Apparent Nonresponse to PCSK9 Inhibition in a Patient With Heterozygous Familial Hypercholesterolemia Due to PCSK9 Gene Duplication
Bibliographic record
Abstract
BACKGROUND: Heterozygous familial hypercholesterolemia is a genetic disorder characterized by persistently elevated low-density lipoprotein (LDL-C) levels and increased cardiovascular risk. Management includes statins as well as nonstatin lipid-lowering agents, such as ezetimibe, bempedoic acid, and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9). Although PCSK9 inhibition is a potent mechanism to reduce levels of LDL-C, a small percentage of patients respond poorly for reasons that are not fully understood. CASE SUMMARY: A 52-year-old woman presented with persistently elevated LDL-C and a history of atherosclerotic cardiovascular disease. Her LDL-C levels remained elevated despite high-intensity statin therapy and ezetimibe. She was treated with various inhibitors of PCSK9 but displayed little or no reduction in LDL-C levels. Genetic testing identified a duplication of the PCSK9 gene. Treatment with a higher dose of evolocumab (420 mg every 2 weeks) led to a more pronounced reduction in LDL-C levels. DISCUSSION: This case identifies PCSK9 gene duplication as a potential mechanism underlying nonresponse to PCSK9 inhibition and suggests that higher dosing of PCSK9 inhibitors may overcome nonresponse in some patients.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".