Men with diabetes may require more aggressive treatment for erectile dysfunction

Abstract

Diabetes mellitus (DM) and erectile dysfunction (ED) are common health problems that markedly increase in prevalence and incidence with advancing age. DM is a known risk factor for developing ED; however, among men with ED it is unknown if DM alters the need for more invasive therapies. We sought to determine whether DM is associated with increased ED severity, reduced effectiveness of first-line (oral) therapies, and therefore higher utilization of second- and third-line therapies. The Inovus I3 database was queried to identify men with ED. Claims were followed for 48 months. Men with incomplete follow-up data and those diagnosed with DM after ED diagnosis were excluded from analysis. Rates of second-line (penile suppositories or injectables) and third-line (penile prostheses) ED therapies were compared between men with and without preexisting DM. Risk of progressing to second- and third-line therapies associated with DM was assessed with logistic regression and Kaplan–Meier analysis. From 1 January 2002 to 31 December 2006, 136 306 men were identified with prevalent and incident ED. Among this group, 19 236 men had DM that preceded their ED diagnosis. Men with DM were more than 50% more likely to be prescribed secondary ED treatments over the 2-year observation period, and more than twice as likely to undergo penile prosthesis surgery. Among a large population-based cohort of men with ED, those with DM are more likely to require more aggressive treatments. These data suggest that ED among men with diabetes may be less responsive to first-line treatments (oral agents), worsen more rapidly, or both.

Introduction

Erectile dysfunction (ED) is the inability to achieve, maintain or sustain an erection firm enough for sexual intercourse that may result from psychological, neurologic, hormonal, arterial, or cavernosal impairment or from a combination of these factors.1, 2 ED is common, with data from the Massachusetts Male Aging Study suggesting that up to 30 million men in the United States are affected.3 ED is a complex medical condition that has a significant impact on a man’s self-esteem and his overall health-related quality of life. As a result, the successful treatment of ED is important to both patients and health-care providers. While lifestyle modifications and the control of cardiovascular risk factors are important for successful ED therapy, additional interventions are often required to achieve a patient’s treatment goals.

Treatments available to men experiencing ED include: oral type-5-selective phosphodiesterase inhibitors (first-line therapy), urethral suppositories or intracavernosal injections of vasoactive medications (second-line therapy) and the surgical implantation of a penile prosthesis (third-line therapy).4, 5, 6 Such treatments are generally implemented in a stepwise fashion until satisfactory erectile function is achieved.

Among the comorbid medical conditions associated with ED, diabetes mellitus (DM) imparts the greatest increase in ED risk.7 Among men with DM, the onset of ED is 10–15 years earlier than in the general population and is associated with a reduction in health-related quality of life and an increase in depressive symptoms, and may be less responsive to oral pharmacological therapy.4, 8, 9 Although the exact pathogenesis of diabetes-associated ED is not completely understood, other diabetic complications associated with ED include hypertension, peripheral neuropathy, nephropathy and retinopathy, suggesting roles for both neurologic and vascular impairment.10, 11, 12, 13

Despite the known associations between DM and ED, the influence of DM on the treatment of ED remains poorly understood. We hypothesized that DM-associated ED may be more severe and therefore may require the utilization of more invasive therapies to achieve satisfactory erections.

Aims

We sought to determine whether DM is associated with increased ED severity, reduced effectiveness of first-line (oral) therapies, and therefore higher utilization of second- and third-line therapies by characterizing treatment modalities among a large population of men with ED, with and without DM.

Materials and methods

In collaboration with the Urologic Diseases of America (UD) Project, the Inovus I3 database was queried to identify men with and treated for ED. The I3 database provides claims data from more than 30 million individuals with United Health Care insurance from across the United States, of which more than half are men. ED was defined by ICD-9 coding (607.84) or by pharmacy claims data demonstrating ED-specific treatment with PDE-5 inhibitors (Sildenafil, Tadalafil, Vardenafil). Men found to have a prescription for ED-specific medication, but without an evidence of a pharmacy claim were excluded from the analysis. ED-associated claims were followed for a minimum of 48 months and men with incomplete follow-up data were excluded from the analysis. This combined group of men was considered the primary ED cohort and was utilized for all subsequent analyses (Figure 1).

Figure 1
figure1

Cohort assembly of adult men with ED from Inovus, 1 January 2002 to 31 December 2006.

DM diagnosis was determined from ICD-9 coding (250) or DM-specific treatments (any insulin formulation, any oral hypoglycemic medication). In order to assure the accurate diagnosis of DM, men were required to have a minimum of two separate ICD-9 codings for DM separated by at least 30 days. Men with DM diagnosed after ED were excluded from the analysis.

Primary ED cohort members with and without DM were queried for at least one subsequent ED treatment event. Treatment events included: (1) medicated urethral suppositories for erection, (2) intracavernosal injection agents and (3) penile prosthesis placement. The utilization of a vacuum erection device was not identifiable via the I3 database as it is not associated with a specific CPT code nor is it provided. Rates of second-line (medicated urethral suppositories for erection or intracavernosal injection) and third-line (penile prostheses) ED therapies were compared between men with and without preexisting DM. The risk of progressing to secondary and tertiary therapies associated with DM was assessed with logistic regression. Additional comparison of the progression to secondary and tertiary therapies was performed with Kaplan–Meier analysis where at-risk-for-progression time was started when ED was first diagnosed, the timescale is months, and individuals were censored once a more advanced therapy was started. This study was approved by our institutional review board.

Main outcome measures

The rates of second-line (penile suppositories or injectables) and third-line (penile prostheses) ED therapies among men with and without preexisting DM.

Results

From 1 January 2002 to 31 December 2006, 691 939 adult male United Health Care subscribers were identified with ED. Of these, 14 386 were excluded for lack of a pharmacy claim and 531 906 were excluded due to incomplete follow-up. An additional 9321 men were excluded due to incident DM (DM that followed ED). Our final study cohort consisted of 136 306 men with ED, of which 19 236 (14%) had preceding DM (Figure 1). Overall, the rate of ED increased with age, and was highest among men aged 60–64 years (Table 1). Rates of ED were highest among nonwhites.

Table 1 Characteristics of men treated for EDa, 2002–2007

Among the 19 236 men with DM, 538 (2.8%) were treated with second-line therapies and among the 117 070 men without DM, 2134 (1.8%) were treated with second-line therapies. Thus, men with DM were 60% more likely to be prescribed second-line ED treatments within 5 years of ED diagnosis compared to men without DM (odd ratio 1.6, 95% confidence interval (CI) 1.4–1.7). Similarly, 125 men with DM (0.8%) underwent third-line therapy compared to 437 men without DM (0.4%), making men with DM more than twice as likely to undergo penile prosthesis placement than men without DM (odd ratio 2.1, 95% CI 1.8–2.6; Table 2).

Table 2 Treatment of erectile dysfunction (n) by second- and third-line therapies among men with and without diabetes mellitus

Among all men with ED, progression to second- and third-line therapies was most dramatic within the first 6 months of ED diagnosis (Figure 2). Men with DM demonstrated a statistically significant increase in their rate of progression toward second- and third-line therapies compared to men without DM (log-rank P-value <0.001). Differences in the occurrence of first-line treatment failure between men with and without DM grew larger over 60 months of follow-up.

Figure 2
figure2

Kaplan–Meier estimates of the proportion of men with ED who progress to second- and third-line treatment.

Discussion

DM and ED are common and costly health conditions that occur more frequently with advancing age. The present study is the first to assess differences in ED treatment between men with and without DM. After diagnosis or initiation of oral therapy, men with DM are 1.6–2.1 times more likely to undergo more aggressive treatments within 5 years of initial ED diagnosis or treatment with oral medications. These data suggest that DM-associated ED may be less responsive to first-line pharmacologic treatment, worsen more rapidly, or both.

These data are particularly important given that the incidence of diabetes is rising in the United States. The increased severity of ED in men with diabetes may lead to higher health-care utilization, and thus appropriate resource allocation and policy regarding coverage may require reassessment. In 2001, ED accounted for over 400 million dollars in Medicare annual medical expenditures.9 The additional unmeasured costs related to over-the counter remedies, prescription drugs for ED, and complications of penile implant surgery such as prosthetic infection and lost work time far exceed the direct costs of treatment. In the United States, the total cost of ED treatments for the 10–20 million affected men in the United States exceeds $3 billion.9 Although unknown, the per capita cost of treatment for diabetes-associated ED is likely to be higher than in nondiabetic patients given the increased severity of symptoms and earlier onset of disease.

This study is unique by being the first to use claims-based data to examine ED in a large community-based cohort of men. Claims-based data analyses have been used extensively to investigate other aspects of urologic care, but there is little data related to ED.14 While it has been shown that a single question can reliably predict ED,15 it is often difficult to obtain this data from more generalized longitudinal cohort studies and there may still be significant inter-individual variability in self-assessment of ED when queried. As a result, this research technique may allow for more accurate assessment of the disease outcome by identifying men who are actually treated for the disease. Further, this approach creates a cohort that is genuinely representative of the general population, thus enhancing the generalizability of our results.

Claims-based data analysis allows us to single out men with severe ED by assessing their use of sequentially more invasive therapeutic modalities. This makes it a potentially innovative tool for examining the progression of ED over time and the severity of ED in different sub-populations of men without the need for expensive urology or ED-specific longitudinal cohort studies. It also allows us to compare ED progression and treatment in men with DM to those without DM who had similar access to care under the Inovus I3 health-care system.

This study does have limitations. Despite our efforts to clearly identify a cohort of men with and without ED and those with and without DM, there is likely still some misclassification between the groups, particularly related to the diagnosis of ED. Specifically, we cannot identify men with ED who did not disclose the ED to a health-care provider or seek any form of treatment. By utilizing outcomes that are defined by treatment modality, we believe that such bias is reduced. The limited length of follow-up in this study also reduces our ability to identify differences in ED treatment between men with and without DM. Further, it is possible that some cases of ED treated by second- and third-line therapies are not truly incident but may have failed treatment with PDE-5 inhibitors or second therapies years earlier (prior to the period of the study).

Despite these limitations, the novel finding of a significantly more progressive and less responsive course for ED in men with DM argues for earlier and possibly more aggressive interventions in men with DM. For example, one approach would be to target all men with DM at an early age (30 years) for a discussion of how their DM may impact their ED in the future and utilize this to motivate compliance with tight DM control therapeutic regimens.

Conclusions

Among a large population-based cohort of men with ED, those with DM are 1.5- to 2.0-fold more likely to proceed with more aggressive treatments. These data suggest that ED among diabetic men may be less responsive to first-line treatments, may worsen more rapidly or both. This work demonstrates that the use of claims-based data to assess ED risk factors, outcomes and cost is a methodology that will be valuable for future ED research.

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Correspondence to T J Walsh.

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Walsh, T., Hotaling, J., Smith, A. et al. Men with diabetes may require more aggressive treatment for erectile dysfunction. Int J Impot Res 26, 112–115 (2014). https://doi.org/10.1038/ijir.2013.46

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Keywords

  • diabetes
  • erectile dysfunction

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