| Title: | Evaluating the Cardiometabolic Efficacy and Safety of Lipoprotein Lipase Pathway Targets in Combination With Approved Lipid-Lowering Targets: A Drug Target Mendelian Randomization Study |
| Journal: | Circulation Genomic and Precision Medicine |
| Published: | 7 Mar 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40052268/ |
| DOI: | https://doi.org/10.1161/circgen.124.004933 |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/7617573 |
Publication 16213
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Abstract
BACKGROUND: Therapies targeting the LPL (lipoprotein lipase) pathway are under development for cardiometabolic disease. Insights into their efficacy-both alone and in combination with existing lipid-lowering therapies-modes of action, and safety of these agents are essential to inform clinical development. Using Mendelian randomization, we aimed to (1) evaluate efficacy, (2) explore shared mechanisms, (3) assess additive effects with approved lipid-lowering drugs, and (4) identify secondary indications and potential adverse effects.</p>
METHODS: We selected triglyceride-lowering genetic variants located in the genes encoding ANGPTL3 (angiopoietin-like 3), ANGPTL4 (angiopoietin-like 4), APOC3 (apolipoprotein C3), and LPL and conducted drug target Mendelian randomization on primary outcomes including coronary artery disease and type 2 diabetes, and secondary outcomes, including apolipoprotein B, waist-to-hip ratio, body mass index, and 233 metabolic biomarkers. We conducted interaction Mendelian randomization analyses in 488 139 UK Biobank participants to test the effect of combination therapy targeting the LPL and LDLR (low-density lipoprotein receptor) pathways. Finally, we investigated potential secondary indications and adverse effects by leveraging genetic association data on 1204 disease end points.</p>
RESULTS: Genetically predicted triglyceride lowering through the perturbation of LPL pathway activation targets ANGPTL4, APOC3, and LPL was associated with a lower risk of coronary artery disease and type 2 diabetes and lower apolipoprotein B. Genetically predicted triglyceride lowering through ANGPTL4 was associated with a lower waist-to-hip ratio, suggestive of a favorable body fat distribution. There was no evidence of a multiplicative interaction between genetically proxied perturbation of ANGPTL4, APOC3, and LPL and that of HMGCR (HMG-CoA reductase) and PCSK9 (proprotein convertase subtilisin/kexin type 9) on coronary artery disease and type 2 diabetes, consistent with additive effects. Finally, associations of genetically predicted LPL pathway targeting were supportive of the broad safety of these targets.</p>
CONCLUSIONS: Our findings provide genetic evidence supporting the efficacy and safety of LPL pathway activation therapies for the prevention of coronary artery disease and type 2 diabetes, alone or in combination with statins or PCSK9 inhibitors.</p>
14 Keywords
- Angiopoietin-Like Protein 3
- Angiopoietin-Like Protein 4
- Apolipoprotein C-III
- Coronary Artery Disease
- Diabetes Mellitus, Type 2
- Female
- Humans
- Hypolipidemic Agents
- Lipoprotein Lipase
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Polymorphism, Single Nucleotide
- Triglycerides
10 Authors
- Eloi Gagnon
- Dipender Gill
- Dominique Chabot
- Héléne T. Cronjé
- Shuai Yuan
- Stephen Brennan
- Sébastien Thériault
- Stephen Burgess
- Benoit J. Arsenault
- Marie-Joe Dib
1 Application
| Application ID | Title |
|---|---|
| 25205 | Identification and characterization of functional variants with a causal role in chronic cardiopulmonary diseases |
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