Introduction: Erectile dysfunction (ED) is a highly prevalent complication of diabetes mellitus (DM), significantly impairing quality of life and psychosocial well‐being. The prevalence of ED is estimated to be over 3.5 times higher in men with diabetes mellitus compared to those without. The aetiology of diabetic ED is multifactorial, stemming from complex diabetes mellitus‐related systemic changes. The pathophysiology of diabetic ED involves interacting pathways, including endothelial dysfunction, accelerated atherosclerosis, autonomic and peripheral neuropathy, structural penile changes, hormonal imbalances, and psychological factors. Methods: A review of the literature was conducted to examine the pathophysiological mechanisms, genetic associations, and treatment modalities related to diabetic ED. Particular attention was given to studies exploring pharmacogenetics and emerging therapeutic interventions. Results: Management is multimodal, including lifestyle changes, counselling, and pharmacological agents (primarily phosphodiesterase type 5 inhibitors (PDE5Is)), but treatment response varies. Genetic studies have identified associations between ED risk/severity and polymorphisms in several candidate genes, including NOS3 (G894T, T786C, VNTR), ARG1/ARG2 (influencing nitric oxide substrate availability), ACE (I/D polymorphism), AR (CAG repeat length affecting androgen sensitivity), and VEGF (promoter polymorphisms). Pharmacogenetic studies suggest that polymorphisms in NOS3 , AR , and VEGF may predict response to PDE5Is or testosterone therapy, while ARG1/ARG2 variations might guide future arginase‐targeted therapies. Emerging treatments like low‐intensity shockwave therapy, platelet‐rich plasma, gene therapy, and stem cell therapy show promise but require more robust evidence. Conclusions: Diabetic ED is a complex condition driven by multiple pathophysiological mechanisms often influenced by an underlying genetic predisposition. Understanding the interplay between pathophysiology and genetics is crucial for developing personalised treatment strategies. While current therapies offer benefits, variability in response highlights the need for tailored approaches. Further research, especially large‐scale pharmacogenetic studies and randomised controlled trials for emerging therapies, is essential to identify reliable biomarkers, optimise treatment selection, and improve outcomes for men with diabetic ED.

This study investigated whether common polymorphisms in the NOS3, VEGF, ACE and ACE2 genes are associated with erectile dysfunction (ED) severity and response to tadalafil treatment in men with diabetes mellitus (DM). Seventy-eight men with DM and ED received tadalafil 5 mg once daily for 3 months. Erectile function was assessed using the 5-item International Index of Erectile Function (IIEF-5) at baseline and post-treatment. Genotyping was performed using competitive allele-specific PCR and conventional PCR for the ACE insertion/deletion polymorphism. Tadalafil significantly improved median IIEF-5 scores from 14 (IQR 11–17) to 19.5 (IQR 16–22) (p < 0.001), with 47 patients (60.3%) classified as responders (≥ 4-point increase). A nominal association with baseline ED severity was observed for ACE2 rs2285666, as T allele carriers had lower odds of moderate-to-severe ED compared with C allele carriers (OR 0.20, 95% CI 0.04–0.94; p = 0.041). However, no associations remained significant after correction for multiple testing. These findings suggest that common polymorphisms in these genes do not significantly predict tadalafil response in men with DM and ED.

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.