Risk of malignant melanoma in first line agents for erectile dysfunction

Elizabeth Lai, Mercer University College of Pharmacy

According the Erectile Dysfunction Guidelines from the American Urological Association, erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance.  The guidelines suggest that the cause of ED is due to the lack of arterial blood flow and reduction of venous outflow.  Comorbidities affecting blood flow can also affect erectile function and the risk of developing ED is increased by comorbidities such as diabetes, heart disease, and hypertension as mentioned in the guidelines.  Therefore, proper management of such comorbidities may reduce the likelihood of developing ED.  According to the guidelines, lifestyle modifications such as regular physical activity and avoidance of smoking may prevent or reverse ED, but currently there is not enough evidence to support this.1

Phosphodieasterase type 5 (PDE5) inhibitors are the standard first-line therapy option for the treatment of ED, hydrolyzing cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), which are messengers in the intracellular cascade of smooth muscle relaxation.  The presence of PDE5 is prevalent in the corpus cavernosum, so inhibition of PDE5 prevents breakdown of cGMP, promoting relaxation of the corpus cavernosum smooth muscle and allowing an erection to occur when sexually stimulated.1  The available oral PDE5 inhibitors include sildenafil (Viagra®, Revatio®), tadalafil (Adcirca®, Cialis®), avanafil (Stendra®), and vardenafil (Levitra®, Staxyn®).1

Title: Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma2
Design Nested case-control study, N = 24390
Objective To examine the association between use of PDE5 inhibitors and melanoma risk, including data on specific PDE5 inhibitors, number of prescriptions, and melanoma stage
Study Groups Men with filled PDE5 inhibitor prescriptions
Cases (n = 435) Controls (n = 1713) All men (n = 2148)
Men without filled PDE5 inhibitor prescriptions
Cases (n = 3630) Controls (n = 18612) All men (n = 22242)
Methods Using the Prostate Cancer Data Base Sweden (PCBaSe 3.0), a 614601 prostate cancer-free group was randomly selected in a 1:5 ratio matching year of birth and county.  The incidence of melanoma cases diagnosed from 2006 to 2012 were identified and free from other cancers.  Five controls were randomly selected from each case of malignant melanoma.  Using the Swedish Melanoma Register, information on location and stage of melanoma cases were obtained and categorized into stages.  The Swedish Prescribed Drug Register was used to determine number of filled PDE5 inhibitors and included to determine the relationship between number of filled PDE5 inhibitors and melanoma risk.  Multivariable conditional logistic regression analyses were performed to estimate odds ratios (ORs) adjusting for Charlson comorbidity index (CCI), marital status, educational level, and disposable income.  Significance level was set to P value < 0.05 and 2-sided tests were used.
Duration 2006-2012
Primary Outcome Measure Risk of melanoma, overall and by stage and risk of basal cell carcinoma in multivariable logistic regression analysis from melanoma cases diagnosed from 2006 through 2012
Baseline Characteristics Men with filled PDE5 inhibitor prescriptions
Cases Controls All men
Age, median 69 70 70
No comorbidity 355 1327 1682
Married 304 1127 1431
Men without filled PDE5 inhibitor prescriptions
Cases Controls All men
Age, median 75 75 75
No comorbidity 2463 12111 14574
Married 2508 11717 14225
Results Odds ratio (95% CI) of malignant melanoma by number of filled prescriptions of PDE5 inhibitor and demographic factors
Filled prescriptions for PDE5 inhibitors
None: 1 (reference) 1: 1.41 (1.17-1.69) 2-5: 1.24 (1.03-1.48) ≥6: 1.28 (1.04-1.58)
Comorbidity
CCI 0: 1 (reference) CCI 1: 0.92 (0.84-1.02) CCI 2+: 0.79 (0.71-0.87)
Marital status
Not currently married: 1 (reference) Married: 1.30 (1.21-1.40)
Educational level
Low: 1 (reference) Middle: 1.36 (1.26-1.48) High: 1.47 (1.34-1.62)
Annual income, %
1-25: 1 (reference) 26-50: 1.23 (1.11-1.36) 51-75: 1.50 (1.36-1.67) 76-100: 1.54 (1.38-1.72)
Odds ratio (95% CI) of filled Prescriptions for PDE5 inhibitors and risk of melanoma by stage
All stages
None: 1.00 (reference) 1: 1.32 (1.10-1.59) 2-5: 1.14 (0.95-1.37) ≥6: 1.17 (0.95-1.44)
Stage 0
None: 1.00 (reference) 1: 1.86 (1.36-2.53) 2-5: 1.21 (0.87-1.69) ≥6: 1.45 (1.00-2.10)
Stage I
None: 1.00 (reference) 1: 1.18 (0.89-1.55) 2-5: 1.23 (0.95-1.60) ≥6: 1.20 (0.89-1.62)
Stage II-IV
None: 1.00 (reference) 1: 0.94 (0.60-1.48) 2-5: 0.77 (0.50-1.20) ≥6: 0.77 (0.46-1.29)
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions In a Swedish cohort of men, the use of PDE5 inhibitors was associated with a modest but statistically significant increased risk of malignant melanoma. However, the pattern of association (e.g., the lack of association with multiple filled prescriptions) raises questions about whether this association is causal.

The results of this study revealed significant risk of low stage malignant melanoma but not high-stage melanoma.  However, men with more than one filled prescriptions did not show an increased risk than men who filled one prescription.  A comparison of short-acting and long-acting PDE5 inhibitors showed similar results.  The strengths of the study was due to a large sample size, results with P value of <0.05 results showed statistical significance, and detailed information of filled PDE5 inhibitor prescriptions, melanoma stage information, socioeconomic factors and comorbidities.  Limitations of the study includes the proportion of younger men since the median age of men diagnosed melanoma in the US is 64, but the median age in the study population was 70 years old.  In addition, previous studies in the US reported some men obtaining PDE5 inhibitors without prescriptions.

References

  1. Montague DK, Jarow JP, Broderick GA, et al. The Management of Erectile Dysfunction: An Update. American Urological Association Education and Research, Inc. 2005.  Available at: https://www.auanet.org/common/pdf/education/clinical-guidance/Erectile-Dysfunction.pdf.  Accessed on June 25, 2015.
  2. Loeb S, Folkvaljon Y, Lambe M, et al. Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma. JAMA. 2015;313(24):2449-2455. 
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