The impact of carbohydrate restriction-induced elevations in low-density lipoprotein cholesterol on progression of coronary atherosclerosis: the ketogenic diet trial study design.

BACKGROUND: Despite innovations in pharmacotherapy to lower lipoprotein cholesterol and apolipoprotein B, risk factors for atherosclerotic cardiovascular disease (ASCVD), ASCVD persists as the leading global cause of mortality. Elevations in low-density lipoprotein cholesterol (LDL-C) are a well-known risk factor and have been a main target in the treatment of ASCVD. The latest research suggests that ketogenic diets are effective at improving most non-LDL-C/apolipoprotein B cardiometabolic risk factors. However, ketogenic diets can induce large increases in LDL-C to >190 mg/dl in some individuals. Interestingly, these individuals are often otherwise lean and healthy. The influence of increased levels of LDL-C resulting from a carbohydrate-restricted ketogenic diet on the progression of atherosclerosis in otherwise metabolically healthy individuals is poorly understood. This observational study aims to assess and describe the progression of coronary atherosclerosis in this population within 12 months. METHODS: Hundred relatively lean individuals who adopted ketogenic diets and subsequently exhibited hypercholesterolemia with LDL-C to >190 mg/dl, in association with otherwise good metabolic health markers, were enrolled and observed over a period of 12 months. Participants underwent serial coronary computed tomography angiography scans to assess the progression of coronary atherosclerosis in a year. RESULTS: Data analysis shall begin following the conclusion of the trial with results to follow. CONCLUSION: Ketogenic diets have generated debate and raised concerns within the medical community, especially in the subset exhibiting immense elevations in LDL-C, who interestingly are lean and healthy. The relationship between elevated LDL-C and ASCVD progression in this population will provide better insight into the effects of diet-induced hypercholesterolemia.

Increased low-density lipoprotein cholesterol on a low-carbohydrate diet in adults with normal but not high body weight: A meta-analysis.

BACKGROUND: Low-density lipoprotein (LDL) cholesterol change with consumption of a low-carbohydrate diet (LCD) is highly variable. Identifying the source of this heterogeneity could guide clinical decision-making. OBJECTIVES: To evaluate LDL cholesterol change in randomized controlled trials involving LCDs, with a focus on body mass index (BMI) in kg/m2. METHODS: Three electronic indexes (Pubmed, EBSCO, and Scielo) were searched for studies between 1 January, 2003 and 20 December, 2022. Two independent reviewers identified randomized controlled trials involving adults consuming <130 g/d carbohydrate and reporting BMI and LDL cholesterol change or equivalent data. Two investigators extracted relevant data, which were validated by other investigators. Data were analyzed using a random-effects model and contrasted with results of pooled individual participant data. RESULTS: Forty-one trials with 1379 participants and a mean intervention duration of 19.4 wk were included. In a meta-regression accounting for 51.4% of the observed variability on LCDs, mean baseline BMI had a strong inverse association with LDL cholesterol change [ß = -2.5 mg/dL/BMI unit, 95% confidence interval (CI): -3.7, -1.4], whereas saturated fat amount was not significantly associated with LDL cholesterol change. For trials with mean baseline BMI <25, LDL cholesterol increased by 41 mg/dL (95% CI: 19.6, 63.3) on the LCD. By contrast, for trials with a mean of BMI 25-<35, LDL cholesterol did not change, and for trials with a mean BMI ≥35, LDL cholesterol decreased by 7 mg/dL (95% CI: -12.1, -1.3). Using individual participant data, the relationship between BMI and LDL cholesterol change was not observed on higher-carbohydrate diets. CONCLUSIONS: A substantial increase in LDL cholesterol is likely for individuals with low but not high BMI with consumption of an LCD, findings that may help guide individualized nutritional management of cardiovascular disease risk. As carbohydrate restriction tends to improve other lipid and nonlipid risk factors, the clinical significance of isolated LDL cholesterol elevation in this context warrants investigation. This trial was registered at PROSPERO as CRD42022299278.

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.

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, in association with HDL cholesterol ≥ 80 mg/dL and triglycerides ≤ 70 mg/dL. This triad of markers occurs primarily in lean metabolically healthy subjects, with the magnitude of increase in LDL-C inversely associated with body mass index. 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 single subject crossover experiment aimed to test the hypothesis that adding carbohydrates, in the form of Oreo cookies, to an LMHR subject on a ketogenic diet would reduce LDL-C levels by a similar, or greater, magnitude than high-intensity statin therapy. 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, providing 100 g/d of additional carbohydrates for 16 days. Throughout this arm, ketosis was monitored and maintained at levels similar to the subject's standard ketogenic diet using supplemental exogenous d-ß-hydroxybutyrate supplementation four times daily. Following the discontinuation of Oreo supplementation, the subject maintained a stable ketogenic diet for 3 months and documented a return to baseline weight and hypercholesterolemic status. During study arm 2, the subject received rosuvastatin 20 mg daily for 6 weeks. Lipid panels were drawn water-only fasted and weekly throughout the study. Baseline LDL-C was 384 mg/dL and reduced to 111 mg/dL (71% reduction) after Oreo supplementation. Following the washout period, LDL-C returned to 421 mg/dL, and was reduced to a nadir of 284 mg/dL with 20 mg rosuvastatin therapy (32.5% reduction). In conclusion, in this case study experiment, short-term Oreo supplementation lowered LDL-C more than 6 weeks of high-intensity statin therapy in an LMHR subject on a ketogenic diet. This dramatic metabolic demonstration, consistent with the lipid energy model, should provoke further research and not be seen as health advice.

Physiologic Adaptation to Macronutrient Change Distorts Findings from Short Dietary Trials: Reanalysis of a Metabolic Ward Study.

An influential 2-wk cross-over feeding trial without a washout period purported to show advantages of a low-fat diet (LFD) compared with a low-carbohydrate diet (LCD) for weight control. In contrast to several other macronutrient trials, the diet order effect was originally reported as not significant. In light of a new analysis by the original investigative group identifying an order effect, we aimed to examine, in a reanalysis of publicly available data (16 of 20 original participants; 7 female; mean BMI, 27.8 kg/m2), the validity of the original results and the claims that trial data oppose the carbohydrate-insulin model of obesity (CIM). We found that energy intake on the LCD was much lower when this diet was consumed first compared with second (a difference of -1164 kcal/d, P = 3.6 × 10-13); the opposite pattern was observed for the LFD (924 kcal/d, P = 2.0 × 10-16). This carry-over effect was significant (P interaction = 0.0004) whereas the net dietary effect was not (P = 0.4). Likewise, the between-arm difference (LCD - LFD) was -320 kcal/d in the first period and +1771 kcal/d in the second. Body fat decreased with consumption of the LCD first and increased with consumption of this diet second (-0.69 ± 0.33 compared with 0.57 ± 0.32 kg, P = 0.007). LCD-first participants had higher ß-hydroxybutyrate levels while consuming the LCD and lower respiratory quotients while consuming LFD when compared with LFD-first participants on their respective diets. Change in insulin secretion as assessed by C-peptide in the first diet period predicted higher energy intake and less fat loss in the second period. These findings, which tend to support rather than oppose the CIM, suggest that differential (unequal) carry-over effects and short duration, with no washout period, preclude causal inferences regarding chronic macronutrient effects from this trial.

Thyroid markers and body composition predict LDL-cholesterol change in lean healthy women on a ketogenic diet: experimental support for the lipid energy model.

Introduction: There is a large heterogeneity in LDL-cholesterol change among individuals adopting ketogenic diets. Interestingly, lean metabolically healthy individuals seem to be particularly susceptible, with an inverse association between body mass index and LDL-cholesterol change. The lipid energy model proposes that, in lean healthy individuals, carbohydrate restriction upregulates systemic lipid trafficking to meet energy demands. To test if anthropometric and energy metabolism markers predict LDL-cholesterol change during carbohydrate restriction. Methods: Ten lean, healthy, premenopausal women who habitually consumed a ketogenic diet for ≥6 months were engaged in a three-phase crossover study consisting of continued nutritional ketosis, suppression of ketosis with carbohydrate reintroduction, and return to nutritional ketosis. Each phase lasted 21 days. The predictive performance of all available relevant variables was evaluated with the linear mixed-effects models. Results: All body composition metrics, free T3 and total T4, were significantly associated with LDL-cholesterol change. In an interaction model with BMI and free T3, both markers were significant independent and interacting predictors of LDL-cholesterol change. Neither saturated fat, HOMA-IR, leptin, adiponectin, TSH, nor rT3 was associated with LDL-cholesterol changes. Discussion: Among lean, healthy women undergoing carbohydrate restriction, body composition and energy metabolism markers are major drivers of LDL-cholesterol change, not saturated fat, consistent with the lipid energy model.

Metabolic Health Immersion for Medical Education: A Pilot Program with Continuous Glucose Monitors in Medical and Dental Students.

Diet-related chronic diseases are increasing in prevalence and poised to dominate the future careers of current medical students. While the value of nutritionally-informed care and nutrition-based health interventions is increasingly recognized, nutrition education is inconsistently and often inadequately included in medical school curricula. One obstacle to incorporating nutrition into medical and dental school curricula is the density of existing coursework, with incorporation of new material necessitating removal of other material. One solution is to engage students outside the classroom in immersive education in nutrition and metabolism using health-wearables. We report the Metabolic Health Immersion for Medical Education pilot program, spearheaded and designed by Harvard Medical students centering on use of continuous glucose monitors (CGM). Students reported enjoyment with the study, felt encouraged to improve health behaviors, and shared that the experience enhanced their understanding of nutrition and metabolism, was valuable to their medical education, and would influence their future patient care. This study demonstrates proof-of-principle that metabolic health immersion opportunities for health care trainees provide a means of helping to address the current deficit in medical school nutrition education.

A Company Is Only as Healthy as Its Workers: A 6-Month Metabolic Health Management Pilot Program Improves Employee Health and Contributes to Cost Savings.

Chronic diet-related metabolic diseases, including diabetes and obesity, impose enormous burdens on patient wellness, healthcare costs, and worker productivity. Given the interdependent nature of the human and economic costs of metabolic disease, companies should be incentivized to invest in the health of their workforce. We report data from an ongoing pilot program in which employees of a manufacturing company with obesity, prediabetes, or diabetes are being treated by a metabolic health clinic using a carbohydrate restriction, community-orientated telemedicine approach. 10 patients completed the first 6 months of the program, and all lost weight, with a mean weight reduction of 38.4 lbs (17.4 kg). Improvements in HbA1c, fasting glucose, HOMA-IR, triglycerides, C-reactive protein, and systolic blood pressure were also observed across the group. Furthermore, the 10-year risk of having a major cardiovascular event, as calculated by the American Heart Association risk calculator, decreased from a mean of 9.22 to 5.18%, representing a 44% relative risk reduction. As a result of improvements in their metabolic health, patients were able to discontinue medications, leading to an estimated annualized cost savings of USD 45,171.70. These preliminary data provide proof-of-principle that when companies invest in the metabolic health of their workers, both parties stand to gain.

Short-term hyper-caloric high-fat feeding on a ketogenic diet can lower low-density lipoprotein cholesterol: the cholesterol drop experiment.

PURPOSE OF REVIEW: Conventional knowledge holds that saturated fat is the primary dietary driver of increases in low-density lipoprotein-cholesterol (LDL-C), and that high LDL-C seen among some persons consuming low-carbohydrate, high-fat diets is driven by increased saturated fat intake. This simple paradigm cannot account for the lipid patterns, nor for the magnitude of effect, observed in 'lean mass hyper-responders' on low-carbohydrate diets. The Lipid Energy Model (LEM) provides an alternative explanation for LDL-C increases seen in persons without obesity who adopt ketogenic diets and makes testable predictions, including that acute overfeeding, including increased saturated fat consumption, would decrease LDL-C levels. RECENT FINDINGS: This study reports data from an n  = 1 experiment, performed in duplicate, in which the subject consumed three ketogenic diets for 5 days that varied in caloric content: weight-maintenance (2278 kcal/day), hypo-caloric (1135 kcal/day), and hyper-caloric (4116 kcal/day). Consistent with the LEM, LDL-C and apolipoprotein B increased following caloric restriction and decreased following overfeeding, despite increased saturated fat consumption. Data from a case series of 24 individuals who underwent similar protocols similarly found that overfeeding on a ketogenic diet decreased LDL-C. SUMMARY: This n = 1 study and associated case series provide data that short-term overfeeding can lower LDL-C in the context of carbohydrate restriction.

The Lipid Energy Model: Reimagining Lipoprotein Function in the Context of Carbohydrate-Restricted Diets.

When lean people adopt carbohydrate-restricted diets (CRDs), they may develop a lipid profile consisting of elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs). The magnitude of this lipid profile correlates with BMI such that those with lower BMI exhibit larger increases in both LDL-C and HDL-C. The inverse association between BMI and LDL-C and HDL-C change on CRD contributed to the discovery of a subset of individuals-termed Lean Mass Hyper-Responders (LMHR)-who, despite normal pre-diet LDL-C, as compared to non-LMHR (mean levels of 148 and 145 mg/dL, respectively), exhibited a pronounced hyperlipidemic response to a CRD, with mean LDL-C and HDL-C levels increasing to 320 and 99 mg/dL, respectively, in the context of mean TG of 47 mg/dL. In some LMHR, LDL-C levels may be in excess of 500 mg/dL, again, with relatively normal pre-diet LDL-C and absent of genetic findings indicative of familial hypercholesterolemia in those who have been tested. The Lipid Energy Model (LEM) attempts to explain this metabolic phenomenon by positing that, with carbohydrate restriction in lean persons, the increased dependence on fat as a metabolic substrate drives increased hepatic secretion and peripheral uptake of TG contained within very low-density lipoproteins (VLDL) by lipoprotein lipase, resulting in marked elevations of LDL-C and HDL-C, and low TG. Herein, we review the core features of the LEM. We review several existing lines of evidence supporting the model and suggest ways to test the model's predictions.

Case Report: Hypercholesterolemia "Lean Mass Hyper-Responder" Phenotype Presents in the Context of a Low Saturated Fat Carbohydrate-Restricted Diet.

Emerging evidence suggests that "leanness" and good metabolic health markers may predict larger increases in LDL cholesterol (LDL-C) in response to carbohydrate restriction. Specifically, a recent cohort study demonstrated an inverse association between BMI and LDL-C change among individuals on carbohydrate-restricted diets and identified a subgroup of "Lean Mass Hyper-Responders" (LMHR) who exhibit exceptional increases in LDL-C, in the context of low triglycerides and high HDL-C. We present the case of one subject, LM, who adopted a ketogenic diet for management of ulcerative colitis. He subsequently experienced an increase in LDL-C from 95 to 545 mg/dl, at peak, in association with HDL-C >100 mg/dl and triglycerides ~40 mg/dl, typical of the emergent LMHR phenotype. Assessments of LM's dietary intake, lipid panels, and BMI are consistent with prior data and suggest that the LMHR phenomenon is not dependent on saturated fat intake but inversely associates with BMI changes. Finally, computed tomography angiography conducted on LM after over 2 years of hypercholesterolemia revealed no evidence of calcified or non-calcified plaque.

Elevated LDL Cholesterol with a Carbohydrate-Restricted Diet: Evidence for a "Lean Mass Hyper-Responder" Phenotype.

BACKGROUND: People commencing a carbohydrate-restricted diet (CRD) experience markedly heterogenous responses in LDL cholesterol, ranging from extreme elevations to reductions. OBJECTIVES: The aim was to elucidate possible sources of heterogeneity in LDL cholesterol response to a CRD and thereby identify individuals who may be at risk for LDL cholesterol elevation. METHODS: Hypothesis-naive analyses were conducted on web survey data from 548 adults consuming a CRD. Univariate and multivariate regression models and regression trees were built to evaluate the interaction between body mass index (BMI) and baseline lipid markers. Data were also collected from a case series of five clinical patients with extremely high LDL cholesterol consuming a CRD. RESULTS: BMI was inversely associated with LDL cholesterol change. Low triglyceride (TG) to HDL cholesterol ratio, a marker of good metabolic health, predicted larger LDL cholesterol increases. A subgroup of respondents with LDL cholesterol ≥200 mg/dL, HDL cholesterol ≥80 mg/dL, and TG ≤70 mg/dL were characterized as "lean mass hyper-responders." Respondents with this phenotype (n = 100) had a lower BMI and, remarkably, similar prior LDL cholesterol versus other respondents. In the case series, moderate reintroduction of carbohydrate produced a marked decrease in LDL cholesterol. CONCLUSIONS: These data suggest that, in contrast to the typical pattern of dyslipidemia, greater LDL cholesterol elevation on a CRD tends to occur in the context of otherwise low cardiometabolic risk.

Exogenous d-ß-hydroxybutyrate lowers blood glucose in part by decreasing the availability of L-alanine for gluconeogenesis.

BACKGROUND: Interventions that induce ketosis simultaneously lower blood glucose and the explanation for this phenomenon is unknown. Additionally, the glucose-lowering effect of acute ketosis is greater in people with type 2 diabetes (T2D). On the contrary, L-alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D and infusing of ketones lower circulating L-alanine blood levels. In this study, we sought to determine whether supplementation with L-alanine would attenuate the glucose-lowering effect of exogenous ketosis using a ketone ester (KE). METHODS: This crossover study involved 10 healthy human volunteers who fasted for 24 h prior to the ingestion of 25 g of d-ß-hydroxybutyrate (ßHB) in the form of a KE drink (ΔG® ) on two separate visits. During one of the visits, participants additionally ingested 2 g of L-alanine to see whether L-alanine supplementation would attenuate the glucose-lowering effect of the KE drink. Blood L-alanine, L-glutamine, glucose, ßHB, free fatty acids (FFA), lactate and C-peptide were measured for 120 min after ingestion of the KE, with or without L-alanine. FINDINGS: The KE drinks elevated blood ßHB concentrations from negligible levels to 4.52 ± 1.23 mmol/L, lowered glucose from 4.97 ± SD 0.39 to 3.77 ± SD 0.40 mmol/L, and lowered and L-alanine from 0.56 ± SD 0.88 to 0.41 ± SD 0.91 mmol/L. L-alanine in the KE drink elevated blood L-Alanine by 0.68 ± SD 0.15 mmol/L, but had no significant effect on blood ßHB, L-glutamine, FFA, lactate, nor C-peptide concentrations. By contrast, L-alanine supplementation significantly attenuated the ketosis-induced drop in glucose from 28% ± SD 8% to 16% ± SD 7% (p < .01). CONCLUSIONS: The glucose-lowering effect of acutely elevated ßHB is partially due to ßHB decreasing L-alanine availability as a substrate for gluconeogenesis.

Case Report: Ketogenic Diet Is Associated With Improvements in Chronic Obstructive Pulmonary Disease.

Chronic Obstructive Pulmonary Disease (COPD) is a debilitating inflammatory respiratory condition that presents with worsening breathing difficulties and it is assumed to be progressive and incurable. As an inflammatory disease, COPD is associated with recruitment of immune cells to lung tissue and increased levels of pro-inflammatory cytokines, including TNF-α, IL-1ß, IL-6, IL-8, and GM-CSF. Low-carbohydrate ketogenic diets have anti-inflammatory properties that could, in theory, improve COPD symptoms and progression. Herein, we report on a 54-year-old patient (C.A.) with COPD who adopted a ketogenic diet (70% calories from fat). Subsequently, C.A. experienced a reduction in inflammatory markers in association with a meaningful improvement in lung function. His inflammatory markers decreased into the normal range and his forced expiratory volume increased by 37.5% relative to its pre-ketogenic diet value. Future research should explore nutritional ketosis and ketogenic diets as possible therapeutic options for individuals with COPD.

Exogenous ketosis in patients with type 2 diabetes: Safety, tolerability and effect on glycaemic control.

INTRODUCTION: Ketogenic diets have shown to improve glycaemic control in patients with type 2 diabetes. This study investigated the safety, tolerability, and effects on glycaemic control in patients with type 2 diabetes of an exogenous ketone monoester (KE) capable of inducing fasting-like elevations in serum ß-hydroxybutyrate (ßHB) without the need for caloric or carbohydrate restriction. METHODS: Twenty one participants (14 men and 7 women, aged 45 ± 11 years) with insulin-independent type 2 diabetes, and unchanged hypoglycaemic medication for the previous 6 months, were recruited for this non-randomised interventional study. Participants wore intermittent scanning glucose monitors (IS-GM) for a total of 6 weeks and were given 25 ml of KE 3 times daily for 4 weeks. Serum electrolytes, acid-base status, and ßHB concentrations were measured weekly and cardiovascular risk markers were measured before and after the intervention. The primary endpoints were safety and tolerability, with the secondary endpoint being glycaemic control. RESULTS: The 21 participants consumed a total of 1,588 drinks (39.7 litres) of KE over the course of the intervention. Adverse reactions were mild and infrequent, including mild nausea, headache, and gastric discomfort following fewer than 0.5% of the drinks. Serum electrolyte concentrations, acid-base status, and renal function remained normal throughout the study. Compared to baseline, exogenous ketosis induced a significant decrease in all glycaemic control markers, including fructosamine (335 ± 60 µmol/L to 290 ± 49 µmol/L, p < .01), HbA1c (61 ± 10 mmol/mol to 55 ± 9 mmol/mol [7.7 ± 0.9% to 7.2 ± 0.9%], p < .01), mean daily glucose (7.8 ± 1.4 mM to 7.4 ± 1.3 mM [140 ± 23 mg/dl to 133 ± 25 mg/dl], p < .01) and time in range (67 ± 11% to 69 ± 10%, p < .01). CONCLUSIONS: Constant ketone monoester consumption over 1 month was safe, well tolerated, and improved glycaemic control in patients with type 2 diabetes.

Precision Nutrition for Alzheimer's Prevention in ApoE4 Carriers.

The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer's disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer's disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood-brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer's risk reduction.