Researchers recently explored the role of lipid-lowering drug targets in diabetic retinopathy using Mendelian randomization. They found that peroxisome proliferator-activated receptor gamma enhancement is associated with a lower risk of diabetic retinopathy, particularly in its early and proliferative stages, and could be a potential therapeutic avenue.
In the study, published in British Journal of Ophthalmology, the researchers assessed causal relationships among lipid traits, lipid-lowering drug targets, and full-course diabetic retinopathy (DR), which can be further broken into three main courses that depend on lesion severity: background DR, severe nonproliferative DR (NPDR), and proliferative DR (PDR).
“At present, the main treatment strategies for DR include panretinal photocoagulation, antivascular endothelial growth factor drug treatment, and surgical treatment, which have the drawbacks of being invasive and having multiple complications,” wrote the study authors, who were led by Jiahui Cao, of the Guangdong Eye Institute at Southern Medical University in China.
They extracted genetic variants linked to lipid traits from the Global Lipids Genetics Consortium and UK Biobank and obtained DR-related genetic data from the FinnGen consortium.
The researchers used two-sample Mendelian randomization (MR) to analyze the relationship between lipid levels and DR risk. They used drug-target MR to examine the effects of genes encoding lipid-lowering drug targets and mediation MR analysis to investigate whether the impact of peroxisome proliferator-activated receptor gamma (PPARG) was mediated through glucose metabolism.
They found no statistically significant causal relationship between traditional lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, total cholesterol) and full-course DR after adjusting for multiple comparisons. However, PPARG activation was significantly associated with a lower risk of DR. Specifically, the odds ratio (OR) for background DR was 0.12 (P = .005) and 0.25 (P = .006) for PDR with PPARG activation. Apolipoprotein B (ApoB) inhibition was linked to an increased risk of PDR (OR = 1.19, 95% confidence interval [CI] = 1.02–1.38, P = .022), while lipoprotein lipase (LPL) and PPARG showed protective effects against type 2 diabetes, a major risk factor for DR. The protective effect of PPARG on DR was largely mediated by glucose control rather than the lipid-lowering effect. Mediation proportions were 27.8% (95% confidence interval [CI] = 5.4%–50.3%, P = .015) for lower fasting insulin levels and 36.4% (95% CI = 11.1%–61.8%, P = .005) for lower HbA1c levels.
While “dyslipidaemia is one of the most common comorbidities of diabetes mellitus and plays a significant role in full-course DR’s pathogenesis … this study could not provide compelling evidence to support the association between lipid traits and DR … [and] recent studies did not obtain a significant association between dyslipidaemia and DR,” the study authors noted.
“Given the results of our analysis,” they wrote, “PPARG enhancement is significantly associated with a lower risk of background DR and PDR. PPARG is the main modulator of adipogenesis, which can enhance lipid storage, insulin sensitivity, and glucose metabolism through the lipid-stealing effect. Furthermore, PPARG is associated with inflammation, angiogenesis, neural homeostasis, and redox balance, which are all vital pathological mechanisms of DR,” the study authors indicated.
The researchers were not able to directly equate genetic effects with short-term drug interventions, and limited data on severe NPDR may have affected results. They suggested further research on correlations among LPL, ApoB, and full-course DR as well as any effects of PPARG agonists on the retinal structures of patients with DR.
“PPARG is a promising candidate drug target for full-course DR,” the study authors concluded.
No competing interests were declared.