Risk reduction of ASCVD attributed to lowering of remnant cholesterol from statins, fibrates, APOC3 inhibitors, and ANGPTL3 inhibitors: a cohort study

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Conflicts of Interest

Identified Weaknesses

Rating Explanation

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Paper Summary

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New Cholesterol Drugs *Might* Be Great for Your Heart (But We Need a Real Trial to Know)

This observational cohort study suggests that lowering remnant cholesterol, as seen with new APOC3 and ANGPTL3 inhibitors, could reduce 10-year ASCVD risk by 1.4%-4.1%, with greater reductions seen in statin users. However, these are predictions based on observational data and previous genetic studies, assuming a causal link between remnant cholesterol and ASCVD; large randomized controlled trials are needed to confirm these findings.

Possible Conflicts of Interest

Anne Langsted has received honoraria/consultancies from Amarin and Novartis. Anne Langsted and Anette Varbo are employed at Novo Nordisk. Børge G. Nordestgaard reports consultancies/talks for AstraZeneca, Sanofi, Ionis, Amgen, Amarin, Novartis, Novo Nordisk, Esperion, Lilly, Arrowhead, and Marea.

Identified Weaknesses

Observational Study, not RCT

The study's predictions are based on an observational cohort, not a randomized controlled trial (RCT). Observational studies can show correlations but not definitively prove cause-and-effect relationships. Only an RCT with a control group and rigorous design can definitively prove if lowering remnant cholesterol actually reduces ASCVD events.

Reliance on Unconfirmed Causality

The study's results rely on previous genetic and observational data, assuming a causal relationship between remnant cholesterol and ASCVD. While suggestive, this causal link is yet to be confirmed by large-scale intervention trials. Predictions are based on this assumption, which might not hold true in reality.

Potential Residual Confounding

While the study adjusted for various known risk factors, there is always the possibility of residual confounding. Unknown factors could influence both remnant cholesterol and ASCVD risk, making the study's predictions less accurate.

Limited Generalizability

The study population consists solely of white Europeans, limiting the generalizability of findings to other ethnic groups. Different populations may have different genetic and environmental factors influencing cholesterol metabolism and ASCVD risk.

Reliance on Early-Phase Trial Data

The predictions are based on assumptions of specific reductions in remnant cholesterol (15%, 30%, 50%, and 80%) mirroring those seen in small, early-phase trials. Actual reductions achieved in larger, later-phase trials might differ, impacting predicted risk reductions.

Rating Explanation

This is a well-conducted observational study with interesting findings. However, it cannot prove cause-and-effect due to inherent limitations of observational designs. Its reliance on unconfirmed causality between remnant cholesterol and ASCVD and limited generalizability weaken the conclusions. The declared conflicts of interest also impact the rating.

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Topic Hierarchy

Domain:

Health Sciences

Field:

Medicine

Subfield:

Cardiology and Cardiovascular Medicine

File Information

Original Title:

Risk reduction of ASCVD attributed to lowering of remnant cholesterol from statins, fibrates, APOC3 inhibitors, and ANGPTL3 inhibitors: a cohort study

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August 20, 2025 at 08:05 PM

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