- Email: [email protected]
Re: Increased Risk of Non-fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men
175
EUROPEAN UROLOGY 66 (2014) 173–178
Expert’s comments: Metformin, a first-line antidiabetic drug belonging to the biguanide family, has been associated with a decreased risk of subsequent cancers and an improved cancer-related outcome [1]. In a meta-analysis of 20 studies including >13 000 cancer patients with type 2 diabetes, metformin use increased overall survival by 34% and cancer-specific survival by 38% for all patients with cancer compared with nonmetformin use [2]. In patients with PCa treated with external-beam radiation therapy, metformin use was associated with improvement in all outcomes compared with the diabetic nonmetformin group. In men experiencing biochemical failure, metformin use was also independently correlated with a decrease in the development of castration-resistant PCa (CRPC) [3]. In nondiabetic patients with chemotherapynaive CRPC, metformin use led to disease stabilization and prolongation of prostate-specific antigen doubling time in some patients [4]. The antineoplastic activity of metformin has been related to reduced hyperinsulinemia and glycemic levels. In addition, metformin selectively blocks the growth of cancer stem cells and inhibits the metabolic stress response that may stimulate the inflammatory pathway associated with a number of cancers. Because metformin is not believed to influence the transformation of benign cells to malignant cells but rather to modulate cellular energy, metformin may have a greater impact on cancer survival than on incidence. Metformin may also have other benefits for nondiabetic patients who require androgen deprivation therapy (ADT) through its insulin-sensitizing effects because ADT can be associated with insulin resistance and metabolic syndrome.
Because metformin is inexpensive, with only minor side effects in men with and without diabetes, and because PCa is a slow-growing disease, this drug could play a role in secondary prevention strategies [5]. Further studies are necessary to show which PCa patients may benefit from this therapy. Conflicts of interest: The author has nothing to disclose.
References [1] La Vecchia C, Bosetti C. Metformin: are potential benefits on cancer risk extended to cancer survival? Oncologist 2013;18:1245–7. [2] Yin M, Zhou J, Gorak EJ, et al. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist 2013;18:1248–55. [3] Spratt DE, Zhang C, Zumsteg ZS, et al. Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. Eur Urol 2013;63:709–16. [4] Rothermundt C, Hayoz S, Templeton AJ, et al. Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). Eur Urol. In press. http://dx.doi.org/ 10.1016/j.eururo.2013.12.057 [5] Penney KL, Stampfer MJ. The time is ripe for a randomized trial of metformin in clinically localized prostate cancer. J Clin Oncol 2013;31:3054–5. Dorothea Weckermann* Department of Urology, Klinikum Augsburg, Augsburg, Germany *Department of Urology, Klinikum Augsburg, Stenglinstraße 2, Augsburg, Bavaria 86156, Germany. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2014.03.037
PLoS One 2014;9:e85805
person-years before to 11.52 person-years after; rate ratio: 2.19; 95% CI, 1.27–3.77). There was no corresponding increase in MI rate in men who filled a PDE5-I prescription (3.48 per 1000 person-years before to 3.75 per 1000 personyears after; rate ratio: 1.08; 95% CI, 0.93–1.24).
Experts’ summary: Finkle and colleagues recently performed a secondary data analysis to investigate potential associations between testosterone supplementation therapy (TST) and cardiovascular events. The authors used a large commercial database that covered claims from 2006 to 2010 and compared two cohorts of men: those who filled new prescriptions for TST and those who filled a new prescription for phosphodiesterase type 5 inhibitors (PDE5-Is). The investigators then evaluated the rates of myocardial infarction (MI), as determined by International Classification of Diseases, 9th revision, codes, before and within 3 mo after filling the first prescription in these groups. The authors identified 55 593 men who filled a prescription for TST and 167 279 men who filled a prescription for a PDE5-I. Rates of MI increased in the 3 mo after filling a TST prescription (from 3.48 per 1000 person-years before to 4.75 per 1000 person-years after; rate ratio: 1.36; 95% confidence interval [CI], 1.03–1.81). The increase was more pronounced in the subset of men 65 yr of age (5.27 per 1000
Experts’ comments: The work by Finkle and colleagues is a secondary data analysis of a large Claims and Encounters Database aimed at determining whether TST use was associated with cardiovascular events. The findings are similar to those from a retrospective cohort analysis of veterans with advanced cardiovascular disease [1] and the Testosterone in Older Men (TOM) trial [2]. Although these three studies have potentially concerning findings, they also exhibit methodological flaws that limit the credibility of their results. For example, in the study by Vigen et al. [1], hypogonadal veterans who previously had an MI or stroke and later received TST were excluded rather then being assigned to the no-testosterone arm for analysis. Furthermore, the authors’ conclusions of there being increased risks of MI or stroke associated with TST were based on KaplanMeier estimates, not the absolute rates of MI or stroke. In the TOM study [2], the authors recorded as cardiac events findings that are known side effects of testosterone such as hypertension and lower extremity edema.
Re: Increased Risk of Non-fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men Finkle WD, Greenland S, Ridgeway GK, et al.
176
EUROPEAN UROLOGY 66 (2014) 173–178
The concerning methodology in the study by Finkle et al. is the authors’ use of men taking PDE5-Is as a purported benign control group. PDE5-Is were originally developed as a treatment for cardiovascular diseases such as angina [3] and are currently approved by the US Food and Drug Administration as treatments for pulmonary hypertension. They also have known cardiovascular benefits [3] including findings from a recent randomized placebo-controlled trial that showed PDE5-I use in heart failure patients was associated with improvements in left ventricular ejection fraction, diastolic function, exercise tolerance, and overall clinical condition [4]. The potential cardiovascular benefits of PDE5-Is may have contributed to the differences in MI rates found in the study, and this limitation was not discussed in the publication. Neither Vigen et al. nor Finkle et al. evaluated serum testosterone levels after beginning TST. Consequently, it is difficult to ascertain whether these men were compliant with the medication or even responded to therapy. Multiple previous studies have found that low testosterone is associated with an increased risk of cardiovascular disease [5] and that TST is associated with a reduction in mortality in hypogonadal men [6]. The increased rate of MIs in the TST cohort of the Finkle et al. study may have been the result of preexisting cardiovascular risk factors present within the low testosterone group that were not present in the PDE5-I group. As mentioned previously, it is also possible that PDE5-I use in the so-called control group provided some cardiovascular-protective effect. The question now becomes how these results affect clinical practice. There is clearly a need for large prospective placebo-controlled randomized trials such as the Women’s Health Initiative to determine definitively the cardiovascular risks of TST. However, until this occurs, physicians should consider adding to their patient counseling a discussion about putative cardiovascular risks associated with TST including the limitations of the current studies. The recent publications described represent an opportunity
Re: Global Effects of Smoking, of Quitting, and of Taxing Tobacco Jha P, Peto R. N Engl J Med. 2014;370:60–8 Experts’ summary: In this outstanding review, Jha et al. [1] summarize the reasons and effects of smoking on global health, highlighting the benefits of smoking cessation and discussing reasons affecting tobacco consumption. Still approximately 50% and 10% of young men and women, respectively, take up smoking with relatively few ever stopping. This has led to a steady increase in the annual tobacco-attributable death toll. Interestingly, smoking patterns have changed over the last century. Initially, smoking rates increased substantially in many highincome countries, followed by increasing rates in the middleand low-income countries. In addition increasing rates of daily cigarette consumption were observed during the last century with comparable changes according to the income classes.
for well-informed physicians to have thorough discussions with their patients about the risks and benefits of TST and, if prescribed, to enter into an agreement with the patient to enable appropriate oversight during treatment. Conflicts of interest: Larry I. Lipshultz participates in clinical trials and is a consultant and speaker for both Auxilium and Endo. The other authors have nothing to disclose.
References [1] Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829–36. [2] Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363:109–22. [3] Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebocontrolled study. Circ Heart Fail 2011;4:8–17. [4] Ioakeimidis N, Kostis JB. Pharmacologic therapy for erectile dysfunction and its interaction with the cardiovascular system. J Cardiovasc Pharmacol Ther 2014;19:53–64. [5] Oskui PM, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc 2013;2:e000272. [6] Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012;97:2050–8.
James M. Dupree, Ranjith Ramasamy, Jason R. Kovac, Gavin Langille, Larry I. Lipshultz* Department of Urology, Baylor College of Medicine, Houston, TX, USA *Corresponding author. 6624 Fannin Street, #1700, Houston, TX 77030, USA. E-mail address: [email protected] (L.I. Lipshultz). http://dx.doi.org/10.1016/j.eururo.2014.03.038
The authors found that in middle age patients, mortality rates among cigarette smokers were 2–3 fold increased compared to never smokers. Throughout adulthood this likely leads to a reduction in life span by an average of about 10 years, which mainly impairs the life expectancy of those killed by smoking in the middle age, as those otherwise might have had a life expectancy of decades. In contrast, smoking cessation increases life expectancy. Tobacco taxes and consumption are clearly inversely related especially in low-income and less educated groups. Moreover, banning advertisement may further help decrease overall consumption. Although most former smokers quit unaided, physician support or multimedia based counseling can increase the likelihood of successful quitting. The authors estimated that decreasing smoking prevalence could prevent several tens of millions of tobaccoattributable deaths during the next few decades. Experts’ comments: Tobacco use is a major preventable cause of premature death and disease worldwide. Smoking is the best-established
EUROPEAN UROLOGY 66 (2014) 173–178
Expert’s comments: Metformin, a first-line antidiabetic drug belonging to the biguanide family, has been associated with a decreased risk of subsequent cancers and an improved cancer-related outcome [1]. In a meta-analysis of 20 studies including >13 000 cancer patients with type 2 diabetes, metformin use increased overall survival by 34% and cancer-specific survival by 38% for all patients with cancer compared with nonmetformin use [2]. In patients with PCa treated with external-beam radiation therapy, metformin use was associated with improvement in all outcomes compared with the diabetic nonmetformin group. In men experiencing biochemical failure, metformin use was also independently correlated with a decrease in the development of castration-resistant PCa (CRPC) [3]. In nondiabetic patients with chemotherapynaive CRPC, metformin use led to disease stabilization and prolongation of prostate-specific antigen doubling time in some patients [4]. The antineoplastic activity of metformin has been related to reduced hyperinsulinemia and glycemic levels. In addition, metformin selectively blocks the growth of cancer stem cells and inhibits the metabolic stress response that may stimulate the inflammatory pathway associated with a number of cancers. Because metformin is not believed to influence the transformation of benign cells to malignant cells but rather to modulate cellular energy, metformin may have a greater impact on cancer survival than on incidence. Metformin may also have other benefits for nondiabetic patients who require androgen deprivation therapy (ADT) through its insulin-sensitizing effects because ADT can be associated with insulin resistance and metabolic syndrome.
Because metformin is inexpensive, with only minor side effects in men with and without diabetes, and because PCa is a slow-growing disease, this drug could play a role in secondary prevention strategies [5]. Further studies are necessary to show which PCa patients may benefit from this therapy. Conflicts of interest: The author has nothing to disclose.
References [1] La Vecchia C, Bosetti C. Metformin: are potential benefits on cancer risk extended to cancer survival? Oncologist 2013;18:1245–7. [2] Yin M, Zhou J, Gorak EJ, et al. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist 2013;18:1248–55. [3] Spratt DE, Zhang C, Zumsteg ZS, et al. Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. Eur Urol 2013;63:709–16. [4] Rothermundt C, Hayoz S, Templeton AJ, et al. Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). Eur Urol. In press. http://dx.doi.org/ 10.1016/j.eururo.2013.12.057 [5] Penney KL, Stampfer MJ. The time is ripe for a randomized trial of metformin in clinically localized prostate cancer. J Clin Oncol 2013;31:3054–5. Dorothea Weckermann* Department of Urology, Klinikum Augsburg, Augsburg, Germany *Department of Urology, Klinikum Augsburg, Stenglinstraße 2, Augsburg, Bavaria 86156, Germany. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2014.03.037
PLoS One 2014;9:e85805
person-years before to 11.52 person-years after; rate ratio: 2.19; 95% CI, 1.27–3.77). There was no corresponding increase in MI rate in men who filled a PDE5-I prescription (3.48 per 1000 person-years before to 3.75 per 1000 personyears after; rate ratio: 1.08; 95% CI, 0.93–1.24).
Experts’ summary: Finkle and colleagues recently performed a secondary data analysis to investigate potential associations between testosterone supplementation therapy (TST) and cardiovascular events. The authors used a large commercial database that covered claims from 2006 to 2010 and compared two cohorts of men: those who filled new prescriptions for TST and those who filled a new prescription for phosphodiesterase type 5 inhibitors (PDE5-Is). The investigators then evaluated the rates of myocardial infarction (MI), as determined by International Classification of Diseases, 9th revision, codes, before and within 3 mo after filling the first prescription in these groups. The authors identified 55 593 men who filled a prescription for TST and 167 279 men who filled a prescription for a PDE5-I. Rates of MI increased in the 3 mo after filling a TST prescription (from 3.48 per 1000 person-years before to 4.75 per 1000 person-years after; rate ratio: 1.36; 95% confidence interval [CI], 1.03–1.81). The increase was more pronounced in the subset of men 65 yr of age (5.27 per 1000
Experts’ comments: The work by Finkle and colleagues is a secondary data analysis of a large Claims and Encounters Database aimed at determining whether TST use was associated with cardiovascular events. The findings are similar to those from a retrospective cohort analysis of veterans with advanced cardiovascular disease [1] and the Testosterone in Older Men (TOM) trial [2]. Although these three studies have potentially concerning findings, they also exhibit methodological flaws that limit the credibility of their results. For example, in the study by Vigen et al. [1], hypogonadal veterans who previously had an MI or stroke and later received TST were excluded rather then being assigned to the no-testosterone arm for analysis. Furthermore, the authors’ conclusions of there being increased risks of MI or stroke associated with TST were based on KaplanMeier estimates, not the absolute rates of MI or stroke. In the TOM study [2], the authors recorded as cardiac events findings that are known side effects of testosterone such as hypertension and lower extremity edema.
Re: Increased Risk of Non-fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men Finkle WD, Greenland S, Ridgeway GK, et al.
176
EUROPEAN UROLOGY 66 (2014) 173–178
The concerning methodology in the study by Finkle et al. is the authors’ use of men taking PDE5-Is as a purported benign control group. PDE5-Is were originally developed as a treatment for cardiovascular diseases such as angina [3] and are currently approved by the US Food and Drug Administration as treatments for pulmonary hypertension. They also have known cardiovascular benefits [3] including findings from a recent randomized placebo-controlled trial that showed PDE5-I use in heart failure patients was associated with improvements in left ventricular ejection fraction, diastolic function, exercise tolerance, and overall clinical condition [4]. The potential cardiovascular benefits of PDE5-Is may have contributed to the differences in MI rates found in the study, and this limitation was not discussed in the publication. Neither Vigen et al. nor Finkle et al. evaluated serum testosterone levels after beginning TST. Consequently, it is difficult to ascertain whether these men were compliant with the medication or even responded to therapy. Multiple previous studies have found that low testosterone is associated with an increased risk of cardiovascular disease [5] and that TST is associated with a reduction in mortality in hypogonadal men [6]. The increased rate of MIs in the TST cohort of the Finkle et al. study may have been the result of preexisting cardiovascular risk factors present within the low testosterone group that were not present in the PDE5-I group. As mentioned previously, it is also possible that PDE5-I use in the so-called control group provided some cardiovascular-protective effect. The question now becomes how these results affect clinical practice. There is clearly a need for large prospective placebo-controlled randomized trials such as the Women’s Health Initiative to determine definitively the cardiovascular risks of TST. However, until this occurs, physicians should consider adding to their patient counseling a discussion about putative cardiovascular risks associated with TST including the limitations of the current studies. The recent publications described represent an opportunity
Re: Global Effects of Smoking, of Quitting, and of Taxing Tobacco Jha P, Peto R. N Engl J Med. 2014;370:60–8 Experts’ summary: In this outstanding review, Jha et al. [1] summarize the reasons and effects of smoking on global health, highlighting the benefits of smoking cessation and discussing reasons affecting tobacco consumption. Still approximately 50% and 10% of young men and women, respectively, take up smoking with relatively few ever stopping. This has led to a steady increase in the annual tobacco-attributable death toll. Interestingly, smoking patterns have changed over the last century. Initially, smoking rates increased substantially in many highincome countries, followed by increasing rates in the middleand low-income countries. In addition increasing rates of daily cigarette consumption were observed during the last century with comparable changes according to the income classes.
for well-informed physicians to have thorough discussions with their patients about the risks and benefits of TST and, if prescribed, to enter into an agreement with the patient to enable appropriate oversight during treatment. Conflicts of interest: Larry I. Lipshultz participates in clinical trials and is a consultant and speaker for both Auxilium and Endo. The other authors have nothing to disclose.
References [1] Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829–36. [2] Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363:109–22. [3] Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebocontrolled study. Circ Heart Fail 2011;4:8–17. [4] Ioakeimidis N, Kostis JB. Pharmacologic therapy for erectile dysfunction and its interaction with the cardiovascular system. J Cardiovasc Pharmacol Ther 2014;19:53–64. [5] Oskui PM, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc 2013;2:e000272. [6] Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012;97:2050–8.
James M. Dupree, Ranjith Ramasamy, Jason R. Kovac, Gavin Langille, Larry I. Lipshultz* Department of Urology, Baylor College of Medicine, Houston, TX, USA *Corresponding author. 6624 Fannin Street, #1700, Houston, TX 77030, USA. E-mail address: [email protected] (L.I. Lipshultz). http://dx.doi.org/10.1016/j.eururo.2014.03.038
The authors found that in middle age patients, mortality rates among cigarette smokers were 2–3 fold increased compared to never smokers. Throughout adulthood this likely leads to a reduction in life span by an average of about 10 years, which mainly impairs the life expectancy of those killed by smoking in the middle age, as those otherwise might have had a life expectancy of decades. In contrast, smoking cessation increases life expectancy. Tobacco taxes and consumption are clearly inversely related especially in low-income and less educated groups. Moreover, banning advertisement may further help decrease overall consumption. Although most former smokers quit unaided, physician support or multimedia based counseling can increase the likelihood of successful quitting. The authors estimated that decreasing smoking prevalence could prevent several tens of millions of tobaccoattributable deaths during the next few decades. Experts’ comments: Tobacco use is a major preventable cause of premature death and disease worldwide. Smoking is the best-established