Combination therapy has proven effective for some men who don’t respond adequately to oral medicines. The idea is to use two drugs with different mechanisms of action for better results. Commonly, sildenafil is used in combination with pellets of alprostadil (synthetic prostaglandin E1) that are inserted into the urethra (the tube in the penis that carries urine from the bladder to the outside of the body). Alprostadil also increases the blood supply to the penis, but by different means.
A substantial body of literature documents the prevalence of ED in men with diabetes. Unfortunately, the majority of these studies do not distinguish between type 1 and type 2 disease, and, therefore, it is difficult to determine if prevalence rates between the two forms of diabetes differ significantly. Acknowledging this limitation in the literature, prevalence estimates of ED in cross-sectional studies of diabetic populations range from 20 to 71% (Table 1). Most of these studies did not control for severity of disease, duration of disease, or control of hyperglycemia.
Few simple laboratory tests can help identify obvious causes of organic ED. Initial labs should include HbA1c, free testosterone, thyroid function tests, and prolactin levels. However, patients who do not respond to pharmacological therapy or who may be candidates for surgical treatment may require more in-depth testing, including nocturnal penile tumescence testing, duplex Doppler imaging, somatosensory evoked potentials, or pudendal artery angiography.
Because ED has several causes, sorting out exactly what is causing your problem may take some time. First, make sure your doctor knows about all the medicines you are using, including over-the-counter or herbal products. Drugs frequently used to treat high blood pressure, anxiety, depression, and peptic ulcers can all cause ED. But don’t stop taking any of your medications without first talking to your doctor.
Olsson et al. conducted a randomised, double-blind, placebo-controlled, parallel group, and flexible dose study in 224 men with ED and one CVD, including IHD (20 %) and hypertension (80 %). This study reported that the sildenafil-treated group showed 71 % improvement in ED compared with the placebo-controlled group (24 %).64 Furthermore, no treatment-related cardiovascular adverse events were reported.65 Conti et al. showed in an early study that sildenafil is an effective treatment for ED in patients with IHD; the majority of patients reported improvement in penile erection with it.66 Another double-blind, placebo-controlled study of patients with ED and stable CAD showed statistically significant improvement with sildenafil versus placebo in both the frequency of penetration and frequency of maintained erections after penetration.67
In a prospective human phase 1 open-label and single-arm study reported by Haahr et al. (27), 17 men with refractory post radical prostatectomy ED were given a single intracavernosal injection of autologous adipose-derived regenerative cells (ADRCs) freshly isolated after a liposuction. The procedures were well-tolerated and over a 6-month follow-up period, 8 of 17 men showed improvement of their erectile function.

Your doctor may also choose to lower your dose of certain medications. Or your provider may switch the type of drug you’re taking if it’s interfering with your sex life. Some medicines used for managing blood pressure, insomnia, anxiety, depression, seizures and prostate problems increase the risk for erectile dysfunction. Beta-blockers (for high blood pressure), SSRIs (often used to treat depression) and the class of drugs called benzodiazepines (like Ativan, Xanax, Librium and Valium) are commonly tied to ED. You may want to speak to your doctor about this.

Following the breakthrough in ED treatment using PDE5-inhibitors, Western medicine has now moved on to a new frontier of regenerative medicine, with stem cell and gene therapy leading the way (25). There is a practical need for novel therapy as a significant portion of diabetic or post-prostatectomy ED patients do not respond to oral pharmacotherapy. To date, stem cells derived from different sites including adipose tissue-derived stem cells, bone marrow mesenchymal stem cells and muscle-derived stem cells have been investigated using animal models for ED, to study their effects on neural, vascular, endothelial or smooth muscle regeneration (25,26).
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Heart disease and erectile dysfunction can be related. In fact, ED and heart disease are considered two signs of the same disease process. The smaller arteries in the penis are affected by atherosclerosis sooner, perhaps three or more years before they cause heart disease symptoms.11 A large international study found that men with ED were more likely to die from heart causes; have a heart attack, stroke or be admitted to the hospital with heart failure than men with no or mild ED.12
Nebivolol seems to have an advantage over other beta-blockers when used to treat men with hypertension and ED. It has additional vasodilating effects because it stimulates endothelial release of nitric oxide (NO), resulting in relaxation of smooth muscle in the corpus cavernosum, allowing penile erection.25 Despite limited studies, nebivolol does not seem to worsen erectile function and some studies have demonstrated significant improvement in erectile function with nebivolol compared with second-generation cardioselective beta-blockers.23,26–28
Crossref | PubMed | Scopus (23) | Google ScholarSee all References Similar to sildenafil, vardenafil produces a slight hypotensive effect with an average maximal decrease in blood pressure level of 5 to 10 mm Hg.74x74Gresser, U and Gleiter, CH. Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil—review of the literature. Eur J Med Res. 2002; 7: 435–446
Several drugs can produce erectile difficulties, but blood pressure drugs are near the top. ED is an occasional side effect of BP drugs like thiazide diuretics, loop diuretics, and beta-blockers, all of which can decrease blood flow to the penis and make it difficult to get an erection. However, other BP drugs, such as alpha-blockers, ACE inhibitors, and angioten-sin-receptor blockers, rarely cause ED.
Erectile dysfunction (ED) is highly prevalent affecting at least 50 % of men with diabetes mellitus (DM). DM may cause ED through a number of pathophysiological pathways. These include neuropathy, endothelial dysfunction, cavernosal smooth muscle structural/functional changes, and hormonal changes. Lifestyle changes, diabetes control, and treatment of hypogonadism are important as the first step in ED management since there is no curative treatment for ED. Phosphodiesterase type 5 inhibitors (PDE5i) are the first-line treatment option. Intracavernous administration of vasoactive drugs is commonly used as a second-line medical treatment when PDE5i have failed. Alprostadil is the most widely used drug in this second-line setting. The combination of papaverine, phentolamine, and alprostadil represents the most efficacious intracavernous pharmacologic treatment option that may save non-responders to alprostadil. Penile prosthesis implantation can be considered in treatment refractory cases, with excellent functional and safety results in the properly informed patients.
Based on this testing, EDDM patients were treated with behavioral therapy, intracavernosal (papaverine, PGE-1, or Trimix) or intraurethral PGE-1, a vacuum constriction device (VCD), or implantation of a penile prosthesis. Novel surgical procedures, ligation of incompetent cavernosal veins or penile revascularization, were seldom efficacious with EDDM and were soon abandoned. Although these nonsurgical therapies were efficacious, they were not widely requested because of their invasive or mechanical nature.
PubMed | Google ScholarSee all References As with sildenafil, use of nitrate or NO-donor medications is contraindicated while taking tadalafil because of the potential for marked hypotensive interactions.74x74Gresser, U and Gleiter, CH. Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil—review of the literature. Eur J Med Res. 2002; 7: 435–446
If your doctor says it's OK, you may be able to stop taking blood pressure medications temporarily to see if your sex life improves. To make sure your blood pressure remains within a safe range, you may need frequent blood pressure readings while you're not taking the blood pressure lowering medication that may be causing your sexual difficulties. This can be done with a home blood pressure monitoring device for convenience.
Evaluation of functional capacity is the mainstay for the management of patients with ED.30 However, it should be kept in mind that in men with heart failure sexual activity may affect the heart differently from physical activity of similar METS due to differences in psychological anticipation and sympathetic activation.30,49 Cardiac echocardiography may offer valuable information for left ventricular performance and valvular function. For risk categories of heart failure patients and their management, please refer to Table 3 and Figure 5.
Abstract | Full Text | Full Text PDF | PubMed | Scopus (328) | Google ScholarSee all References Their mean resting systolic and diastolic blood pressure levels decreased by 6% and 11%, respectively, compared with baseline. These patients also experienced a mild decrease in mean resting right atrial pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, and cardiac output. However, the hemodynamic response to exercise was preserved. Phase 2 and 3 trials showed no difference in the rate of adverse events between sildenafil and placebo in patients being treated with antihypertensive medications. The effects of sildenafil on blood pressure level were similar in patients who were taking antihypertensive medications compared with those who were not. In healthy volunteers, no consistent or significant doserelated electrocardiographic (ECG) changes were noted at 1 and 2 hours after doses of sildenafil ranging from 1.25 to 200 mg.3x3Zusman, RM, Morales, A, Glasser, DB, and Osterloh, IH. Overall cardiovascular profile of sildenafil citrate. Am J Cardiol. 1999; 83: 35C–44C
Penile erection is largely a vascular process, and the penile endothelium and smooth muscle tissue are very sensitive to functional and structural changes. Vasculogenic ED results from an impairment of endothelial dependent or independent smooth muscle relaxation (functional vascular ED, initial stages), occlusion of the cavernosal arteries by atherosclerosis (structural vascular ED, late stages), or a combination of these.3 Current data support a complex interplay between endothelial dysfunction, subclinical inflammation, and androgen deficiency (Figure 1). The relationship between ED and CAD at the clinical level is supported by this common pathophysiological basis. The ‘artery size’ hypothesis explains why patients with CAD frequently report ED before CAD detection.10 According to this hypothesis, for a given atherosclerotic burden, the smaller penile arteries suffer obstruction earlier than the larger coronary arteries (Figure 2). The same concept holds also true in the case of non-obstructing atherosclerosis: since the smaller penile artery have a greater endothelial surface and erection requires a large degree of vasodilation to occur when compared with arteries in other organs, the same degree of endothelial dysfunction will be symptomatic in these smaller vessels but subclinical in the larger ones (i.e. coronaries). In the same context, accelerated arterial ageing (as indicated by increased arterial stiffening that also affects large arteries of ED patients) may be a common background.11,12 Erectile dysfunction is associated with an incremental inflammatory and endothelial-pro-thrombotic activation.13 Interestingly, this activation is equal to that found in CAD patients with no ED, while when these two conditions are combined the burden is additive. Androgen deficiency may be also implicated in the common pathogenetic pathways of ED and CVD; however, this warrants further substantiation.2
Abstract | Full Text | Full Text PDF | PubMed | Scopus (95) | Google ScholarSee all References During this period, 130 deaths were reported to the US FDA; 41 of these men died or had cardiac arrest within 4 to 5 hours after taking sildenafil, and 27 died or had cardiac arrest either during or immediately after sexual activity. The average age of these men was 64 years. Of the 77 men in this group who died of documented cardiovascular-related events, 41 died of definite or suspected myocardial infarction, 27 died after cardiac arrest, and 6 had symptoms of cardiac disease at the time of death. Sixteen of the men had taken nitroglycerin or organic nitrates in association with sildenafil; another 3 had nitroglycerin in their possession at the time of death. In 48 men, the cause of death was unknown, and another 3 died of cerebrovascular accidents. Overall, it was concluded that sildenafil was not associated with an excess of cardiovascular death.

Abstract | Full Text PDF | PubMed | Scopus (1528) | Google ScholarSee all References After sexual intercourse, this risk increases approximately 2-fold, to 2 chances per million per hour, but only for the 2 hours after intercourse. For low-risk patients with no history of cardiovascular disease and an annual myocardial infarction risk of 1% per year, the risk increases to 1.01% with weekly sexual activity.8x8Muller, JE, Mittleman, A, Maclure, M, Sherwood, JB, Tofler, GH, and Determinants of Myocardial Infarction Onset Study Investigators. Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion. JAMA. 1996; 275: 1405–1409

Abstract | Full Text | Full Text PDF | PubMed | Scopus (95) | Google ScholarSee all References The use of any NO-donor medications should be avoided for 24 hours after the last dose of sildenafil and even longer if there is a suspected prolonged half-life secondary to such conditions as renal insufficiency.10x10Kloner, RA and Zusman, RM. Cardiovascular effects of sildenafil citrate and recommendations for its use. Am J Cardiol. 1999; 84: 11N–17N
Men can judge themselves pretty harshly when it comes to their performance in between the sheets. The unsettling fear of not being able to rise to the occasion becomes a reccurring nightmare for men that is often equated with failure, loss of dignity, and masculinity. If you suffer from erectile dysfunction (ED), don’t be so hard on yourself, since impotence can almost always be improved with treatment, without having to rely on Viagra or other medications. Whether you suffer from ED, or hope to prevent the condition, here are six tips to overcome impotence without the side effects of the little blue pill.
Gutiérrez-González, Enrique; Castelló, Adela; Fernández-Navarro, Pablo; Castaño-Vinyals, Gemma; Llorca, Javier; Salas-Trejo, Dolores; Salcedo-Bellido, Inmaculada; Aragonés, Nuria; Fernández-Tardón, Guillermo; Alguacil, Juan; Gracia-Lavedan, Esther; García-Esquinas, Esther; Gómez-Acebo, Inés; Amiano, Pilar; Romaguera, Dora; Kogevinas, Manolis; Pollán, Marina; Pérez-Gómez, Beatriz. “Dietary Zinc and Risk of Prostate Cancer in Spain: MCC-Spain Study.” Nutrients. Jan 2019, 11(1).

Following the breakthrough in ED treatment using PDE5-inhibitors, Western medicine has now moved on to a new frontier of regenerative medicine, with stem cell and gene therapy leading the way (25). There is a practical need for novel therapy as a significant portion of diabetic or post-prostatectomy ED patients do not respond to oral pharmacotherapy. To date, stem cells derived from different sites including adipose tissue-derived stem cells, bone marrow mesenchymal stem cells and muscle-derived stem cells have been investigated using animal models for ED, to study their effects on neural, vascular, endothelial or smooth muscle regeneration (25,26).

The mechanisms of action by which antihypertensive medications cause ED are currently unknown. Some investigators have theorized that antihypertensive medications affect erectile function by decreasing blood pressure, which reduces the perfusion pressure needed to maintain sufficient blood flow for erections through atherosclerotic penile arteries.37x37Benet, AE and Melman, A. The epidemiology of erectile dysfunction. Urol Clin North Am. 1995; 22: 699–709
Like all diabetic complications, ED can occur even when you have followed your doctor’s advice and carefully managed your diabetes. Also like all diabetes complications, ED is less likely to occur with good blood sugar control. Poorly controlled diabetes and high cholesterol increase the chances of vascular complications, which may lead to ED or other circulatory problems. In addition, regular smoking and alcohol use can contribute to ED.
Some doctors prefer to start a man on the lowest dose of an oral medicine and increase the dose until an effective one is found. Others prefer to start with the highest dose and go to a lower dose only if a man complains of side effects. In either case, it’s important for a man to communicate with his doctor to let him know how the dose he’s using is working.
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