Using Genetic Variants in the Targets of Lipid Lowering Therapies to Inform Drug Discovery and Development: Current and Future Treatment Options
Abstract
Mendelian randomization studies and “human knock‐out” studies of rare loss‐of‐function coding variants suggest that plasma levels of low‐density lipoprotein‐cholesterol LDL‐C, triglycerides (TGs), and lipoprotein(a) (Lp(a)) are causally associated with the risk of cardiovascular disease, and, therefore, therapies directed against these targets should reduce the risk of cardiovascular events. However, several therapies directed against these targets have failed to reduce the risk of cardiovascular events in large‐scale randomized trials, thus suggesting that causality is not sufficient evidence to establish genetic target validation. Instead, the critical question that needs to be answered to improve drug discovery and development is how much a causal biomarker needs to be changed to produce a clinically meaningful benefit in a short‐term trial. This review describes how to use naturally randomized genetic evidence to accurately anticipate the results of randomized trials evaluating current and future lipid lowering therapies, inform the design of randomized trials, and transform the drug discovery and development process.
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LDL-C lowering variants in HMGCR, PCSK9, NPC1L1 associate with CHD.
“LDL-C lowering variants in HMGCR PCSK9 , NPC1L1 115 associate with CHD”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [107]
A factorial study of MR predicted effects of PCSK9 inhibition and HMGCR inhibition on CHD and type II diabetes exists.
“as, for example, in a factorial study of MR predicted effects of PCSK9 inhibition and HMGCR inhibition on CHD and type II diabetes 107 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [107]
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- Authors
- Ference, B. A.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Ference, Brian A.
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2018-08-06
- Volume
- 105
- Issue
- 3
- Pages
- 568-581
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- OpenAlex
- W2810911464
- Cited by
- 8
- References
- 65
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 1 · 2021: 3 · 2019: 1 · 2018: 1
- FWCI
- 0.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- lipid-lowering therapy, LDL cholesterol, triglycerides, lipoprotein(a), Mendelian randomization, loss-of-function mutations, cardiovascular risk, drug development, randomized trial design, PCSK9 inhibitors, SGLT2 inhibitors
- MeSH terms
- Drug Development, Animals, Hypolipidemic Agents, Forecasting, Humans, Cholesterol, HDL, Cholesterol, LDL, Genetic Variation, Drug Delivery Systems, Treatment Outcome, Drug Discovery, Mendelian Randomization Analysis
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