PDE5i & Melanoma

Discussion in 'Men's Health Forum' started by Michael Scally MD, Apr 7, 2014.

  1. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Li W, Qureshi AA, Robinson KC, Han J. sildenafil Use and Increased Risk of Incident Melanoma in US Men: A Prospective Cohort Study. JAMA Intern Med. JAMA Network | JAMA Internal Medicine | Sildenafil Use and Increased Risk of Incident Melanoma in US Men:

    Importance The RAS/RAF/mitogen-activated protein kinase and extracellular signal–regulated kinase (ERK) kinase/ERK cascade plays a crucial role in melanoma cell proliferation and survival. Sildenafil citrate (viagra) is a phosphodiesterase (PDE) 5A inhibitor commonly used for erectile dysfunction.

    Recent studies have shown that BRAF activation down-regulates PDE5A levels, and low PDE5A expression by BRAF activation or sildenafil use increases the invasiveness of melanoma cells, which raises the possible adverse effect of sildenafil use on melanoma risk.

    Objective To evaluate the association between sildenafil use and risk of incident melanoma among men in the United States.

    Design, Setting, and Participants Our study is a prospective cohort study. In 2000, participants in the Health Professionals’ Follow-up Study were questioned regarding sildenafil use for erectile dysfunction. Participants who reported cancers at baseline were excluded. A total of 25?848 men remained in the analysis.

    Main Outcomes and Measures The incidence of skin cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), was obtained in the self-reported questionnaires biennially. The diagnosis of melanoma and SCC was pathologically confirmed.

    Results We identified 142 melanoma, 580 SCC, and 3030 BCC cases during follow-up (2000-2010). Recent sildenafil use at baseline was significantly associated with an increased risk of subsequent melanoma with a multivariate-adjusted hazard ratio (HR) of 1.84 (95% CI, 1.04-3.22).

    In contrast, we did not observe an increase in risk of SCC (HR, 0.84; 95% CI, 0.59-1.20) or BCC (1.08; 0.93-1.25) associated with sildenafil use. Moreover, erectile function itself was not associated with an altered risk of melanoma. Ever use of sildenafil was also associated with a higher risk of melanoma (HR,?1.92; 95% CI, 1.14-3.22).

    A secondary analysis excluding those reporting major chronic diseases at baseline did not appreciably change the findings; the HR of melanoma was 2.24 (95% CI, 1.05-4.78) for sildenafil use at baseline and 2.77 (1.32-5.85) for ever use.

    Conclusions and Relevance Sildenafil use may be associated with an increased risk of developing melanoma. Although this study is insufficient to alter clinical recommendations, we support a need for continued investigation of this association.
  2. Babylon

    Babylon Junior Member

    This is very interesting, and concerning as well. With as many young guys using sildenafil today, I wonder if we will see a spike in melanoma in the near future. Any more info on this?
  3. biceps72

    biceps72 Member

    I can't easily comprehend why there might be a connection?

    IF there is a connection might there also be a relationship with cialis and Levitra?
  4. toolman

    toolman Member

    This would be another one of gods cruel ironies...
  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma.

    A new JAMA study suggests an association between use of phosphodiesterase type 5 (PDE5) inhibitors for erectile dysfunction and increased melanoma risk, but the finding may be confounded by demographic factors.

    Researchers identified over 4000 Swedish men with incident malignant melanoma and 20,000 age-matched controls without melanoma; some 440 and 1700 of these men, respectively, had filled prescriptions for PDE5 inhibitors (e.g., sildenafil).

    In adjusted analyses, PDE5-inhibitor users were significantly more likely than nonusers to be diagnosed with melanoma (odds ratio, 1.21); risk was higher among those who filled single versus multiple prescriptions. PDE5-inhibitor use was associated significantly with melanoma stages 0 and I, but not with stages II to IV.

    Both PDE5-inhibitor use and melanoma were more common among men with higher incomes and education levels, suggesting that — despite appropriate adjustment — the association between PDE5-inhibitor use and melanoma is not causal.

    Other observations that raise questions about causality include the absence of a dose-response relation and the lack of association between PDE5-inhibitor use and early (but not advanced) melanoma.

    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. http://jama.jamanetwork.com/article.aspx?articleid=2338254

    Importance The target for the oral erectile dysfunction drugs, phosphodiesterase type 5 (PDE5) inhibitors, is part of a pathway implicated in the development of malignant melanoma. An increased risk of melanoma in sildenafil users was recently reported.

    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.

    Design, Setting, and Participants Nationwide, population-based, nested case-control study in the Swedish Prescribed Drug Register, the Swedish Melanoma Register, and other health care registers and demographic databases in Sweden, including 4065 melanoma cases diagnosed from 2006 through 2012 and 5 randomly selected controls per case with matching year of birth.

    Exposures Number of filled prescriptions for the PDE5 inhibitors sildenafil and vardenafil or tadalafil.

    Main Outcomes and Measures Risk of melanoma; overall and by stage and risk of basal cell carcinoma in multivariable logistic regression analyses.

    Results Of 4065 melanoma cases, 435 men (11%) had filled prescriptions for PDE5 inhibitors, as did 1713 men of 20 325 controls (8%). In multivariable analysis, there was an increased risk of melanoma in men taking PDE5 inhibitors (OR, 1.21 [95% CI, 1.08-1.36]). The most pronounced increase in risk was observed in men who had filled a single prescription (OR, 1.32 [95% CI, 1.10-1.59]; exposure rate, 4% for cases vs 3% for controls), but was not significant among men with multiple filled prescriptions (for 2-5 prescriptions: OR, 1.14 [95% CI, 0.95-1.37], 4% for cases and 3% for controls; for ≥6 prescriptions: OR, 1.17 [95% CI, 0.95-1.44], 3% for cases vs 2% for controls). PDE5 inhibitors were significantly associated with melanoma stage 0 (OR, 1.49 [95% CI, 1.22-1.83], 13% for cases vs 8% for controls) and stage I (OR, 1.21 [95% CI, 1.02-1.43], 12% for cases vs 10% for controls), but not stage II through IV (OR, 0.83 [95% CI, 0.63-1.09], 6% for cases vs 7% for controls). The risk estimates were similar for sildenafil and vardenafil or tadalafil. PDE5 inhibitor use was also associated with an increased risk of basal cell carcinoma (OR, 1.19 [95% CI, 1.14-1.25], 9% for cases vs 8% for controls). Men taking PDE5 inhibitors had a higher educational level and annual income, factors that were also significantly associated with melanoma risk.

    Conclusions and Relevance 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 (eg, the lack of association with multiple filled prescriptions) raises questions about whether this association is causal.
  6. foreveryoung

    foreveryoung Member


    I'm a big fan of tanning and I take viagra by the mouthful every other day or more
  7. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    In their conclusion, the authors note the overall association and question whether the risk of malignant melanoma associated with PDE5 inhibitor use is causal. However, the pattern of these associations do more than raise questions about the causal relationship between use of PDE5 inhibitors and malignant melanoma; they almost certainly negate it—per the authors’ own prespecified subanalyses. We are thus left with a statistically significant—but noncausal and likely clinically irrelevant—association.

    In the absence of any evidence of causality, the association between use of PDE5 inhibitors and an increased risk of melanoma is most likely due to ascertainment bias and/or unmeasured confounding. For example, men who obtain PDE5 inhibitor prescriptions are more likely to be seen by health care providers and thus are more likely have their skin observed, leading to the increased detection of low-stage melanoma. The same rationale likely explains the higher incidence of melanoma among married men—more eyes on their skin.

    The problem here is that the subtleties of causal inference are often lost in the lay press and in the courtroom, and the conclusion that PDE5 inhibitor use is associated with malignant melanoma and “may” be causal may prove sufficient to drive a wave of groundless, expensive lawsuits. Drug injury plaintiff attorneys certainly do not delve into dose-response relationships, temporality, or effect sizes, let alone unmeasured confounding.

    One example website already states: “The recent medical study finding which indicates an association between each of these PDE5 inhibitor drugs with invasive melanoma skin cancer might be of particular concern to patients that have used any of these drugs… We are currently investigating cases of melanoma in men who used viagra, cialis, Levitra…, as possible drug injury lawsuits”.

    The effects of presenting this study as a positive association between PDE5 inhibitors and malignant melanoma despite lacking evidence of causality may have serious, deleterious consequences for patients who would benefit from, but may not be prescribed PDE5 inhibitors, as well as for physicians and society who may face an increased number of lawsuits generated not by sound evidence, but by groundless fear.

    Tasian GE, Cooperberg MR. Re: Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma. Eur Urol 2016;69(2):374-5. Re: Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma - European Urology
  8. Dr JIM

    Dr JIM Member

    Absolutely one of your best summations Michael Scally MD!!

    One that I can't even begin to replicate, so I'll spare you folk the drivel :)

    One can only hope Meso members READ YOUR POST!!!
  9. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Shkolyar E, Li S, Tang J, Eisenberg ML. Risk of Melanoma With Phosphodiesterase Type 5 Inhibitor Use Among Patients With Erectile Dysfunction, Pulmonary Hypertension, and Lower Urinary Tract Symptoms. The Journal of Sexual Medicine. Redirecting

    Background - Phosphodiesterase type 5 inhibitors (PDE5is), a treatment for erectile dysfunction, pulmonary hypertension (pHTN), and lower urinary tract symptoms (LUTS), have been implicated in melanoma development.

    Aim - We sought to determine the association between PDE5i use and melanoma development among patients with erectile dysfunction, pHTN, and LUTS.

    Methods - This was a retrospective cohort study of subjects contained within the Truven Health MarketScan claims database, which provides information on insurance claims in the United States for privately insured individuals, from 2007–2015. Individuals taking PDE5i were identified through pharmacy claims. A comparison group of men diagnosed with conditions for which PDE5i are prescribed was assembled.

    Outcomes - Cox proportional hazard models were used to estimate the hazard ratio (HR) (95% CI) of incident melanoma, basal cell carcinoma, and squamous cell carcinoma.

    Results - Of 610,881 subjects prescribed PDE5i, 636 developed melanoma (0.10%). The control group had 8,711 diagnoses of melanoma. There was an association between increased PDE5i tablet use and melanoma (HR 1.05, 95% CI 1.05–1.09). This association was also present between PDE5i use and basal cell carcinoma (HR 1.04, 95% CI 1.02–1.07) and squamous cell carcinoma (HR 1.04, 95% CI 1.01–1.07). In patients with pHTN and LUTS prescribed PDE5is, there was no relationship between exposure and melanoma incidence (HR 0.74, 95% CI 0.48–1.13; and HR 1.03, 95% CI 0.97–1.10, respectively).

    Clinical Implications - There is little evidence for a clinically relevant association between PDE5i use and melanoma incidence.

    Strengths & Limitations - Our current work represents the largest study to date evaluating the relationship between PDE5i use and melanoma risk, and the first to examine all current indications of PDE5i use among men and women. Limitations include a patient population limited to commercially insured individuals, unknown patient medication compliance, and lack of information on patient skin type, lifestyle, and sun-exposure habits.

    Conclusion - There is a slight association between higher-volume PDE5i use and development of melanoma, basal cell carcinoma, and squamous cell carcinoma. This association among all skin cancers implies that confounding may account for the observed association.
  10. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Erectile Dysfunction Medications and Skin Cancer

    OBJECTIVE: To examine the relationship between phosphodiesterase 5 inhibitor drugs (PDE5i) and skin cancers in a large-scale study of Veterans.

    METHODS: This was a retrospective database review using the Department of Veterans Affairs Informatics and Computing Infrastructure database (VINCI). VINCI was searched 19 years for Veterans who received PDE5i treatment of erectile dysfunction. A non-PDE5i group of Veterans was selected for comparison analysis. Follow-up time, outpatient clinic visits and incidence of malignant melanoma (MM) and basal cell carcinoma (BCC) were measured in both groups.

    RESULTS: A total of 2.55 million Veterans were included in this study (1.27 million in each group). Mean age of the PDE5i group and non-PDE5i group was 59.2 years (SD+/-10.8) and 58.7 (SD+/- 10.8), respectively. Mean follow-up time for the PDE5i group was 8.9 years (SD+/- 4.2) and 8.5 years (SD+/- 4.3) for non-PDE5i group.

    Odds ratio(OR) for MM and BCC in the PDE5i group was 1.25 (CI 95%, 1.22-1.28, p<0.0001) and 1.49 (CI 95%, 1.46-1.51, p<0.0001), respectively. PDE5i users showed more mean outpatient visits/year (8.9 SD+/- 9.50) compared to non-PDE5i users (5.9 SD +/-10.0), (p<0.0001).

    CONCLUSIONS: Veterans prescribed PDE5is to treat erectile show a minimal increased risk of malignant melanoma and a greater risk of basal cell carcinoma compared to non-PDE5i users. PDE5i users visited outpatient VA clinics at a higher rate than non-PDE5i users in this study. These findings suggest confounding variables are likely involved in the relationship between skin cancers and PDE5i use. PDE5i drugs remain a safe treatment for erectile dysfunction.

    Christie A, Vera PL, Higgins M, Kumar S, Lane M, Preston D. Erectile Dysfunction Medications and Skin Cancer: An analysis in US Veterans. Urology 2019. https://www.sciencedirect.com/science/article/pii/S0090429519301311