Diabetes mellitus (DM) affects over 500 million people worldwide, with projections indicating a continued rise in prevalence in the coming decades [1]. Cardiovascular disease (CVD) remains the principal cause of morbidity and mortality in this population, accounting for more than half of diabetes-related deaths [2]. Among the various complications of DM, sexual dysfunction (SD) and peripheral artery disease (PAD) are highly prevalent yet often underappreciated contributors to the overall cardiovascular risk burden.

SD in diabetes includes erectile dysfunction (ED) in men and female SD (FSD), with reported prevalence rates of 35–75% in men and 20–45% in women, respectively [3, 4]. Both conditions are closely linked to endothelial dysfunction, impaired nitric oxide (NO) bioavailability, and diabetic neuropathy, all of which contribute to systemic vascular disease. Importantly, ED has been identified as an independent predictor of future cardiovascular events, sometimes preceding overt coronary or peripheral vascular disease [5].

PAD is another major macrovascular complication of DM, characterized by atherosclerotic obstruction of lower extremity arteries. Its prevalence is estimated at 20–30% among diabetic patients, significantly higher than in the general population [6]. PAD not only leads to functional impairment and risk of limb ischemia but also strongly predicts major adverse cardiovascular events (MACE), including myocardial infarction and stroke [7].

Although SD and PAD have been studied extensively as separate complications, there is a growing recognition of their interrelationship through shared vascular and neural mechanisms. Both are considered manifestations of systemic endothelial dysfunction and advanced atherosclerosis, and both may serve as early warning signs of increased cardiovascular risk in diabetic patients. Despite this, the mechanistic links between SD and PAD in diabetes have not been comprehensively summarized.

The purpose of this review is to synthesize current knowledge on the vascular and neural mechanisms linking SD and PAD in patients with diabetes, and to discuss their implications for cardiovascular risk prediction, screening, and management.

This review differs from prior publications by providing an integrated discussion of both vascular and neural mechanisms that jointly underlie SD and PAD in diabetes. Unlike earlier reviews that have examined these complications separately, our aim is to synthesize them within a unified pathophysiological and clinical framework relevant to cardiovascular risk assessment.

SD is among the most common complications of diabetes, significantly affecting quality of life and often serving as an early marker of systemic vascular disease. In men, ED is the predominant manifestation, while women with diabetes frequently experience FSD, encompassing decreased libido, arousal difficulties, lubrication problems, and orgasmic disorders.

ED prevalence in men with diabetes is reported to be two to three times higher than in non-diabetic men, with onset occurring approximately 10–15 years earlier [8]. The prevalence increases with age, poor glycemic control, and longer diabetes duration. In women, meta-analyses indicate that diabetic women have a 1.5- to 2-fold higher risk of developing SD compared to non-diabetic women [9]. Recent meta-analyses and cohort studies have confirmed these prevalence patterns and further emphasized the multifactorial nature of SD in diabetes, integrating vascular, neural, and hormonal determinants [10–13].

The underlying mechanisms are multifactorial, involving both vascular and neural pathways. Endothelial dysfunction and reduced NO bioavailability impair penile smooth muscle relaxation, leading to compromised erectile function [14]. Similarly, in women, impaired clitoral and vaginal blood flow caused by microvascular damage contributes to decreased arousal and lubrication. Autonomic neuropathy further disrupts neurogenic vasodilation and genital sensory function [15]. Hormonal dysregulation, including reduced testosterone in men and altered estrogen levels in women, can exacerbate sexual difficulties. Psychological factors such as depression and anxiety also play a reinforcing role.

ED has been recognized as an independent predictor of cardiovascular events in men with diabetes. Large cohort studies demonstrate that ED precedes coronary artery disease by several years, making it a sentinel marker for subclinical vascular disease [16]. Similarly, FSD, though less studied, has been associated with poor metabolic control and higher cardiovascular risk, though longitudinal evidence remains limited [17]. More recent studies have strengthened this association, demonstrating that ED serves as an early clinical marker of systemic vascular impairment even in asymptomatic diabetic patients [18–20].

Validated questionnaires such as the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI) are widely used to assess sexual health in clinical and research settings. Penile Doppler ultrasound and nocturnal penile tumescence testing may provide additional objective evaluation in men, whereas vascular and hormonal assessments can be considered in women with persistent dysfunction.

The presence of SD in diabetic patients often indicates broader endothelial impairment and correlates with increased risk for PAD and cardiovascular events. As such, SD should not be considered merely a quality-of-life issue but also a potential early signal of systemic vascular pathology (Table 1). These updated findings reinforce the clinical importance of routinely assessing sexual function in diabetic populations as part of comprehensive cardiovascular risk evaluation. Updated international guidelines also support the integration of vascular and sexual health assessment into comprehensive diabetes management [21, 22].

PAD is more common in diabetes and presents earlier. U.S. population data show higher PAD prevalence in adults with diabetes versus those without after adjustment for age and risk factors [23]. Ankle-brachial index (ABI)-based cohorts and meta-analyses confirm increased incidence of cardiovascular events and mortality when PAD is present [24]. TransAtlantic Inter-Society Consensus (TASC II) also highlights diabetes as a major PAD accelerator across vascular beds [25].

Presentation ranges from asymptomatic disease to claudication and chronic limb-threatening ischemia. ABI ≤ 0.90 supports diagnosis; however, medial arterial calcification in diabetes can elevate ABI and mask disease [25, 26]. In suspected noncompressible arteries (ABI > 1.40) or when ABI is borderline, the toe-brachial index (TBI) and toe pressures improve detection [27]. Duplex ultrasound defines anatomy and flow; computed tomography/magnetic resonance (CT/MR) angiography is used for mapping when revascularization is considered [25, 28].

Hyperglycemia, dyslipidemia, hypertension, and inflammation drive accelerated atherosclerosis and impaired endothelial function in diabetes, producing diffuse, distal disease with poor collateralization [25]. Mechanisms include oxidative stress, advanced glycation end products (AGEs), smooth muscle dysfunction, and impaired vascular repair [25]. These processes overlap with those implicated in SD, reflecting shared systemic vasculopathy.

PAD in diabetes signals high systemic risk. Low ABI associates with approximately twofold higher risk of major cardiovascular events and all-cause mortality in pooled analyses [24, 28]. Limb outcomes are worse in diabetes due to neuropathy, infection risk, and impaired wound healing, raising ulceration and amputation rates [29].

Guidelines advise ABI screening in diabetic patients with exertional leg symptoms, nonhealing wounds, age ≥ 50 with additional risk factors, or age ≥ 65 regardless of symptoms; the TBI is recommended when ABI is noncompressible [21, 22]. Identifying PAD should trigger intensive risk modification: smoking cessation, statins, blood pressure control, antiplatelet therapy when indicated, glycemic optimization, exercise therapy, and timely referral for revascularization in limb-threatening ischemia [21, 22] (Table 1).

Prospective cohorts and meta-analyses show ED independently predicts total CVD, coronary heart disease (CHD), stroke, and all-cause mortality beyond traditional risk factors [47, 48]. The artery-size hypothesis provides a mechanistic clinical framework in which smaller penile arteries manifest atherosclerosis earlier than coronary or peripheral beds, explaining the temporal lead of ED before overt CVD [49].

Population studies indicate ED associates with lower ABI and higher PAD prevalence; ED can uncover previously undiagnosed PAD and may justify ABI screening in at-risk men [50]. Recent NHANES analyses reaffirm an independent association between ED and PAD after multivariable adjustment [51]. These data align with shared vascular mechanisms outlined earlier [33–37].

Penile duplex Doppler parameters, especially reduced cavernosal peak systolic velocity and arterial wall abnormalities, correlate with generalized vascular disease and predict adverse cardiovascular outcomes [52, 53]. Such measures can refine vascular risk assessment in men with ED, complementing ABI/TBI for lower-limb perfusion [26, 27].

FSD is more prevalent in diabetes and is associated with worse metabolic control; evidence connecting FSD to hard cardiovascular outcomes is limited but consistent with microvascular and neurovascular impairment [4, 17].

Inflammatory markers and endothelial dysfunction indices track with both ED and PAD, and lower EPC levels reflect impaired vascular repair capacity across phenotypes [36–38, 54]. These signals support a systemic vasculopathy linking genital and limb vascular beds.

Across epidemiology, imaging, and biomarkers, ED clusters with PAD and global atherosclerosis often precede clinical CVD events [47–49]. Incorporating sexual health assessment and simple vascular tests (ABI/TBI, targeted penile Doppler) may improve early cardiovascular risk identification in diabetes [21, 22, 52].

Recognition of SD and PAD in diabetes has direct implications for cardiovascular risk stratification and clinical management. SD, particularly ED in men, should be regarded not only as a quality-of-life issue but also as an early vascular warning sign. Its presence warrants a careful reassessment of overall atherosclerotic cardiovascular risk and should prompt formal screening for PAD and other complications. The ABI remains the cornerstone diagnostic tool for PAD, although in patients with noncompressible vessels, the TBI and toe pressures provide superior diagnostic accuracy [21, 26]. In symptomatic or high-risk patients, duplex ultrasonography offers further evaluation, while CT or MR angiography is reserved for those being considered for revascularization [22].

Once SD or PAD is identified, aggressive risk modification becomes essential. Smoking cessation, statin therapy, blood pressure control, antiplatelet therapy where indicated, and optimization of glycemic management are all priorities in accordance with major diabetes and cardiovascular guidelines [21, 22]. Supervised exercise therapy has demonstrated clear benefit for claudication and should be the first-line intervention [55, 56]. Pharmacologic therapy such as cilostazol can be considered for symptom relief in the absence of heart failure [57, 58]. In the context of type 2 diabetes and elevated cardiovascular risk, glucose-lowering therapies with proven cardiovascular benefit, including glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors, should be integrated into the treatment plan [59, 60].

Addressing sexual health requires coordination between specialties. Cardiology, endocrinology, urology, and vascular medicine must work in concert to optimize patient outcomes. Risk stratification of sexual activity should follow established cardiovascular guidelines, ensuring that patients with unstable or severe disease are stabilized before resuming sexual activity [61]. The Princeton consensus offers a structured approach to evaluating ED in the context of CVD, including risk categories based on exercise tolerance and medication use [62]. Phosphodiesterase type-5 inhibitors remain the mainstay of pharmacologic management for ED and can be safely used in most patients not receiving nitrates [41, 61, 62]. For women, systematic assessment of sexual function is often neglected, but FSD is common in diabetes and deserves structured evaluation and management. Interventions should include attention to glycemic control, management of depression, hormonal status, and comorbid pelvic floor disorders [4, 17, 21].

Patient education plays a pivotal role in the management of both SD and PAD. Structured diabetes education programs, such as Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND), have demonstrated efficacy in improving lifestyle factors, adherence, and cost-effectiveness in long-term care [63, 64]. Education should include information on foot checks, recognition of PAD symptoms, open discussion of sexual health, and reinforcement of lifestyle modifications, including exercise and diet. By integrating education into routine care, clinicians can empower patients to recognize early signs of vascular complications and engage more actively in risk reduction.

In practical terms, a clinical algorithm begins with systematically asking about sexual function and leg symptoms during diabetes visits. When dysfunction is reported, this should trigger reassessment of cardiovascular risk, targeted vascular testing, and appropriate therapeutic adjustments. Confirmed PAD requires initiation of guideline-directed medical therapy and, if necessary, referral for revascularization in cases of limb-threatening ischemia. Coordinated, multidisciplinary care supported by structured patient education offers the best chance of reducing both cardiovascular events and quality-of-life impairments associated with these complications (Table 4).

This review offers a unique synthesis by combining vascular and neural mechanisms into a single conceptual model linking SD and PAD in diabetes. This integrated perspective aims to highlight overlapping pathophysiological pathways and their translational relevance, which have not been comprehensively summarized in previous literature.

Despite growing evidence that SD and PAD share vascular and neural mechanisms in diabetes, several gaps remain in both research and clinical practice. First, much of the available data concerns ED in men, whereas FSD is underexplored. Although small observational studies suggest that women with diabetes have impaired genital blood flow and worse sexual function, longitudinal studies linking these findings to cardiovascular outcomes are lacking [4, 17]. Addressing this gap requires prospective cohorts and mechanistic imaging studies specifically designed for women. Future research should aim to resolve current inconsistencies by standardizing diagnostic definitions and employing longitudinal designs to better clarify causal pathways.

Second, most epidemiological studies are cross-sectional, which limits the ability to infer temporal relationships and causality between SD, PAD, and cardiovascular events. Long-term prospective cohorts are needed to determine whether combined screening for SD and PAD improves the prediction of cardiovascular outcomes beyond traditional risk factors [47–51].

Third, while endothelial dysfunction, inflammation, and neuropathy have been identified as overlapping mechanisms, the translation of mechanistic biomarkers into clinical risk stratification tools is still incomplete. Circulating EPCs, arterial stiffness indices, and inflammatory markers show promise but lack validation in large diabetic populations with integrated sexual health and PAD outcomes [36–38, 53]. More translational research is required to bridge this mechanistic–clinical gap.

Fourth, education and behavioral interventions are established components of diabetes care, but their specific impact on SD and PAD has not been systematically studied. Existing trials, such as DESMOND, demonstrate benefits for weight and smoking cessation [63, 64], but they rarely include sexual health or PAD endpoints. Designing education programs that explicitly incorporate vascular complication awareness, sexual health counseling, and self-care practices could address an important unmet need.

Finally, current management algorithms for ED and PAD are still siloed across disciplines. Multidisciplinary strategies that integrate endocrinology, cardiology, urology, gynecology, and vascular medicine remain underutilized. Implementation research is needed to test whether coordinated care models improve both vascular outcomes and quality of life. Large-scale trials incorporating novel antidiabetic agents with proven cardiovascular benefit, such as GLP-1 receptor agonists and SGLT2 inhibitors, could also explore their influence on SD and PAD endpoints [65, 66].

In summary, the future direction of research should include prospective, sex-specific studies, validation of vascular biomarkers, integration of education and behavioral interventions, and multidisciplinary trials targeting both SD and PAD. Such efforts will strengthen the evidence base and support a more comprehensive approach to cardiovascular risk reduction in diabetes.

SD and PAD are common complications of diabetes that reflect the same systemic vascular and neural injury underlying CVD. Both arise from overlapping mechanisms, including endothelial dysfunction, atherosclerosis, microvascular damage, and autonomic neuropathy, and together indicate heightened cardiovascular risk. ED and, to a growing extent, FSD often precede overt CVD and should be regarded as early clinical warning signs rather than isolated quality-of-life concerns. Likewise, the presence of PAD in diabetes identifies patients at particularly high systemic risk.

Integrating sexual health assessment and PAD screening into routine diabetes care can enable earlier identification of at-risk individuals and support timely preventive interventions. Multidisciplinary management, combining optimal medical therapy, patient education, and use of antidiabetic agents with proven cardiovascular benefit, may improve both prognosis and quality of life. Further research should clarify sex-specific aspects, validate mechanistic biomarkers, and evaluate coordinated care models. Recognizing the shared neurovascular basis of SD and PAD offers a pathway toward more precise and preventive cardiovascular risk management in diabetes.