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Perspective

The Marketing of Viagra: Causes of ED and Nonpharmaceutical Approaches Were Obscured

Jack McCain

INTRODUCTION

The year 2018 saw the 20th anniversary of the introduction of a revolutionary drug, Viagra (sildenafil), which was approved by the FDA on March 27, 1998, as the first safe and effective oral drug for erectile dysfunction (ED). For about two decades thereafter, even casual viewers of the National Football League couldn’t help but notice the barrage of Pfizer’s television commercials for Viagra. These spots about action in the bedroom became as much a part of the broadcasts as the action on the field (see page 765 for transcripts of vintage Viagra commercials). But with Teva’s introduction of generic sildenafil in December 2017 (via an agreement with Pfizer, which launched its own generic product the same month, for half the $65 price of brand-name Viagra [Lee 2017]) and with more generic versions expected after Viagra’s patent expires in 2020, the need for Pfizer to market to men (and women) with pointed messages about the benefits of Viagra had run its course (Crupi 2017). Even though these ads have been absent for the past two seasons, their messages live on. Having used the direct-to-consumer ads to build nationwide awareness of ED and to promote a novel and relatively easy-to-use pharmacological treatment for ED that was far more appealing than previous approaches (penile implants, vacuum pumps, penile injections), Pfizer again leads the U.S. ED drug market. For the two-month period ended January 31, 2019, Viagra and its own generic version of the product held 65% of ED drug market share, with the generic product accounting for 90% of that share (Lovelace 2019). Competitors Cialis [tadalafil] and Levitra [vardenafil] trailed with market shares of 30% and 5%, respectively, for their branded and generic products.

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Here’s what U.S. television viewers learned about ED and Viagra over the years, through words and pictures:

  • Even apparently active, healthy-looking men who appear to be in early middle age get ED—implying that most men can expect to experience ED eventually, especially if they are older, not especially active, and not in the best of health
  • Good-looking men with ED in early middle age have attractive female partners who look even younger
  • Attractive women aren’t bothered by ED, knowing that an oral drug treatment enables their men to get and keep an erection 
  • Provided a man takes action, ED need not be a relationship-breaker—Viagra enables a man to get and keep relationships
  • Men with ED should ask their doctors if Viagra is right for them (and their partners should encourage them to do so if they don’t think of it themselves or feel embarrassed about asking)
  • A man with ED should ask his doctor if his heart is healthy enough for sex
  • Erections lasting 4 hours or more are not desirable and warrant medical intervention 

This article, however, deals more with what television viewers did not learn. Because the TV advertisements reflected the narrow commercial interests of the product’s manufacturer, many relevant topics went unmentioned, such as those raised by the following questions that a curious man with ED might put to his doctor:

  • Why do I have ED? 
  • Could my ED have been prevented, or is it just an inevitable consequence of aging?
  • Is my ED a condition in its own right, to be treated with Viagra and left at that, or is it a sign that I may have other problems that need attention, extending to therapies other than or in addition to Viagra? 
  • If ED is just another discomfiting aspect of normal aging, is it impossible for my ED to regress? Or will I need to take Viagra for the rest of my life?

The authors of a 2017 review (Mobley 2017) seem to have reinforced one of these commercials’ implicit messages, stating, “The reality is that ED is a normal part of ageing.” If that indeed is the case, Viva Viagra!, as the actors once sang. In another otherwise very useful review (Shamloul 2013), after noting that 35% of men fail to respond to sildenafil and other members of its class, the authors hold out hope for the development of some other pharmaceutical “cure” for ED, or even a genetic or cell-based approach. This statement reinforces the notion that ED is a disease in its own right (it is, after all, a dysfunction, with neurogenic, psychogenic, or, most commonly, vasculogenic etiologies) for which there someday may be a product that’s even more effective than sildenafil. 

Although ED is associated with physiologic and psychologic factors related to increasing age, it generally is not regarded as a function of normal aging (McVary 2015). Neither is it an inevitable consequence of normal aging, as some writers claim (Kaya 2017, Mobley 2017), any more than cardiovascular disease (CVD), for which increasing age also is a strong risk factor, is an inevitable consequence of aging. In fact, if a television viewer goes to Viagra’s U.S. website, www.viagra.com, he or she will read, “[ED is] not just a part of aging that you have to accept. It’s a real medical condition, so it should be addressed like one.” The webpage on which this statement appears also lists the following medical conditions that can cause ED, with a paragraph or two about each: depression, diabetes, heart disease, high blood pressure, high cholesterol, obesity, prostate cancer treatment, and spinal cord injury. 

ED and CVD share many risk factors in addition to age, and any therapy that purports to be a cure for ED is likely to do little to address the underlying cause(s) of ED and CVD and their modifiable risk factors. Lifestyle modification, which long has been recommended as the foundation of therapy for CVD risk factors, is capable of addressing the numerous modifiable risk factors that ED shares with CVD, such as smoking, hypertension, high levels of low-density lipoprotein cholesterol (LDL), low levels of high-density lipoprotein cholesterol (HDL), physical inactivity, obesity, metabolic syndrome, type 2 diabetes, and depression. In a prospective study, the presence of several of these CVD risk factors in men of early middle age was found to predict development of ED up to 25 years later (Fung 2004). Compared to men with no CVD risk factors, men with one, two, or three risk factors were 50%, 72%, and 120% more likely, respectively, to develop ED. 

Instead of being an inevitable consequence of normal aging, ED seems to be more closely correlated with declining health than increasing age: As the years accumulate, so do risk factors for ED and CVD. The belief that ED and other forms of sexual dysfunction are a normal part of aging is a leading reason behind men’s failure to consult a physician about ED (Laumann 2009). 

The same recent review that claims ED is part of normal aging (Mobley 2017) nevertheless states that “ED is frequently, if not usually, directly related to endothelial dysfunction.” The endothelium that lines smooth muscle of the corpus cavernosum is a major source of nitric oxide (NO), which is the most important of the neurotransmitters needed to produce an erection (Kapur 2007). At the beginning of an erection, NO is supplied primarily by cavernous nerves, after which endothelial NO sustains the erection. Endothelial dysfunction is commonly advanced as an underlying cause of most cases of ED as well as cardiovascular disease, leading to the pithy admonition, “ED [erectile dysfunction] is ED [endothelial dysfunction]!” (Jackson 2013, Solomon 2008). Endothelial dysfunction tends to become manifest in the penile vasculature earlier than it does elsewhere in the body, for reasons that are not fully understood (Musicki 2015). It follows, however, that if ED is a part of normal aging and if ED usually is directly related to endothelial dysfunction, then endothelial dysfunction also could be regarded as part of normal aging. That is unlikely to be true, even though endothelial dysfunction is associated with increasing age. On the other hand, if endothelial dysfunction is not a consequence of normal aging, and if most cases of ED arise from endothelial dysfunction, then steps to prevent or ameliorate endothelial dysfunction should be effective in preventing and treating many cases of ED, reducing the need for drug treatment specifically aimed at ED. Such steps aimed at endothelial dysfunction also could simultaneously reduce a man’s risk of CVD, owing to the numerous shared risk factors. 

Prevalence of ED

ED—commonly defined as the inability to get and maintain an erection sufficient for satisfactory sexual intercourse—is a common form of sexual dysfunction. Because different definitions of ED have been used in attempts to quantify its prevalence and degree, estimates vary. One widely cited study suggests about 18 million U.S. men aged 20 years or older have ED, defined as being sometimes able or never able to get and keep an erection (Selvin 2007). In this study, a sedentary lifestyle was associated with ED: Among men age 40 years and older, those who reported engaging in no physical activity during the previous 30 days were twice as likely to have ED as men who engaged in vigorous physical activity (odds ratio, 1.94; 95% CI, 1.32-2.83); P < 0.05). In addition, the odds of men aged 40 years and older having ED increased with daily hours of television, video, and computer use (Figure 1)

Figure 1 Age-Adjusted Odds Ratios of ED in Men 40 Years of Age and Older, by Daily Hours of Television, Video, and Computer Use

Source: Selvin 2007
For all comparisons with reference group (gray column), P < 0.05.

Despite the impression that may be left by television commercials, ED is not the only form of sexual dysfunction in men or even the most common form in some age groups. Results of a nationwide survey published at the beginning of the Age of Viagra (Laumann 1999) showed that in men between the ages of 19 and 59 years, the prevalence of ED, as well as of low desire, increases with age, in contrast to premature ejaculation and performance anxiety (Figure 2). Compared with men in the youngest age group, men aged 50 to 59 were 3.6 times as likely to report problems with ED. Notably, men in poor-to-fair health were at increased risk of ED and all other kinds of sexual dysfunction. Compared with men in better health, men in poor-to-fair health were about three times more likely to experience ED and low desire and twice as likely to experience premature ejaculation. 

Figure 2 Most Prevalent Kinds of Sexual Dysfunction Reported by Men 19 to 59 Years Old

Source: Laumann 1999
Data are from the National Health and Social Life Survey, a national probability sample of 1,749 women and 1,410 men ages 19 to 59. Men ages 50–59 years were 3.6 times as likely as men ages 19–29 years to report ED.

Another nationwide survey examined sexual behaviors and sexual dysfunction in an older group comprising 1,550 women and 1,455 men aged 57 to 85 years (Lindau 2007). In this population, ED was more prevalent than in the survey of younger men discussed above, but premature ejaculation was less prevalent (Figure 3). As in the survey discussed above, respondents reporting their health as poor or fair were more likely than people in better health to report sexual dysfunction, including ED. Moreover, men reporting their health as poor or fair were 79% less likely to be sexually active than men in very good or excellent health. In terms of severity of sexual dysfunction, premature ejaculation rivals ED. The reason ED has received so much commercial attention while premature ejaculation receives almost none is, of course, that there are no relatively expensive brand-name drugs for men with premature ejaculation. 

Figure 3 Most Prevalent Kinds of Sexual Dysfunction Reported by Sexually Active Men 57 to 85 Years of Age

Source: Lindau 2007
Data are from the National Social Life, Health, and Aging Project (NSHAP), a nationally representative probability sample comprising 1,550 women and 1,455 community-dwelling men ages 57 to 85 years. In the aggregate, ED was reported as a bothersome problem by 37% of sexually active men; low desire, 28%; premature ejaculation, 28%; and performance anxiety, 27%. “Sexually active” was defined as having had sex with at least one partner during the previous 12 months.

Physiology and Pathophysiology of Penile Erections

In healthy men, erections occur in response to erotic thoughts or physical stimulation or, commonly, both. Healthy males also experience involuntary sleep-related erections (SRE) throughout life (Hirshkowitz 2005, van Driel 2014). Such erectile activity occurs cyclically, in association with REM sleep, about every 80 minutes, with each SRE lasting about 20 minutes; an early morning erection actually is the last SRE in the night’s cycle. The presence or absence of SREs can be used to help discern the etiology of ED, because normal SREs indicate that nerves between the spinal cord and penis are functioning properly and that penile tissue and vascularization are normal, suggesting that any ED in the context of normal SREs has psychogenic origins, The absence or intermittent appearance of SREs points toward ED with an organic etiology (vasculogenic, hormonal, neurogenic), with the caveat that diminished REM sleep in older men may reduce the frequency and rigidity of SREs (Hirshkowitz 2005, McVary 2015, Miner 2014). Distinguishing psychogenic ED from organic ED is important for determining appropriate therapeutic approaches (Miner 2014). Men with ED that is predominantly psychogenic are more likely to benefit from psychosexual counseling. In contrast, men whose ED is thought to be vasculogenic (the most common organic cause) will benefit from cardiovascular risk assessment. 

Besides SREs, other indications that a man’s ED is largely psychogenic in its origins are that its onset is acute and temporally associated with problems involving his sexual partner, it occurs only under certain circumstances, his noncoital erections are rigid, he has a history of psychosexual problems, and he experiences primary fear and anxiety (Miner 2014). In contrast, indications that a man’s ED is largely organic include its onset being gradual, its occurrence under all circumstances, the lack of rigidity in noncoital erections, and the ED being the cause, not the consequence, of any psychosexual problems, interpersonal issues, or anxiety and fear. 

Prior to the introduction of PDE-5 inhibitors, when implantation of surgical prostheses was a leading therapeutic option for men with ED, formal SRE testing was recommended because the surgical procedure destroys erectile tissue. With the widespread availability of oral ED drugs, however, a test of a PDE-5 inhibitor is warranted, reserving SRE testing for men who fail medical therapy (Hirshkowitz 2005). SRE testing also may be useful in men who haven’t responded to psychosexual counseling and in men who may have occult sleep disorders such as obstructive sleep apnea or periodic limb movement disorder, both of which occur during sleep and adversely affect sleep quality and SREs (Hirshkowitz 2005). 

PDE-5 Inhibition

The PDE-5 inhibitors help to indirectly increase levels of a key molecule in male sexual function, nitric oxide (NO), which promotes the vascular relaxation that results in erection (Lue 2000, McVary 2007). NO concentrations increase in smooth muscle cells after NO is released by parasympathetic nerve fibers as well as by endothelial cells. The diffusion of NO activates an enzyme, guanylyl cyclase, which converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). cGMP activates a cGMP-specific kinase that helps decrease intracellular calcium levels, resulting in smooth muscle relaxation; a parallel cyclic adenosine monophosphate (cAMP) pathway also lowers intracellular calcium levels. cGMP gradually is degraded by 5-hydrolase-phosphodiesterase (PDE-5).

The potential of sildenafil as an oral ED treatment was discovered through serendipity while the compound was being investigated for treatment of angina (Goldstein 2019). Sildenafil acts through inhibition of PDE-5, thereby maintaining high concentrations of cGMP; other PDE-5 inhibitors approved by the FDA include vardenafil (Levitra, Bayer Corp.; 2003) tadalafil (Cialis, Lilly Research Laboratories; 2003), and avanafil (Stendra, Vivus, Inc.; 2012). In the absence of sufficient levels of endogenous NO, none of the PDE-5 inhibitors will be effective. Among the conditions that can lower levels of NO, through their effects on NO or NO synthase (NOS), are diabetes, the metabolic syndrome, elevated lipid levels, atherosclerosis, and lower urinary tract symptoms (McVary 2007). In the absence of sexual desire, PDE-5 inhibitors also will be ineffective. 

Because of its inhibition of PDE-5, sildenafil also can increase cGMP levels in pulmonary vascular smooth muscle cells, resulting in vasodilation of the pulmonary vascular bed along with some systemic vasodilatation. In 1998, under the Pfizer brand name Revatio, sildenafil was approved by the FDA for treatment of adults with pulmonary arterial hypertension (PAH) to improve their capacity for exercise and prevent worsening of the condition. Revatio sometimes has been prescribed for men who don’t have PAH but do have ED, thus providing them with a less-expensive alternative to Viagra. 

The systemic effects of sildenafil may give it broader uses beyond its current indications for ED and PAH (Vasquez 2016). A recent nationwide Swedish cohort study of men less than 80 years old experiencing their first myocardial infarction (N = 43,145) suggests that PDE-5 inhibitors administered post MI may be cardioprotective, because the risks of mortality and hospitalization for heart failure were 33% and 40% lower, respectively, in 3,068 men receiving PDE-5 inhibitors (92%) or alprostadil (8%), compared with men not receiving them (Andersson 2017). (Improved outcomes were seen only in the men receiving PDE-5 inhibitors.) An alternative explanation for the results is simply that men who did not take ED drugs post MI were in poorer health at baseline than the men who did; among the men who did not receive ED drugs post MI, rates of stroke, COPD, and PAD were twice as high and the rate of heart failure was three times higher compared with the men who received ED drugs. Even if the results of the Swedish study reflect the benefits of PDE-5 inhibition, more research is needed before PDE-5 inhibitors can be prescribed routinely to reduce the risk of CVD through their ability to lower blood pressure. 

ED as predictor of metabolic syndrome, diabetes, CVD, and mortality

Accumulating evidence suggests that ED is associated with increased risk of metabolic syndrome, diabetes, cardiovascular disease, CVD mortality, and all-cause mortality. Using data from the 2003–2004 National Health and Nutrition Examination Survey (NHANES) and the National Death Index, investigators found that, over 7.75 years of follow-up, the adjusted risk of all-cause mortality was 70% greater in men with ED (defined as being sometimes able or never able to get and keep an erection satisfactory for intercourse) compared with men without ED (hazards ratio, 1.70; 95% CI, 1.01–2.85; P = 0.04) (Loprinzi 2015). The sample consisted of 1,790 men (mean age, 45.4 years; range 20–85), 244 of whom were deceased at follow-up. Compared with men without ED, those with ED lost 7.4 years of potential life. 

In a prospective study conducted in greater Boston, the Massachusetts Male Aging Study (MMAS), in which 1,709 men 40 to 70 years of age were followed for a mean of 15 years, ED was associated with adjusted hazard ratios of 1.26 (95% CI, 1.01–1.57) and 1.57 (94% CI, 1.00–2.05) for all-cause mortality and CVD mortality, respectively (Araujo 2009). In a follow-up analysis of participants in the MMAS who were free of ED, diabetes, and heart disease at baseline, development of ED was predicted by the presence at baseline of risk factors for coronary heart disease, including smoking, overweight, hypertension, and diet (Feldman 2000). 

In a prospective study of men without a history of CHD or stroke (N=2,561), severe or moderate ED (IIEF-5 scores of 5 to 16), but not mild ED (scores of 17 to 21), was associated, using the Framingham algorithms, with considerably increased 10-year risks of CHD or stroke in comparison with men with no ED (Figure 4) (Ponholzer 2005).

Figure 4 10-Year Risk of CHD, by Age and ED Severity

Source: Ponholzer 2005
In the CHD cohort (panel A), the 10-year risk of CHD in men with moderate to severe ED (IIEF-5 score 5–16) was 65% greater (13.2% vs 8.0%; P 20% constitutes high-risk status. In the stroke cohort (panel B), the 10-year risk of stroke in men with moderate to severe ED was 43.0% greater (13.3% vs 9.3%; P = 0.04) compared with men with no ED.

A meta-analysis of 12 prospective cohort studies involving 36,744 patients (Dong 2011) likewise found modest positive associations (relative risk of an outcome for men with ED vs reference group) for four important outcomes, including all-cause mortality (Table 1). Another meta-analysis of 14 studies enrolling 92,757 participants (Vlachopoulos 2013) generated similar relative risk ratios for the same outcomes (Table 2)

Table 1 Relative Risk of CVD Outcomes and All-Cause Mortality in Men With ED
Condition Relative risk
(95% CI)
P value
Cardiovascular disease 1.48 (1.25–1.74) P < 0.001
Coronary heart disease 1.46 (1.31–1.63) P < 0.001
Stroke 1.35 (1.19–1.54) P < 0.001
All-cause mortality 1.19 (1.05–1.34) P = 0.005
Source: Dong 2011
Table 2 Relative Risk of CVD Outcomes and All-Cause Mortality in Men With ED
Condition Relative risk
(95% CI)
P value
Cardiovascular disease 1.44 (1.27–1.63) P < 0.001
Coronary heart disease 1.62 (1.34–1.96) P < 0.001
Stroke 1.39 (1.23–1.57) P < 0.001
All-cause mortality 1.25 (1.12–1.39) P < 0.001
Source: Vlachopoulos 2013
Metabolic Syndrome

The metabolic syndrome was defined in Adult Treatment Panel III as the presence of at least three of the following five components: waist >40 inches; systolic BP >130 mm Hg or diastolic BP >85 mm Hg, or use of antihypertensives; HDL <40 mg/dL
or use of lipid medications; fasting glucose ≥100 mg/dL; or triglycerides >150 mg/dL (NCEP 2002). This definition or an approximation of it is used in studies investigating the association between the metabolic syndrome and ED. Data from the MMAS showed that, over the course of 15 years, the presence of ED at baseline in otherwise healthy men predicted development of the metabolic syndrome in men whose baseline BMI was <25 (Kupelian 2006). Compared with men with similarly low BMI but no or minimal ED, these men with moderate or complete ED were at twice the risk of developing the metabolic syndrome. Likewise, in a study in which 100 subjects with metabolic syndrome were matched for age (mean, 38 years) and BMI (mean, 27) with 50 healthy controls, the prevalence of ED was twice as great in the metabolic syndrome group as in the control group (27% vs 13%; P = 0.03) (Esposito 2005). Moreover, as the number of components of the metabolic syndrome increased, so did the prevalence of ED, rising from about 20% in men with only three components to about 40% in men with 5 components. 

Given that the metabolic syndrome predicts increased risk of type 2 diabetes and cardiovascular disease, Kupelian et al expressed the hope that apparently healthy men with ED despite a relatively low BMI would be motivated to modify their lifestyles in order to reduce their risk of development diabetes and cardiovascular disease. Bacon et al (2006) similarly hoped that telling men that lifestyle modification could reduce their risk of developing ED would be a more powerful motivator than telling them that lifestyle modification could reduce their risk of heart disease. 

Online CVD Risk Calculators

After two decades of Viagra commercials and nearly as many years of Cialis commercials (featuring his-and-her outdoor bathtubs) that focus on treating ED with a convenient oral drug, without any unsettling suggestion that ED might warrant asking a physician questions beyond whether one’s heart is healthy enough for sex, men (or their partners) might consider employing one or more of several easy-to-use online risk calculators to get an idea of a man’s 10-year risk of CVD. The new hypertension guideline states that the evidence is insufficient to recommend screening all men with ED for CVD risk factors (Whelton 2017), but many authors believe screening for CVD risk factors should be a routine part of the evaluation of men with ED (Basu 2016, Kupelian 2006, Loprinzi 2015, Ponholzer 2005) and some recommend the use of specific calculators to estimate CVD risk in men presenting with ED (Basu 2016, Miner 2014). In its current guideline for ED, the American Urological Association sets forth this clinical principle: “Men should be counseled that ED is a risk marker for underlying CVD and other health conditions that may warrant evaluation and treatment” (Burnett 2018).

Regardless of his ED status, an interested man (or woman) can use one of these risk calculators by himself, print the results, and take them to an appointment with a physician to foster a discussion about steps that might be helpful in addition to a prescription for a PDE-5 inhibitor or even to preclude the use of such drugs. The risk calculator recommended in the new high blood pressure clinical practice guideline (Whelton 2017) to establish the threshold for treatment of high blood pressure is the ACC/AHA Pooled Cohort Equations (http://tools.acc.org/ASCVD-Risk-Estimator/), which have been validated for U.S. adults aged 45 to 79 years in the absence of concurrent statin therapy. In addition to recommending lifestyle modification for men with vasculogenic ED, Miner and colleagues recommend using this calculator to stratify such patients according to their ASCVD risk (low, <5%; intermediate, 5% to 10%; or high, >10%) (Miner 2018). 

Framingham Risk Score 

The Framingham risk calculator (https://www.framinghamheartstudy.org/fhs-risk-functions/cardiovascular-disease-10-year-risk/) yields a 10-year risk of CVD from longitudinal data generated by the famous Framingham Heart Study (D’Agostino 2008). A 10-year risk ≥20% is regarded as high; 5% to <20%, intermediate; <5%, low. The third Princeton Consensus panel recommends using the Framingham Risk Score as a starting point to evaluate CVD risk and subclinical atherosclerosis in men with ED. (All three of the Princeton conferences were multidisciplinary explorations of the intersection of sexual activity and cardiac health.) The panel also noted that in younger men (age 30 to 60 years), the presence of ED alone warrants consideration of CVD risk regardless of the Framingham score (Nehra 2012). Some physicians urge that any young man with ED (age 20 to 40 years) receive careful evaluation for organic and psychogenic causes of his ED (Capogrosso 2016, Cohen 2015). 

The same group of multidisciplinary experts who participated in the third Princeton Consensus Conference later published a review (Miner 2014) in which they recommended that the Framingham Risk Score be used initially to estimate the 10-year risk of CVD in all men with ED, especially those with vasculogenic ED. For men at all levels of risk, they recommend risk factor management. For men at high risk, they also recommend referral to a cardiologist; for intermediate risk, they recommend further testing via noninvasive means (e.g., exercise stress testing or carotid intima-media thickness [cIMT], a marker of arteriosclerosis and atherosclerosis in the carotid arteries whose use for detecting subclinical CVD is discussed further below). 

Miner et al also suggested adding ED to the Framingham algorithms to improve the tool’s ability to predict CVD risk in men age 30 to 60, provided additional studies demonstrate the value of doing so. 

QRISK3 

The latest version of the QRISK risk calculator (https://qrisk.org/three/) used by the National Health Service (NHS) in Great Britain, QRISK3, stands apart from Framingham and ASCVD calculators by incorporating ED among its variables. QRISK3 is the third such tool for predicting 10-year risk of CVD since the introduction of the original QRISK in 2007. The previous version, QRISK2, already was in widespread use by the NHS.

Despite a strong association between ED and increased risk of CVD, until recently it was believed that ED did not improve prediction of the risk of developing CVD, in middle-aged and older men, beyond the traditional risk factors used to calculate the Framingham risk score (Araujo 2010). In a recent large study encompassing all primary care practices in England using a specific kind of electronic medical record, researchers compiled data for 2 cohorts, one to derive updated algorithms (QRISK3) incorporating new risk factors to predict a person’s 10-year risk of CVD and one to validate the scores (Hippisley-Cox 2017). The derivation cohort comprised 981 primary-care practices and 7.9 million patients aged 25 to 84 years; the validation cohort, 328 separate practices and 2.7 million patients. ED was among the new risk factors evaluated, and the researchers believe it is likely to be an independent risk factor for CVD. Uddin and colleagues recently observed that although ED has been added to the QRISK calculator, it remains absent from U.S. risk calculators. Their findings (discussed below) strengthen the already-strong argument for adding it, and for “more aggressive preventive therapy” in men with ED (Uddin 2018). 

Another risk factor newly added to the QRISK calculator is depression, among other serious mental illnesses. Neither the Framingham risk score nor the ASCVD risk calculator incorporates depression or any mental illness. Both a consequence of and a risk factor for CVD and ED (Laumann 2009, McVary 2015), depression can be ameliorated through increased physical activity. In a placebo-controlled trial, aerobic exercise performed three times a week at a moderate level (17.5 kcal/kg/week) was shown to be an effective therapy for mild-to-moderate major depressive disorder in adults aged 20 to 45 years (Dunn 2005). In another clinical trial enrolling older adults, aged 50 years or older, with major depressive disorder, an exercise training program was as effective as drug treatment (sertraline) or the combination of exercise and sertraline in achieving clinically significant reductions in depressive symptoms (Blumenthal 1999). 

PROCAM 

This calculator (https://www.mdapp.co/cardiovascular-risk-procam-score-calculator-255/) was developed during the Prospective Cardiovascular Münster (PROCAM) study, which enrolled 5,389 middle-aged men (age 35 to 65), among whom 325 acute coronary events were reported during 10 years of follow-up. Unlike the other three risk calculators, this calculator is based on data from men only. The PROCAM calculator constructed for use in clinical practice generates a score from 0 to 87. A 10-year risk of an acute coronary event >20% is regarded as high risk, which corresponds to a PROCAM score >53. In the PROCAM cohort, these high-risk patients accounted for 71.3% of observed acute coronary events while constituting only 7.5% of the cohort (Assmann 2002).

Noninvasive testing for subclinical CVD

A recent meta-analysis strengthens the argument for the use of two noninvasive technologies for assessing subclinical CVD in men whose CVD risk appears to be low per traditional CVD risk factors (Osondu 2017). These technologies are cIMT and flow-mediated dilation (FMD) of the brachial artery, a marker of endothelial dysfunction. cIMT is measured by ultrasound of the common carotid artery or the internal carotid arteries, or both, with results expressed in millimeters. FMD uses ultrasound to measure the percentage change over time in the diameter of the brachial artery after deflation of a cuff. In 12 cIMT studies enrolling 1,264 participants, cIMT was greater (mean, 0.09 mm; 95% CI, 0.06–0.12 mm) in men with ED compared with men without ED. In 15 FMD studies enrolling 2,025 participants, FMD was 2.6 percentage points less (95% CI, -3.12–-2.15) in men with ED compared with men without ED. Osondu et al argue that these two tests easily can be used, in conjunction with the IIEF-5, in primary care practices to assess subclinical CVD in men who otherwise appear to be at low risk. 

However, a recent longitudinal study involving a subpopulation from the Multi-Ethnic Study of Atherosclerosis (MESA) shows that seven baseline metrics of cardiovascular health (see Table 3), a concept intended by the American Heart Association to extend beyond the mere absence of CVD (Lloyd-Jones 2010), are associated with ED prevalence nine years later irrespective of endothelial function as assessed by FMD at baseline (Lane-Cardova 2017). Designed to investigate the factors underlying subclinical CVD and its progression, MESA enrolled 3,212 men aged 45 to 84 without overt CVD at baseline. The sample analyzed by Lane-Cordova and colleagues consisted of 1,136 men (mean age, 59 years; mean CVH score, 8.3) for whom a baseline CVH score could be calculated and for whom FMD and ED data also were available (from exam 1 at baseline and exam 5 at nine years after baseline, respectively). In this study, each metric for a participant was scored as 0 (poor), 1 (intermediate), or 2 (ideal), generating a total score ranging from 0 to 14. A total of 0 to 7 points was regarded as indicating the person was in low cardiovascular health; 8–11, moderate; 12–14, high. After nine years, the prevalence of ED in each category was 58%, 41%, and 33%, respectively. The lower the CVH score, the greater the prevalence of ED at nine years: Among men with CVH scores of 1 or 2 , the prevalence of ED was 100%; among men with a score of 13, the prevalence of ED was 15%. 

Table 3 Metrics Defining Ideal Cardiovascular Health in Persons Age ≥21 Years
Health Behavior/Factor Criteria Defining Ideal CVH
Smoking status Never smoked or quit >12 months ago
Body-mass index (BMI) <25 kg/m2
Physical activity ≥150 minutes/week moderate intensity
or
≥75 minutes /week vigorous intensity
or
Combination of above
Healthy diet
(based on Dietary Approaches to Stop Hypertension [DASH])
Including but not limited to:
  • Fruits and vegetables: ≥4.5 cups/day
  • Fish (preferably oily): ≥2 3.5-oz. servings/week
  • Fiber-rich whole grains (≥1.1 g fiber/10 g carbohydrate): ≥3 1-oz-equivalent servings/day
  • Sodium: <1,500 mg/day
  • Sugar-sweetened beverages: ≤450 kcal (36 oz.)/week
Total cholesterol <200 mg/dL (untreated)
Blood pressure <120/<85 mm Hg (untreated)
Fasting plasma glucose <100 mg/dL (untreated)
Source: Lloyd-Jones 2010

After only 3.8 years of follow-up of 1757 men in MESA who were free of CHD or CVD at baseline, the proportion of hard CHD events and hard CVD events was higher in men who self-reported ED (being “never able” or “sometimes able” to achieve an erection) than in those without self-reported ED – 3.4% vs 1.4% (P < 0.001) for hard CHD events (MI, cardiac arrest, CHD death) and 6.3% vs 2.6% (P < 0.001) for hard CVD events (CHD events + fatal and nonfatal stroke). After adjusting for several CHD and CVD risk factors, the HR of 1.9 (95% CI, 1.1–3.4) for hard CVD events remained statistically significant (Uddin 2018). 

The low number of men with high CVH at baseline (n = 79), vs 387 and 670 in the low and moderate CVH categories, respectively, along with the small number of older men within the high CVH group (number not reported), may have limited the ability of the study to identify some cases ED associated with FMD-detected endothelial dysfunction in age-adjusted analyses. 

If a man knows his blood pressure and his cholesterol and glucose levels, he can readily see from Table 3 how close he comes to being in ideal cardiovascular health, and so can his physician(Lloyd-Jones 2010). This information may be useful if the man is interested in preventing or treating ED, along with reducing his risk of type 2 diabetes and CVD, and it can be used in conjunction with any of the risk calculators to construct ‘what if?” scenarios. 

Progression and Regression of ED and Modification of CVD Risk Factors

ED is not a static condition. Once ED emerges, it does not necessarily continue to worsen but may in fact regress, regardless of the man’s age (Travison 2011). Over approximately three years of follow-up in the Men’s Attitudes to Life Events and Sexuality (MALES) study, men with ED who were younger than 50 years old were more likely to experience regression of ED than its progression. In MMAS and MALES, men aged 50 to 79 with ED were more likely to experience progression of ED than regression. Even so, regression was not rare in the older age ranges; the probability of regression was about 25% to 30%. Numerous modifiable risk factors for ED can be addressed through the following interventions. 

Benefits of tighter blood pressure control. In a retrospective cohort study using electronic health records of men aged 26 to 60 who were newly diagnosed with hypertension but who lacked an ED diagnosis at baseline (N = 39,320, all being Northern California Kaiser Permanente members), the better the control of the patients’ systolic BP over time, the lower the incidence of ED (Hsiao 2019). The overall incidence of ED was 13.9%. After an average follow-up of 55 months among men whose average systolic BP during their last two years in the study was <120 mmHg, ED incidence was 12.5%; 120 to 139 mmHg, 13.9%; 140 to 159 mm Hg, 14.9%; ≥160 mmHg, 14.4%. In addition, the lower the average systolic BP, the longer the time to ED diagnosis: <120 mmHg, 34 months; 120 to 139 mmHg, 30 months; 140 to 159 mmHg, 22 months; ≥160 mmHg, 22 months. 

In addition to having hypertension, most members of this cohort were overweight (BMI 25 to 30, 43%) or obese (BMI >30, 43%), and 14% had diabetes at baseline. Elevated BMI and diabetes join hypertension as well-known CVD risk factors. Even so, 19% of men in this study took no antihypertensives during the last two years of the study, leading the authors to express the hope that if fear of heart attack and stroke didn’t motivate men to take their antihypertensives, fear of ED might. 

Benefits of lifestyle modification. Lifestyle modification—diet and exercise—has been associated with a reduced risk of developing ED as well as with improved erectile function in men who already have ED. For example, in a randomized controlled trial enrolling 110 obese middle-aged men (mean BMI, 36 [range, 30 to 49]; mean age, 43 years) with ED (mean IIEF-5 score, 13, indicating moderate ED), men in the intervention group (n=55) were given detailed information about how to lose ≥10% of their body weight through diet and exercise, while men in the control group were given only general information about diet and exercise (Esposito 2004). After two years, the overall change in the IIEF-5 score in the intervention group was an increase of 3 points, from 13.9 to 17 (mild ED), while the change in the control group was negligible, rising from 13.5 to 13.6. Importantly, one-third (n=17) of the intervention group achieved an IIEF score ≥22, indicating no ED, versus only three men in the control group (P = 0.001). In addition, members of the intervention group achieved statistically significant improvements in numerous clinical and metabolic parameters, including weight, BMI, waist-to-hip ratio, systolic BP, diastolic BP, total cholesterol, HDL, triglycerides, and glucose.

Benefits of following a Mediterranean diet. Several of the coauthors who undertook the above-mentioned study of the effects of diet and exercise on ED in obese men also examined the effects of dietary change alone (changing to a Mediterranean diet) on ED in 65 middle-aged men with ED and the metabolic syndrome who were otherwise healthy (Esposito 2006). At baseline, their mean age was 44 years; mean BMI, 28 (i.e., overweight but not obese); and mean IIEF-5 score, 14.6, indicating mild-moderate ED. The intervention group (n=35) was instructed about the Mediterranean diet and received counseling from a nutritionist once a month for the first 12 months and every other month during the second 12 months, along with behavioral and psychological counseling. A Mediterranean diet is rich in fruits and vegetables, fish, high-fiber whole grains, olive oil, nuts, and legumes. Through randomized controlled trials it has been shown to reduce the risk of CVD morbidity and mortality in primary and secondary prevention, and it is compares favorably with others interventions in reducing such risk (Widmer 2015).

The control group received oral and written information about diet but not individualized advice. Both groups received information about increasing their physical activity. After two years, the mean IIEF-5 score for the Mediterranean diet group had increased from 14.4 at baseline to 18.1, while in the control group it increased only slightly, from 14.9 at baseline to 15.2 (P < 0.01 for the difference between groups at two years). In addition, 13 men in the Mediterranean diet group but only two men in the control group achieved an IIEF score ≥22 (P = 0.01), indicating restoration of normal erectile function. In the intervention group, statistically significant improvements in markers of endothelial dysfunction also were seen. 

Benefits of physical activity. A meta-analysis of seven randomized controlled studies enrolling 478 patients with ED at baseline showed a modest improvement in ED scores as measured by the IIEF in patients who engaged in supervised or unsupervised activity compared with those who received standard care (Silva 2017). These studies were heterogeneous, varying in patient population with respect to the predisposing factor (ischemic heart disease, metabolic syndrome, hypertension, obesity, radical prostatectomy, presence of two or more CVD risk factors), mean age (44 to 69), nature of intervention, IIEF score at baseline (5.1 to 13.8), and duration of follow-up (two months to two years). Despite these differences, the pooled analysis showed a statistically significant increase of 3.9 points in IIEF scores in the intervention groups vs the control groups. Subgroup analyses showed statistically significantly improved scores in men with established CHD, CVD risk factors alone, or radical prostatectomy. With the exception of exercises to strengthen pelvic floor muscles, all the physical activity/exercise interventions provided a statistically significant benefit in IIEF scores. 

In a cohort of 593 men aged 40 to 70 from the MMAS who were free of ED at baseline and had not been treated for CVD or diabetes, those who remained sedentary during a mean 8.8 years of follow-up were at the highest risk of developing ED, while the lowest risk of developing ED was among the men who either remained physically active or initiated physical activity (Derby 2000). 

Because the 2003-2004 National Health and Nutrition Examination Survey (NHANES) included data for both ED and physical activity measured via accelerometry, researchers were able to use these data to explore the association between physical activity and ED in 692 men between the age of 50 and 85 (Loprinzi 2015a). In this sample, the weighted mean age was 62.5 years, and 54% of the men had ED. Moderate-to-vigorous physical activity ranged from 0 to 158 minutes per day (mean, 19 min/d). For every increase of 30 minutes per day in moderate-to-vigorous physical activity, men reduced their risk of ED by 43% (OR 0.57; 95% CI, 0.40–0.81; P = 0.004). 

In a study using data from 295 healthy controls from a case-control study of prostate cancer risk factors, researchers investigated the effect of exercise on erectile function and found that highly active men (≥18 MET hours/week), but not men with lesser levels of activity, had statistically and clinically significantly higher erectile function (Simon 2015). One MET is defined as expending 1 kcal/kg/hour, which approximates the energy expended by sitting quietly. In a study that examined the effects of different kinds and levels of physical activity, the age-adjusted risk of developing ED in healthy men aged 40 to 79 years who were free of ED at baseline was 20% to 30% less among those who participated in ≥2.5 hours per week of tennis, racquetball/squash, running, or walking; 1.5 hours of jogging or rowing, calisthenics, or using an exercise machine; or one hour of swimming, compared with men who did not pursue these activities, during 14 years of follow-up (Bacon 2006). The study also found that the relative risk of ED increased with rising BMI (Figure 5)

Figure 5 Relative Risk of Developing ED, by Body Mass Index (BMI)

Source: Bacon 2006
In the Health Professionals Followup Study cohort (N=22,086), the risk of developing ED (“poor” or “very poor” erectile function) during 14 years of follow-up increased with rising BMI in men who were healthy and had “good” or “very good” erectile function at baseline. BMI between 25.0 and 29.9 is regarded as overweight; ≥30.0, obese. For green columns, P < 0.05 vs the reference group (gray).

In addition, the study showed that, regardless of the level of physical activity, being overweight or obese increased a man’s risk of ED. In the subgroup of relatively young men (age 40 to 54 years), the relative risk of ED in obese men (BMI ≥30.0) who engaged in little physical activity (<2.7 METs/week) was 3.9 compared with men whose BMI was <25.0 and who were in the upper quintile of physical activity (>32.6 METs/week). The concluding paragraph of this article follows: 

Overall, during 14 years of follow-up erectile function [sic] was more likely to develop in older men with no major diseases and good erectile function at the start of the study if they were overweight, obese, smoked and were less physically active at baseline. Although these factors are known predicators of cardiovascular disease and cancer, for many men reducing the long-term risk of erectile dysfunction may be a motivating reason to maintain a healthy lifestyle. 

Support for this article was provided by the National Institutes of Health and Pfizer; a Pfizer employee was a coauthor of the article, which did not mention Viagra, sildenafil, and PDE-5 inhibitors. The concluding remarks quoted above were not referenced during the two decades that Pfizer’s Viagra commercials were shown to football fans. Neither was the message of a review mentioned above (Miner 2014) — that all men with vasculogenic ED require a cardiovascular workup. Pfizer provided financial support for this article, too, in the form of funding for the editorial services of two writers employed by a medical communications company. 

CONCLUSION

Some physicians regard an office visit by a man presenting with ED as an opportunity not just to treat the patient’s immediate concern but also to screen the patient for CVD risk factors and to initiate treatment if one or more of these risk factors is present (Brock 2014, Gandaglia 2014, Jackson 2006, Shah 2016, Shoshany 2017, Skeldon 2015, Thompson 2005). For many men, the therapy will be lifestyle modification—improved diet and increased physical activity, along with smoking cessation, if relevant (Jackson 2006). In that case, the salient question isn’t just, “Is my heart healthy enough for sex?” (It probably is [Jackson 2006, Kostis 2005, Rosen 2006].) Rather, other important questions are, “Why do I have ED? What can I do to address it, beyond taking Viagra? Is my heart healthy enough for moderate or vigorous exercise?” But two decades of Viagra commercials have followed a familiar formula in direct-to-consumer advertising: telling audiences that if you have a given problem, their product is the solution. Viagra’s U.S. website presents a different message that provides some practical advice that, if followed, could preclude the need for Viagra, but the television commercials didn’t direct viewers to the website to find this advice, although Viagra.com sometimes appeared on the screen without further explanation. 

A simple explanation probably lies behind the stark difference between Viagra’s television commercials and its U.S. website: market research. In the early days of Viagra, a commercial featured a middle-aged man, Bob, smiling as he entered a party scene. Noticing something different about him, in a positive way, the hostess asks Bob if he had gotten a haircut. He says he had not. Another acquaintance asks if he has lost weight. No, he hasn’t. A third person, an attractive middle-aged woman, asks, “Did you just talk to the doctor?” They place their foreheads together, intimately—she apparently is his wife—and the voiceover announcer says, “What’s different? He finally asked his doctor about Viagra. Find out if a free sample is right for you.” 

The message of this commercial is that merely asking a doctor about Viagra and then anticipating using it (after the doctor says, “Yes, Bob, Viagra is right for you!”) suffices to enhance a man’s sense of well-being and his perception of himself to the extent that other people notice a change in him. The objective of this commercial was to lower a formidable barrier to the provision of American men’s health care: getting a man to see a doctor in the first place. Once that barrier has been breached, the next step is to show the man how Viagra fits with his concept of what it means to be a man. A Swedish study (Åsberg 2009) provides some insight into Viagra’s approach. Unlike the United States and New Zealand, Sweden does not allow direct-to-consumer advertising, but when Viagra was launched there, Pfizer promoted it through a website. Among the features of the website was the results of a Swedish public opinion poll listing the top 10 characteristics of a “manly man” from a Swedish perspective: being practical and handy, being potent, having a well-paying job, having an attractive partner, being physically fit and muscular, having an attractive appearance, interested in sports, always ready for sex, having technological gadgets, and having a “cool” car. Visitors to the website were asked to select the four characteristics they found most manly; potency and handiness were voted first and second, respectively. Anyone who can recall Viagra’s U.S. television commercials will see that most of these 10 characteristics of manliness figured prominently. Any suggestion that ED could be associated with some other health condition would not fit with the picture of manliness presented to the U.S. television-viewing public and would sound a discordant note with the message that confident, manly American men take Viagra and enjoy its benefits, as do their partners. 

Pfizer once told television viewers, it is the Age of Taking Action. In those Viagra commercials, “taking action” meant merely mustering the courage to ask a doctor about Viagra. It might have been more helpful if “taking action” had been employed more broadly to embrace non-pharmaceutical approaches such as turning off the television and going for a brisk walk. 

Author bio: 

Jack McCain is a freelance medical writer and editor who lives in Durham, Conn. He has been a writer and editor for P&T and its sibling publication, Managed Care, for many years.

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