page 8)

Suggestions for Improvement

• Expand on Clinical Implications

  High impact. This affects the practical applicability of the study's findings and their relevance to clinical practice. The Conclusions section is the appropriate place for this expansion as it is where the study's overall significance and implications are summarized. While the section briefly mentions the need for further research, it could more explicitly discuss the potential clinical implications of the findings, particularly for LMHR individuals on ketogenic diets. This would provide a clearer connection between the study's findings and their potential impact on patient care, even if preliminary. Ultimately, expanding on the clinical implications would enhance the paper's relevance to clinicians and researchers interested in the management of dyslipidemia in the context of ketogenic diets.

  "These findings are consistent with the lipid energy model and highlight the need for further studies" (Page 8)

  Implementation: Add a few sentences discussing the potential clinical implications. For example: "These findings suggest that dietary interventions, specifically carbohydrate reintroduction, could be a potential strategy for managing elevated LDL-C in LMHR individuals on ketogenic diets. While not a general recommendation, this approach warrants further investigation as a possible alternative or adjunct to pharmacological interventions. Clinicians should be aware of the LMHR phenotype and consider individualized dietary strategies based on patient responses and overall cardiovascular risk."

• Reiterate Study Limitations

  Medium impact. This affects the overall interpretation of the study's findings and the framing of its conclusions. The Conclusions section is a suitable location for this reiteration as it provides a final opportunity to acknowledge the study's limitations before concluding. While the Discussion section thoroughly addressed the study's limitations, briefly reiterating them in the Conclusions would provide a more balanced perspective and reinforce the preliminary nature of the findings. This would also help to temper any potential overgeneralization of the results. Ultimately, reiterating the study's limitations would enhance the overall transparency and scientific rigor of the Conclusions section.

  "In this case study experiment on a lean mass hyper-responder on a ketogenic diet" (Page 8)

  Implementation: Add a sentence or two reiterating the key limitations. For example: "It is important to remember that this was a single-subject study with a unique intervention. Therefore, these results should be interpreted with caution and not be generalized to the broader population or considered as general health advice."

• Address the Oreo Intervention More Directly

  Low impact. This affects the clarity and directness of the Conclusions section. While the use of Oreos is discussed extensively in other sections, the Conclusions section could benefit from a more direct statement about this unconventional intervention choice. Addressing the Oreo intervention more directly would provide a final opportunity to clarify the rationale behind this choice and to reinforce that it was not intended as a dietary recommendation. This would also help to manage potential misinterpretations of the study's findings. Ultimately, addressing the Oreo intervention more directly would improve the clarity and overall message of the Conclusions section.

  "Oreo cookie supplementation lowered LDL-C by 273 mg/dL over 16 days, a 71% drop" (Page 8)

  Implementation: Add a sentence clarifying the Oreo intervention. For example: "The use of Oreo cookies in this study was intended as a 'metabolic demonstration' to test the effects of carbohydrate reintroduction, not as a suggestion for a healthy dietary intervention. The findings highlight the potential impact of carbohydrates on LDL-C in LMHR individuals but should not be interpreted as an endorsement of Oreo consumption."