Peroxisome proliferator-activated receptor alpha genetic variability and cardiovascular prevention: a precision medicine study in type 2 diabetes

Background: Cardiovascular disease is one of the main causes of mortality in type 2 diabetes patients. Recently the rs6008845 single nucleotide polymorphism (SNP) on the peroxisome proliferator-activated receptor alpha (PPARA) locus) has been found to influence the cardiovascular response to fenofibrate (a PPAR-alpha agonist, whose cardiovascular indication is currently for patients with atherogenic dyslipidaemia). We evaluated the association between this SNP with baseline cardiovascular risk, and with the response to fenofibrate on top of statin, in terms of arterial stiffness and endothelial dysfunction, in a randomized clinical trial in patients with type 2 diabetes. Methods: The present study was a randomized control trial on adult patients with type 2 diabetes at high or very high cardiovascular risk, in statin therapy, low-density lipoprotein (LDL)-c < 100 mg/dL, triglycerides < 200 mg/dL, and HbA1C < 8%. We genotyped rs6008845 and other 5 SNPs on the PPARA locus known to be associated with PPARA expression in different tissues (allowing to build an expression quantitative trait loci genetic risk score – eQtGRS – for PPARA expression). Endothelial function was measured through reactive hyperaemia index (RHI) and arterial stiffness through augmentation index (standardized for 75 bpm, AI75), both using the Endo-PAT system; arterial stiffness was measured through carotid-femoral pulse wave velocity (cfPWV), assessed by the SphygmoCor software. The patients were then randomized to placebo or fenofibrate and were evaluated at baseline and after 12 weeks of treatment. Results: The population analysed comprised 42 subjects, 20 randomized to placebo and 22 to fenofibrate. The study included 7 (16.7%) females, an average of: 12 (8-18) years of diabetes duration, HbA1C =6.6±0.6, total cholesterol = 134.2±23.1 mg/dL, LDL=64.5±17.0 mg/dL, triglycerides =93 (76-120) mg/dL); 15 (35.7%) were treated in secondary prevention; 8 (19.0%) patients used SGLT2 inhibitors, 22 (52.4%) used GLP1-RA. 17 subjects were T/T homozygous for the rs6008845 locus, and 25 showed a non-T/T genotype (T/C+C/C, the genotypes expected to not benefit from the treatment). No significant associations were found between rs6008845 and baseline clinical characteristics, except a nominal lower prevalence among T/T subjects of baseline macrovascular disease (defined as carotid atheromasia and/or prior cardiovascular disease event). No association between baseline conditions and eQtGRS was found either. Overall fenofibrate had no effect on RHI, AI, and cfPWV. However, when stratified by the rs6008845 genotype, fenofibrate reduced AI75 among T/T subjects (estimate=-12.85%, SE=4.72%, p=0.03) but not among carriers of other genotypes (TC/CC, estimate=9.22%, SE=7.42%, p =0.23), with a p for interaction almost significant (0.06). A similar non-significant trend was observed on cfPWV, while on RHI the fenofibrate response was similar across genotypes. Conclusions: These exploratory analyses suggest that subjects carrying the T/T genotype of rs6008845 may experience a cardiovascular benefit from fenofibrate even in the absence of hypertriglyceridemia and on top of statin treatment. Such effect has been observed mainly as a fenofibrate-induced reduction in arterial stiffness, but not on endothelial function. A larger sample size is required to further confirm these findings.