Genetic proxies for CETP inhibition were linked to higher AMD risk

Design

Drug-target Mendelian randomisation and genetic association analyses

Population

457,242 UK Biobank and 7,058 Singapore eye study participants

Primary outcome

Risk of AMD subtypes

Effect

Advanced AMD OR 1.45 (95% CI 1.25-1.67) in Europeans; exudative AMD OR 3.14 (2.16-4.57) in East Asians

CETP inhibitors raise HDL and are being studied again for cardiovascular disease. This study used drug-target Mendelian randomisation in about 457,000 UK Biobank participants and 7,058 participants of a Singapore eye study to ask whether lifelong genetic CETP inhibition is linked to macular degeneration.

Greater genetically proxied inhibition was associated with higher risk of advanced AMD (OR 1.45, 95% CI 1.25-1.67) and early AMD (OR 1.29) in Europeans. In East Asians, it was associated with exudative AMD (OR 3.14), typical neovascular AMD and polypoidal choroidal vasculopathy. In the observational genetic score analysis, the per-standard-deviation effect was small (HR 1.03).

Mendelian randomisation mimics a lifelong exposure and relies on assumptions that cannot all be tested; it is not evidence from treated patients.

This is a safety signal for trialists and regulators to look for, not a reason for any change in current prescribing.

• Genetic proxies for CETP inhibition were linked to higher AMD risk in two ancestries.
• Signals were strongest for exudative AMD and polypoidal choroidal vasculopathy in East Asians.
• This is genetic evidence, not data from patients taking a CETP inhibitor.
• Look for retinal outcomes in reports of CETP inhibitor trials.

Why it matters

If CETP inhibitors return to cardiology, ophthalmologists may be asked about their eye safety before trial data exist.

Don't overread it

Genetic proxies are not drug exposure; this does not show CETP inhibitor drugs cause AMD.

The statistics, in plain English

Mendelian randomisation uses inherited variation as a natural experiment. Odds ratios here describe lifelong genetic differences, which may be larger than the effect of a few years of a drug.

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