Abstract 18: Bempedoic Acid Lowers Low Density Lipoprotein-Cholesterol and Attenuates Aortic Atherosclerosis in LDL Receptor-Deficient ( <i> LDLR <sup>+/-</sup> </i> and <i> LDLR <sup>-/-</sup> </i> ) Yucatan Miniature Pigs
Bibliographic record
Abstract
Bempedoic acid (ETC-1002) is an oral investigational drug that targets hepatic adenosine triphosphate-citrate lyase to reduce cholesterol biosynthesis. In Phase 2 studies (up to 12 weeks in duration), bempedoic acid lowers elevated LDL-cholesterol (C) in patients with hypercholesterolemia. The objective of the present study was to test the ability of bempedoic acid to decrease plasma-C and LDL-C, and attenuate the development of atherosclerosis in a large animal model of familial hypercholesterolemia. Gene targeting has been used to generate Yucatan miniature pigs heterozygous ( LDLR +/- ) or homozygous ( LDLR -/- ) for LDL-receptor (R) deficiency (ExeGen). LDLR +/- pigs (n=12) and LDLR -/- pigs (n=12) were fed a high fat, cholesterol-containing diet (34% kcal fat; 0.2% cholesterol) and orally administered placebo or bempedoic acid at 120 mg/d and at 240 mg/d for 160 days. Bempedoic acid was well tolerated; weight gain, caloric intake, liver enzymes and clinical chemistry analyses were unaffected by treatment. In LDLR +/- pigs at 160 days, compared to placebo, bempedoic acid significantly decreased plasma-C and LDL-C up to 43% ( P <0.01) and 63% ( P <0.002), respectively. Compared to LDLR-/- placebo pigs, in which plasma-C and LDL-C were 5-fold higher than in LDLR +/- placebo pigs, bempedoic acid significantly decreased plasma-C and LDL-C up to 26% ( P <0.04) and 29% ( P <0.03), respectively. Plasma levels of triglycerides and HDL-C, fasting glucose and insulin, and liver lipids were not affected by treatment in either genotype. In the aorta of LDLR +/- pigs, bempedoic acid treatment robustly attenuated total Sudan IV-stained lesion area (-58%, P <0.02) and area of raised lesions in the abdominal aorta (-58%, P <0.03). In LDLR -/- pigs, in which total aortic lesion area (6-fold) and area of raised abdominal lesions (12-fold) were substantially larger compared to LDLR +/- pigs, bempedoic acid significantly decreased total aortic lesion area (-47%, P <0.01) and area of raised abdominal lesions (-50%, P <0.03). The present experiments demonstrate that in a large animal model of LDLR-deficiency and atherosclerosis, long term treatment with bempedoic acid reduces LDL-C and attenuates the progression of aortic atherosclerosis in both LDLR +/- and LDLR -/- miniature pigs.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".