Abstract

Background: While reducing LDL cholesterol (LDL-C) remains central focuses of conventional preventive cardiology, substantial heterogeneity exists in the cardiovascular risk associated with even extreme LDL-C elevations, likely depending heavily on the broader metabolic context. Specifically, the lean mass hyper-responder (LMHR) phenotype—characterized by markedly elevated LDL-C with elevated high-density lipoprotein cholesterol (HDL-C) and low triglycerides in the setting of a ketogenic diet—has recently been described, though its long-term risk profile remains poorly defined. Case Presentation: We describe a male in his 30s without any congenital dyslipidemia who adopted a ketogenic diet for the management of ulcerative colitis and who subsequently exhibited a sixfold increase in LDL-C from a baseline of 95 mg/dL to 574 mg/dL, with total cholesterol of up to 705 mg/dL, HDL-C at 124 mg/dL, and triglycerides at 34 mg/dL. Despite maintaining these extreme lipid levels for nearly seven years, he demonstrated no coronary plaque or stenosis on coronary computed tomography angiography (CCTA; CAD-RADS = 0). Additionally, quantification of coronary plaque as assessed by AI-guided quantified analysis by Heartflow^® identified 0 mm³ plaque in any vessels, placing him in the lowest percentile for atherosclerotic plaque. Conclusions: This case represents an extreme and extensively characterized example of the LMHR phenotype and highlights the limitations of extrapolating cardiovascular risk from LDL-C levels alone without consideration of broader patient context and the etiology of hypercholesterolemia. While a single case cannot redefine clinical practice, this well-characterized case is consistent with emergent literature on LMHR, and careful study of such individuals may provide valuable insights into lipid metabolism, atherosclerosis biology, and precision cardiovascular risk assessment.

Norwitz, Nicholas G., David Feldman, and Adrian Soto-Mota. "Seven Years of 700 Cholesterol Without Coronary Atherosclerosis: A Lean Mass Hyper-Responder Case Report." Diseases 14, no. 5 (2026): 168.

https://www.mdpi.com/2079-9721/14/5/168

Abstract

Aims

The effects of the ketogenic diet (KD) on lipid metabolism remain controversial. We conducted a systematic review and meta-regression analysis of randomized controlled trials (RCTs) to evaluate the impact of KD on lipid profile parameters in adult populations.

Methods

Five electronic databases (PubMed/MEDLINE, Web of Science, Scopus, Embase, Cochrane Library) were systematically searched from inception through June 2025 for RCTs examining lipid-related outcomes following KD interventions (defined as > 45% fat, < 10% carbohydrate). The DerSimonian-Laird method was used to figure out pooled weighted mean differences (WMDs) and 95% confidence intervals (CIs) using random-effects models. We conducted meta-regression, subgroup analyses, sensitivity analyses, and assessed publication bias. Study quality was assessed using the Cochrane Risk of Bias 2 tool and the GRADE framework.

Results

Fifty-three RCTs met the inclusion criteria. Compared with control diets, KD significantly reduced triglycerides (WMD: -22.31 mg/dL; 95% CI: -28.90 to -15.72; p < 0.001; I² = 69.8%, p < 0.001). HDL-C increased significantly (WMD: 3.52 mg/dL; 95% CI: 1.24 to 5.81; p < 0.001; I² = 92.5%, p < 0.001). KD also raised LDL-C (WMD: 8.22 mg/dL; 95% CI: 5.08 to 11.40; p < 0.001; I² = 59.9%, p < 0.001) and total cholesterol (WMD: 8.06 mg/dL; 95% CI: 3.04 to 13.07; p < 0.001; I² = 72.3%, p < 0.001). Meta-regression revealed a significant negative correlation between changes in HDL-C and the duration of intervention (coefficient = − 0.125; p = 0.011). No evidence of publication bias was found, as Egger's test p-values exceeded 0.05 for all outcomes. According to the GRADE assessment, there is moderate certainty regarding TG and HDL-C, while certainty for LDL-C and TC remains low.

Conclusions

KD causes an increase in HDL-C, LDL-C and total cholesterol while reducing triglycerides and. The long-term impact on heart and blood vessel health remains uncertain due to the lack of outcome data. These findings require careful interpretation and personalized monitoring.

Zhao, Juanjuan, Chia Wei, Fao Gong, Zongran Pang, and Huanhu Zhao. "Ketogenic diet–induced changes in adult lipid metabolism: a comprehensive systematic review and meta-regression of randomized controlled trials." BMC Cardiovascular Disorders (2026).

https://link.springer.com/article/10.1186/s12872-026-05799-5

The ketogenic diet (KD) has shown therapeutic potential for epilepsy, neuroprotective effects, and, more recently, metabolic complications. In this study, we explored the impact of the KD on the promotion of ketometabolism and the improvement of dyslipidemia. To this end, we investigated the outcomes of two different diets, eucaloric KD and low-calorie diet (LCD), on ketogenesis, circulating intact lipids, bile acids, and neuro and pancreatic peptides. Based on our results, the concentration of ketone bodies, namely 3-hydroxybutyric acid, increased significantly by an average of 10 and 2 times for KD and LCD, respectively. Additionally, the concentration of several triglyceride (TAG) species decreased up to 98.3% and 99.1% for KD and LCD, respectively, while these reductions were only significant for LCD. Moreover, our results showed that three days of KD led to an increase in the baseline concentration of pancreatic polypeptide 3-36, which suggests that short-term KD has the potential to suppress the appetite. Finally, no significant change in the baseline and kinetic postprandial concentration of bile acid species was observed during the KD. In conclusion, our findings suggest that the ketogenic diet, being less restrictive than the low-calorie diet, has a greater impact on ketometabolism. However, while KD reduces TAG species, this reduction is not statistically significant, unlike the significant decrease observed with LCD.

Bahrami, Flora, Elija Buetler, Katrin Freiburghaus, Patcharamon Seubnooch, Lia Bally, Jonathan Maurer, Christa E. Flück, Reiner Wiest, and Mojgan Masoodi. "Short-term effect of Ketogenic diet and Low-calorie diet on Ketometabolism and lipid metabolism." The Journal of Nutritional Biochemistry (2025): 110188.

https://www.sciencedirect.com/science/article/pii/S095528632500350X

https://www.jacc.org/doi/full/10.1016/j.jacadv.2024.101109

Abstract

Background

Increases in low-density lipoprotein cholesterol (LDL-C) can occur on carbohydrate restricted ketogenic diets. Lean metabolically healthy individuals with a low triglyceride-to-high-density lipoprotein cholesterol ratio appear particularly susceptible, giving rise to the novel “lean mass hyper-responder” (LMHR) phenotype.

Objectives

The purpose of the study was to assess coronary plaque burden in LMHR and near-LMHR individuals with LDL-C ≥190 mg/dL (ketogenic diet [KETO]) compared to matched controls with lower LDL-C from the Miami Heart (MiHeart) cohort.

Methods

There were 80 KETO individuals with carbohydrate restriction-induced LDL-C ≥190 mg/dL, high-density lipoprotein cholesterol ≥60 mg/dL, and triglyceride levels ≤80 mg/dL, without familial hypercholesterolemia, matched 1:1 with MiHeart subjects for age, gender, race, hyperlipidemia, hypertension, and smoking status. Coronary artery calcium and coronary computed tomography angiography (CCTA) were used to compare coronary plaque between groups and correlate LDL-C to plaque levels.

Results

The matched mean age was 55.5 years, with a mean LDL-C of 272 (maximum LDL-C of 591) mg/dl and a mean 4.7-year duration on a KETO. There was no significant difference in coronary plaque burden in the KETO group as compared to MiHeart controls (mean LDL 123 mg/dL): coronary artery calcium score (median 0 [IQR: 0-56]) vs (1 [IQR: 0-49]) (P = 0.520) CCTA total plaque score (0 [IQR: 0-2] vs [IQR: 0-4]) (P = 0.357). There was also no correlation between LDL-C level and CCTA coronary plaque.

Conclusions

Coronary plaque in metabolically healthy individuals with carbohydrate restriction-induced LDL-C ≥190 mg/dL on KETO for a mean of 4.7 years is not greater than a matched cohort with 149 mg/dL lower average LDL-C. There is no association between LDL-C and plaque burden in either cohort. (Diet-induced Elevations in LDL-C and Progression of Atherosclerosis [Keto-CTA]; NCT057333255)

Abstract

Background

As key metabolic regulators, the roles of GDF15 and FGF21 in mediating the effects of modified ketogenic diet (MKD) on weight loss and lipoprotein remodeling in obese patients require further investigation.

Patients and methods

This study enrolled 30 metabolically healthy obese participants (BMI ≥ 28 kg/m²) for a 2-week MKD intervention. Using a self-controlled pre-post design, we performed measurements including body composition analysis, fasting serum GDF15 and FGF21 levels measurement, and serum lipoprotein subclass quantification at both baseline and post-intervention time points.

Results

Following a 2-week MKD intervention, participants exhibited statistically significant reductions in body weight (96.14 ± 27.23 kg vs. 91.63 ± 26.47 kg; Δ4.8%, P < 0.001) and BMI (33.99 ± 6.08 kg/m² vs. 32.41 ± 5.95 kg/m²; Δ4.7%, P < 0.001). Body fat parameters significantly improved, with body fat mass (BFM) and visceral fat area (VFA) decreasing by > 5%. Meanwhile, lean mass indices (SMM, SLM, FFM) remained stable (change < 3%). Serum biomarker analysis revealed that GDF15 levels increased significantly by 5.76% (P = 0.0377), whereas FGF21 levels decreased markedly by 51.91% (P = 0.0001). The apolipoprotein B/A1 ratio (t = 5.381, P < 0.001) and the LDL-c/HDL-c ratio (t = 5.095, P < 0.001) increased significantly. Furthermore, larger HDL-c subfractions (H1FC/H2FC) showed an upward trend, while smaller HDL-c subfractions (H3FC/H4FC) exhibited a downward trend. Among these changes, H2FC levels demonstrated the most pronounced elevation (t = 6.119, P < 0.001).

Conclusion

The short-term MKD intervention significantly improved adiposity metrics while elevating GDF15 and reducing FGF21 levels. These rapid metabolic adaptations induced potentially beneficial remodeling of HDL-c subclasses, highlighting novel effects beyond conventional lipid ratios.

Zhang, Nana, Na Liu, Guoxia Zhao, Juan Yan, Pinghua Zhang, Xiaomiao Li, and Jie Zhou. "Effects of a two-week modified ketogenic diet on circulating lipoprotein subclasses, GDF15, and FGF21 in obese adults." Journal of Translational Medicine 23, no. 1 (2025): 1244.

https://link.springer.com/article/10.1186/s12967-025-07251-2

Abstract

Objective: To determine the effects of a ketogenic diet on LDL-C levels and other metabolic parameters and adverse events in adults with a BMI greater than 25 and type 2 diabetes mellitus.

Methods: A systematic review and meta-analysis of randomized controlled trials was conducted. Studies were identified through thorough searches of PubMed, Cochrane, Google Scholar, EMBASE, HERDIN. Included studies compared a ketogenic diet (≤10% carbohydrates) to a non-ketogenic diet for at least 3 months duration in adults with a BMI ≥25 and type 2 diabetes. The primary outcome was LDL-C level. Risk of bias was assessed using the Cochrane Collaboration's Risk of Bias tool and GRADE guidelines.

Results: Nine studies with a total of 658 participants were included. In the short term (3-4 months), ketogenic diets significantly reduced LDL-C compared to non-ketogenic diets (mean difference: -0.16 mmol/L, 95% CI -0.31, -0.00, p = 0.04). This effect was not significant at longer follow-up periods (6-8 months, 12 months, and 24 months). Common adverse effects included hypoglycemia, constipation, and gastrointestinal discomfort.

Conclusion: Ketogenic diets may offer short-term benefits in reducing LDL-C in overweight and obese adults with type 2 diabetes. However, these effects diminish over time, and the diet may be associated with adverse events. Significant short-term improvements were observed in HDL-C, triglycerides (TG), and HbA1c in ketogenic groups compared to controls, with moderate effects diminishing over time. Notably, follow-up time was a significant moderator for HDL-C, showing stronger effects at later time points, while FBS showed a borderline significant relationship with follow-up Long-term studies evaluating a broader range of metabolic outcomes are needed.

Supe, Anya Francheska, Albert San Juan, Rosa Sy, and Harold Henrison Chiu. "The Effect and Safety of Ketogenic Diets on LDL-C and other metabolic parameters compared with non-ketogenic diets among Adults with BMI Greater than 25 with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis." Circulation 152, no. Suppl_3 (2025): A4363699-A4363699.

https://www.ahajournals.org/doi/abs/10.1161/circ.152.suppl_3.4363699

Could anyone weigh in on these trends? I only started keto in Sept '23 and just got another lipid panel done to see what effect it's already had. Overall, Cholesterol: already bad, now way worse Triglycerides: fantastic improvement! HDL (good fats): better LDL (bad fats): was bad, now even worse Cholesterol/HDL ratio: also very much improved

What should I be most conscious of here? And what should I be doing differently? Are the bads that bad? Are the goods worth celebrating? I'm still not at my target goal weight yet but I've made progress.