This study found a prevalence of erectile dysfunction of 23% in middle-aged men with recent-onset diabetes, which is about double that in men without diabetes. Pathophysiology-based diabetes subgroups showed differences in the prevalence of erectile dysfunction. Men with SIRD had the highest, whereas those with SAID had the lowest erectile dysfunction prevalence. The SIRD and SIDD subgroups showed higher RRs for erectile dysfunction in multivariable models, and these associations were independent of the clustering variables, hs-CRP and depression. In contrast to previous studies on erectile dysfunction in long-standing diabetes, the unique feature of this study is its focus on newly diagnosed disease and the consideration of the heterogeneity of diabetes pathophysiology reflected by the five diabetes subgroups.
The observed erectile dysfunction prevalence of 23% in men with diabetes in GDS was in line with previous reports (20–37%) in men with recent diabetes diagnosis [31,32,33]. In contrast, most studies conducted in men with longer-term diabetes report a higher prevalence ranging from 35 to 90% . Notably, a meta-analysis of 145 studies in men with longer-term type 1 and type 2 diabetes reported an overall erectile dysfunction prevalence of 52.5% . This variation in the prevalence of erectile dysfunction might be attributed to differences in the study populations (age, ethnicity, diabetes duration) and definition of erectile dysfunction (e.g. single item question or validated multi-item scale) [34, 35]. The lower prevalence of erectile dysfunction in our study may relate to the rather young age of our study population (median age 49.4 years), their short diabetes duration (<1 year), their good health status including good glucometabolic control and low prevalence of CVD and CAN , and the use of a multi-item questionnaire to define erectile dysfunction only in sexually active men, unlike several previous studies which used one single item question to assess erectile function regardless of sexual activity.
SIRD, the subgroup characterised by obesity and pronounced insulin resistance, was associated with higher RR for prevalent erectile dysfunction than all the other four subgroups, particularly when compared with MOD, the subgroup characterised by obesity but not by insulin resistance. These associations were robust across models when considering all four subgroups as a reference and in pairwise associations. This finding reinforces that insulin resistance increases the risk of erectile dysfunction  and explains the high prevalence of erectile dysfunction in the metabolic syndrome [8, 21], which is often characterised by insulin resistance as a key feature. The molecular mechanism underlying the association between insulin resistance and erectile dysfunction involves endothelial dysfunction in the penile arteries, decreasing their synthesis and release of endothelial nitric oxide. However, it is unclear whether endothelial damage in penile arteries is related to whole-body insulin resistance, which is characterised by decreased responsiveness of the liver, adipose tissue and skeletal muscle to insulin, or is instead related to decreased endothelial insulin sensitivity. Evidence from in vivo studies suggests that endothelium-specific insulin resistance can induce endothelial dysfunction independently of whole-body insulin resistance . In our study, associations between diabetes subgroups and erectile dysfunction were only slightly attenuated after adjustment for HOMA2-IR, indicating that whole-body insulin resistance may only partly explain the observed associations. HOMA2-IR is primarily an index of hepatic insulin resistance but also shows a good correlation with the hyperinsulinaemic–euglycaemic clamp, the ‘gold-standard’ technique for evaluating insulin-stimulated glucose metabolism and whole-body insulin resistance [16, 38]. Of note, SIRD was the subgroup with the lowest HbA1c in our study, which indicates that glycaemic control may not be a major determinant of erectile dysfunction in adults with recent-onset diabetes.
Low-grade systemic inflammation is present in insulin resistance, obesity and type 2 diabetes suggesting that the association between insulin resistance and endothelial dysfunction in erectile dysfunction might be linked to inflammation. Accumulating evidence supports the fact that elevated circulating concentrations of biomarkers of inflammation such as hs-CRP and IL-6, and biomarkers of vascular inflammation such as sICAM-1 and sE-selectin, indicate increased cardiovascular risk and damage to the endothelium . In turn, vascular damage triggers an inflammatory reaction and release of proinflammatory mediators, promoting insulin resistance and endothelial dysfunction . In our study, while serum levels of IL-6, sICAM-1 and sE-selectin did not differ between men with and without erectile dysfunction, we found an increase in hs-CRP levels similar to other studies [40,41,42,43].
Because insulin resistance precedes diabetes, the development of erectile dysfunction may have started during the prediabetic stage. Studies assessing erectile dysfunction before and after diabetes diagnosis are needed to clarify these relationships. It is also worth mentioning that our findings in men with recent-onset diabetes cannot be generalised to men with long-standing diabetes who are likely to have longer exposure to chronic hyperglycaemia, dyslipidaemia and hypertension associated with greater risk of diabetes-related complications.
Our study showed higher RRs for prevalent erectile dysfunction in men with SIDD after adjustment for the clustering variables, suggesting that low insulin levels not yet compensated with insulin therapy might be involved in erectile dysfunction in men newly diagnosed with diabetes. However, because diabetes subgroup allocation can change over time as a result of treatment and disease progression, a repeated erectile dysfunction assessment is necessary to confirm this finding. Of note, SIRD and SIDD are different in their clinical presentation. Men with SIRD have a pronounced insulin resistance, but also higher BMI and the highest prevalence of hypertension and impaired kidney function based on eGFR. On the other hand, men with SIDD have the worst glycaemic control and highest prevalence of CAN. The observation that both subgroups appear to have similarly increased prevalence of erectile dysfunction suggests a different mechanism underlying their erectile dysfunction. In SIDD, the more classical concept of glucotoxicity seems to be operative, whereas in SIRD pathomechanisms related to insulin resistance such as lipotoxicity, oxidative stress and low-grade inflammation could contribute to their erectile dysfunction. Indeed, individuals with SIRD also present with a higher degree of dyslipidaemia and markers of inflammation . If confirmed in other studies, these observations would have clinically relevant implications.
Differences in erectile dysfunction between diabetes subgroups reported in our study further support the evidence about differences in complications between novel diabetes subgroups. Ahlqvist et al showed a higher risk for CVD in SIRD, although this was explained by sex and age . Because erectile dysfunction and CVD share endothelial dysfunction as a common feature, our findings consolidate the increased risk of SIRD for vascular diseases. Also, Zaharia et al  observed a higher prevalence of NAFLD in SIRD; thus, we hypothesised that a higher prevalence of erectile dysfunction might be found in this subgroup . The mechanism underlying both conditions might involve insulin resistance and, to some extent, low serum testosterone [11, 36, 44,45,46]. Unfortunately, we did not have information on testosterone levels in our study. Thus, we cannot rule out the potential confounding effect of hypogonadism.
Moreover, findings from the GDS and the Scandinavian cohorts showed a higher prevalence of CKD in SIRD [15, 16]. Given that almost 70% of men with CKD report erectile dysfunction , a high prevalence of erectile dysfunction in SIRD was plausible. In addition to the higher prevalence of diabetes complications in SIRD, we previously demonstrated that a higher proinflammatory state also characterises this subgroup . These characteristics make it the subgroup that might benefit from early diagnosis and treatment to prevent complications. In this context, it is interesting that a recent clinical trial showed a reduced incidence of erectile dysfunction in men with type 2 diabetes and high cardiovascular risk treated with the GLP-1 receptor agonist dulaglutide . Given the phenotypic similarities between the study population of this trial and the SIRD subgroup, this drug might be of particular therapeutic benefit for individuals with SIRD.
Comparing the proportions of diabetes subgroups in included vs excluded participants did not indicate any selection bias. However, a certain degree of selection bias was evident when comparing the baseline characteristics. For example, the participants included in the present analysis had a slightly better cardiometabolic risk profile than those who were excluded, which might have attenuated the differences between diabetes subgroups.
The strengths of our study are the inclusion of men with type 1 diabetes and type 2 diabetes and the information on the clustering variables, which allowed us to investigate the prevalence of erectile dysfunction in the novel diabetes subgroups. Furthermore, the study included adults within their first year of diabetes diagnosis so that findings were not confounded by long-term hyperglycaemia and the increasing prevalence of other diabetes-related complications.
Our study also has some limitations that warrant consideration when interpreting the results. Limitations include its sample size (specifically limiting the statistical power of pairwise comparisons between diabetes subgroups and of comparisons with non-diabetic men) and its restriction to men from Germany. Therefore, our findings need validation in studies with larger sample sizes and more diverse populations. In addition, although we used a validated questionnaire to assess erectile dysfunction, our assessment is limited because the IIEF questionnaire only evaluates erectile dysfunction acquired during the last 4 weeks, whereas ‘persistent’ erectile dysfunction can only be confirmed if lasting more than 3–6 months , and if complemented by a physical examination. Circulating levels of sex hormones and information on primary or secondary hypogonadism were not available for the study sample, meaning that their analysis in the context of the novel diabetes subgroups was not possible. Another limitation is the potential response bias; as this study involved an outcome related to male sexuality, questions concerning sexual performance may feel too personal for some men and increase the likelihood of not answering.
Our study shows that novel diabetes subgroups have different prevalences of erectile dysfunction. Men with SIRD, which is characterised by pronounced insulin resistance and an increased inflammatory state, and men with SIDD, which is characterised by insulin deficiency, have the highest RRs for erectile dysfunction. This finding suggests that metabolic risk factors for erectile dysfunction may differ between diabetes subgroups. The high prevalence of erectile dysfunction in SIRD and SIDD corroborates their high risk for diabetes-related complications and calls for comprehensive screening and early treatment in these subgroups. Detailed longitudinal analyses in the GDS and future studies on therapeutic responses in the context of precision diabetes medicine will clarify whether these findings will translate into clinical benefits.