Folate Pathway Polymorphisms and Tadalafil Response in Men with Diabetes Mellitus and Erectile Dysfunction: An Exploratory Study

Background/Objectives: Erectile dysfunction (ED) is a common complication of diabetes mellitus (DM), largely driven by endothelial dysfunction and impaired nitric oxide signaling. Although phosphodiesterase type 5 inhibitors (PDE5i) such as tadalafil are effective, treatment response varies considerably between individuals. Genetic variation in the folate–homocysteine pathway may influence endothelial function and contribute to this variability. To investigate the association of selected polymorphisms in folate–homocysteine pathway genes (MTHFR rs1801133 and rs1801131, MTR rs1805087 and MTRR rs1801394) with ED severity and response to tadalafil treatment in men with DM. Methods: In this prospective exploratory pharmacogenetic study, 78 men with DM and ED were treated with tadalafil 5 mg once daily for three months. ED was assessed using the International Index of Erectile Function (IIEF-5) questionnaire before and after treatment. The pre-specified primary endpoint was treatment response, defined as a ≥4-point increase in IIEF-5 score (based on the minimal clinically important difference for the IIEF erectile function domain). Genotyping was performed using competitive allele-specific PCR. Associations between genetic variants and treatment outcomes were evaluated using logistic regression. Results: Before treatment 24 patients (30.8%) had moderate or severe ED. No significant associations were observed between the investigated polymorphisms and baseline ED severity. IIEF-5 scores significantly increased during the three-month tadalafil treatment period, with 80.8% of patients showing improvement and 60.3% achieving a clinically relevant increase of ≥4 points in IIEF-5 score. None of the investigated polymorphisms was associated with the primary endpoint after Bonferroni correction across the three global genotype tests. In the secondary ‘any improvement’ analysis, a nominal association was observed for MTR rs1805087 in a small subgroup (n = 5 GG carriers; unadjusted OR = 0.15, 95% CI 0.02–0.89; p = 0.037), which was attenuated after multivariable adjustment (OR = 0.16, 95% CI 0.02–1.08, p = 0.060) and is regarded as hypothesis-generating only. Conclusions: Genetic variation in the folate pathway does not appear to influence baseline ED severity or tadalafil responsiveness in men with DM, although this exploratory study was not powered to exclude modest genetic effects. These preliminary findings require confirmation in larger studies that also incorporate plasma homocysteine and B-vitamin measurement.