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Cited by 10Genetic Associations and EpidemiologyLipoproteins and Cardiovascular HealthDiabetes, Cardiovascular Risks, and Lipoproteins

Multiomic Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations

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Rosoff, Daniel B., Wagner, Josephin, Jung, Jeesun, Pacher, Pal, Christodoulides, Constantinos, Davey Smith, George, Ray, David, Lohoff, Falk W.·2025·Diabetes
DOI 10.2337/db24-0451PMC PMC11664021
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Abstract

The prevalence of type 2 diabetes (T2D) varies among populations of different races/ethnicities. The influence of genetically proxied LDL cholesterol lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA reductase (HMGCR) on T2D in non-European populations is not well established. A drug target Mendelian randomization approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and Europe (EUR). Our study did not find relationships between genetically proxied PCSK9 inhibition and T2D risk in the EAS (odds ratio [OR] 1.02; 95% CI 0.95–1.10), SAS (1.05; 0.97–1.14), HISP (1.03; 0.94–1.12), or EUR population (1.04; 0.98–1.11). However, in the AFR population, primary analyses suggested an increased risk of T2D resulting from PCSK9 inhibition (OR 1.53; 95% CI 1.058–2.22; P = 0.024), although this was not supported in sensitivity analyses. Genetically proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR 1.44; 95% CI 1.30–1.61; P = 9.8 × 10−12), EAS (1.36; 1.22–1.51; P = 4.2 × 10−10), and EUR populations (1.52; 1.21–1.90; P = 3.3 × 10−4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-EUR populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in SAS, EAS, and EUR cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases. Article Highlights:

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  • The discordance between the meta-analysis and Mendelian randomization studies on diabetes risk most likely arises because genetic studies reflect lifetime exposure compared to short-term pharmacological interventions.

    “Furthermore, we found no significant association between PCSK9 inhibition and diabetes (RR 1.04; 95% CI 0.77 to 1.41; I2 = 0%), despite the weak signal reported in some Mendelian randomization studies[30,31], with the discordance most likely arising from the fact that genetic studies reflect lifetime exposure as compared to short-term pharmacological interventions.”

    From Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials (2026) · cites this paper as [31]

    The Introduction (page unavailable) notes that trials found no adverse effect of PCSK9 inhibition on diabetes risk while early MR studies suggested an increase, though more recent MR studies did not confirm it. The Discussion (page unavailable) distinguishes genetic effects of long-term HMGCR inhibition from shorter statin therapy, but does not say that exposure duration is the most likely explanation for the PCSK9 findings. (LLM, conf=0.85)

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Authors
Rosoff, D. B., Wagner, J., Jung, J., Pacher, P., Christodoulides, C., Davey Smith, G., Ray, D., & Lohoff, F. W.
Affiliations
  • National Institutes of Health (US)
  • 4Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
  • University of Oxford (GB)
  • 3Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
  • John Radcliffe Hospital (GB)
Corresponding author
Lohoff, Falk W.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2024-10-17
Volume
74
Issue
1
Pages
120-130
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db24-0451
PMC
PMC11664021
OpenAlex
W4403510026
Cited by
10
References
52
Citations by year
2026: 5 · 2025: 5
FWCI
2.65
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/journals/pages/license (vor)
Locations
  • Diabetes (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Explore Bristol Research (publishedVersion)
  • Bristol Research (University of Bristol) (submittedVersion)
Funders
Clinical Center (ZIA-AA000242)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
type 2 diabetes, PCSK9 inhibition, HMGCR inhibition, statins, LDL cholesterol lowering, genetic proxies, drug-target Mendelian randomization, glycemic traits, ethnic differences, African populations, South Asian populations, East Asian populations, Hispanic population, colocalization, triglycerides, HDL cholesterol
MeSH terms
Proprotein Convertase 9, Diabetes Mellitus, Type 2, Europe, Female, Humans, Hydroxymethylglutaryl CoA Reductases, Cholesterol, LDL, Male, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Polymorphism, Single Nucleotide, Mendelian Randomization Analysis

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