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

Table of Contents

Overall Summary

Study Background and Main Findings

In a single-subject crossover experiment, a 27-year-old male lean mass hyper-responder (LMHR) on a ketogenic diet experienced a 71% reduction in LDL-C after 16 days of Oreo cookie supplementation (100g added carbohydrate/day while maintaining ketosis with exogenous ketones). This reduction was greater than the 32.5% reduction observed after 6 weeks of rosuvastatin (20mg/day) following a 3-month washout period. B-HB levels suggested mild ketosis during the first week of Oreo supplementation, decreasing in the second week. The subject gained 1.5kg during the Oreo arm, returning to baseline after washout.

Research Impact and Future Directions

This single-subject study explored the effects of Oreo cookie supplementation and statin therapy on LDL-C in a lean mass hyper-responder (LMHR) following a ketogenic diet. While the 71% LDL-C reduction with Oreos compared to the 32.5% reduction with rosuvastatin is striking, it's crucial to distinguish between correlation and causation. The study design doesn't allow us to definitively conclude that Oreos *caused* the LDL-C reduction. The observed effect could be due to carbohydrate reintroduction itself, the specific composition of Oreos, the exogenous ketones used to maintain ketosis, or other unknown factors.

The practical utility of these findings is limited by the study's inherent limitations. While the Lipid Energy Model (LEM) offers a plausible explanation for the observed effects, the single-subject design, the unconventional intervention, and the lack of a control group without exogenous ketones restrict generalizability. The study's value lies primarily in its potential to generate hypotheses and stimulate further research, rather than providing definitive clinical guidance.

Given the uncertainties, it would be premature to recommend Oreo cookies as a treatment for elevated LDL-C in LMHR individuals on ketogenic diets. Further research with larger sample sizes, diverse carbohydrate sources, and controlled conditions is necessary to validate these findings and explore their clinical implications. Practitioners should exercise caution when interpreting these results and prioritize individualized approaches based on patient-specific factors and overall cardiovascular risk.

Several critical unanswered questions remain. What are the long-term effects of this type of intervention? Do different carbohydrate sources yield similar results? What is the role of exogenous ketones in modulating lipid metabolism? Does the LMHR phenotype represent a distinct metabolic subtype with unique therapeutic considerations? The study's methodological limitations, particularly the single-subject design and the lack of a control for exogenous ketones, significantly affect the interpretation of the findings and underscore the need for more rigorous research to draw definitive conclusions.

Critical Analysis and Recommendations

Effective Communication of Key Findings (written-content)
The abstract clearly presents the study's unique design and striking results, immediately capturing reader interest and highlighting the paradoxical nature of the intervention.
Section: Abstract
Clarify Exogenous Ketone Information (written-content)
Specifying the brand and purity of exogenous ketones is essential for reproducibility and allows for accurate assessment of their potential confounding effects.
Section: Materials and Methods
Justify Washout Period (written-content)
Providing a rationale for the washout duration strengthens the study's internal validity by demonstrating a considered approach to minimizing carry-over effects.
Section: Materials and Methods
Include Statistical Analysis (written-content)
Statistical analysis, even in a single-subject study, is crucial for objectively assessing the magnitude and significance of observed changes and strengthening the validity of conclusions.
Section: Results
Show Individual Data Points in Figures (graphical-figure)
Presenting individual data points alongside connecting lines would enhance transparency and provide a more accurate representation of data variability.
Section: Results
Expand on Multifactorial Influences (written-content)
A deeper exploration of potential contributing factors beyond the LEM would provide a more nuanced understanding of LDL-C regulation in LMHR individuals.
Section: Discussion
Address Confounding by Exogenous Ketones (written-content)
Explicitly addressing potential confounding effects of exogenous ketones is crucial for transparent interpretation and informs future research design.
Section: Discussion
Elaborate on Clinical Implications (written-content)
Discussing potential clinical implications, even if preliminary, enhances the paper's relevance to practitioners and researchers interested in dyslipidemia management.
Section: Discussion

Section Analysis

Abstract

Key Aspects

Strengths

Suggestions for Improvement

Introduction

Key Aspects

Strengths

Suggestions for Improvement

Materials and Methods

Key Aspects

Strengths

Suggestions for Improvement

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)
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.
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...
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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)
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.
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

Strengths

Suggestions for Improvement

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)
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.
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....
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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)
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.
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

Strengths

Suggestions for Improvement

Conclusions

Key Aspects

Strengths

Suggestions for Improvement

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