Geoffrey Hackett

Erectile dysfunction and coronary artery disease prediction: Evidence-based guidance and consensus

•  A significant proportion of men with erectile dysfunction (ED) exhibit early signs of coronary artery disease (CAD), and this group may develop more severe CAD than men without ED (Level 1, Grade A). •  The time interval among the onset of ED symptoms and the occurrence of CAD symptoms and cardiovascular events is estimated at 2–3 years and 3–5 years respectively; this interval allows for risk factor reduction (Level 2, Grade B). •  ED is associated with increased all‐cause mortality primarily due to increased cardiovascular mortality (Level 1, Grade A). •  All men with ED should undergo a thorough medical assessment, including testosterone, fasting lipids, fasting glucose and blood pressure measurement. Following assessment, patients should be stratified according to the risk of future cardiovascular events. Those at high risk of cardiovascular disease should be evaluated by stress testing with selective use of computed tomography (CT) or coronary angiography (Level 1, Grade A). •  Improvement in cardiovascular risk factors such as weight loss and increased physical activity has been reported to improve erectile function (Level 1, Grade A). •  In men with ED, hypertension, diabetes and hyperlipidaemia should be treated aggressively, bearing in mind the potential side effects (Level 1, Grade A). •  Management of ED is secondary to stabilising cardiovascular function, and controlling cardiovascular symptoms and exercise tolerance should be established prior to initiation of ED therapy (Level 1, Grade A). •  Clinical evidence supports the use of phosphodiesterase 5 (PDE5) inhibitors as first‐line therapy in men with CAD and comorbid ED and those with diabetes and ED (Level 1, Grade A). •  Total testosterone and selectively free testosterone levels should be measured in all men with ED in accordance with contemporary guidelines and particularly in those who fail to respond to PDE5 inhibitors or have a chronic illness associated with low testosterone (Level 1, Grade A). •  Testosterone replacement therapy may lead to symptomatic improvement (improved wellbeing) and enhance the effectiveness of PDE5 inhibitors (Level 1, Grade A). •  Review of cardiovascular status and response to ED therapy should be performed at regular intervals (Level 1, Grade A).

Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes.

INTRODUCTION Sexual dysfunction, particularly erectile dysfunction (ED), is common in men with type 2 diabetes, occurring in up to 75% of cases. The prevalence of hypogonadism is also high in men with diabetes and low testosterone is associated with both sexual dysfunction and a reduced response to oral therapy for ED. AIM This study aimed to determine the effect of testosterone replacement with long-acting Testosterone Undecanoate (TU) on sexual function, mood and quality of life vs. placebo over a treatment period of 30 weeks followed by 52 weeks of open-label medication. The study was conducted in a primary care population of men with type 2 diabetes attending their primary care physician for routine visits. METHODS The male diabetic populations of seven general practices were screened at routine diabetes visits to detect symptomatic men with total testosterone levels of 12 nmol/L or less or with free testosterones of 250 pmol/L or less. Two hundred eleven men were screened. A double-blind placebo-controlled study was conducted in 199 men with type 2 diabetes and hypogonadism treated for 30 weeks with either 1,000 mg of TU or matching placebo followed by 52-week open-label follow on. MAIN OUTCOME MEASURES The primary outcome measure, International Index of Erectile Function (IIEF), was used to evaluate sexual dysfunction, and the Ageing Male Symptom (AMS), Hospital Anxiety and Depression Scale, and Global Efficacy Question were used as secondary outcome measures to assess mood and self-reported quality of life. RESULTS Testosterone replacement therapy with long-acting TU improved all domains of sexual function at 30 weeks (erectile function [EF], P = 0.005; intercourse satisfaction, P = 0.015; sexual desire, P = 0.001; overall satisfaction, P = 0.05; and orgasm, P = 0.04), with benefit as early as 6 weeks. Improvements in AMS score were significant in men without depression (P = 0.02) and the presence of depression at baseline was associated with marked reduction in response to both sexual function and psychological scores. All responses in sexual function continued to improve significantly up to 18 months with an improvement in EF score of 4.31 from baseline. In a small cohort of 35 men taking phosphodiesterase type 5 inhibitors, there was no change during the double-blind phase but a nine-point improvement in EF domain during 52-week open-label treatment. After 30 weeks, 46% vs. 17% of patients on active therapy vs. placebo felt that the treatment had improved their health, reaching 70% after open-label therapy. Less obese and older patients responded better to testosterone therapy. There were no significant adverse events. CONCLUSION TU significantly improved all domains of the IIEF and patient reported quality of life at 30 weeks and more significantly after 52-week open-label extension. Improvement was most marked in less obese patient and those without coexisting depression. In men with type 2 diabetes, trials of therapy may need to be given for much longer than 3-6 months suggested in current guidelines.

Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol-delivery form of lidocaine-prilocaine for treating premature ejaculation

To evaluate, in a phase II study, the efficacy and safety of a topical eutectic mixture for premature ejaculation (TEMPE), a metered‐dose aerosol spray containing a eutectic mixture of lidocaine and prilocaine, as a treatment for PE.

Testosterone Replacement Therapy Improves Metabolic Parameters in Hypogonadal Men with Type 2 Diabetes but Not in Men with Coexisting Depression: The BLAST Study

INTRODUCTION The association between testosterone deficiency and insulin resistance in men with type 2 diabetes is well established and current endocrine society guidelines recommend the measurement of testosterone levels in all men with type 2 diabetes or erectile dysfunction. AIM We report the first double-blind, placebo-controlled study conducted exclusively in a male type 2 diabetes population to assess metabolic changes with long-acting testosterone undecanoate (TU). METHODS The type 2 diabetes registers of seven general practices identified 211 patients for a 30-week double-blind, placebo-controlled study of long-acting TU 1,000 mg followed by 52 weeks of open-label use. Because of the established impact of age, obesity, and depression on sexual function, these variables were also assessed for influence on metabolic parameters. MAIN OUTCOME MEASURE Changes in glycated hemoglobin (HbA1c) and the level of testosterone at which response are achieved. RESULTS Treatment with TU produced a statistically significant reduction in HbA1c at 6 and 18 weeks and after a further 52 weeks of open-label medication most marked in poorly controlled patients with baseline HbA1c greater than 7.5 where the reduction was 0.41% within 6 weeks, and a further 0.46% after 52 weeks of open-label use. There was significant reduction in waist circumference, weight, and body mass index in men without depression, and improvements were related to achieving adequate serum levels of testosterone. There were no significant safety issues. CONCLUSIONS Testosterone replacement therapy significantly improved HbA1c, total cholesterol, and waist circumference in men with type 2 diabetes. Improvements were less marked in men with depression at baseline, and therapeutic responses were related to achieving adequate serum testosterone levels. Current advice on 3- to 6-month trials of therapy may be insufficient to achieve maximal response. Patients reported significant improvements in general health.

The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study).

The association between testosterone deficiency and insulin resistance in men with type 2 diabetes is well established. Current Endocrine Society and European Association of Urology guidelines recommend the measurement of testosterone levels in all men with type 2 diabetes and in men suffering from erectile dysfunction. It is recognised that a range of physical symptoms appear as the testosterone level falls but few studies have addressed the threshold at which symptoms improve with physiological replacement. We report the first double‐blind placebo‐controlled study conducted exclusively in a male type 2 diabetes population to assess the metabolic changes with testosterone replacement.

ORIGINAL RESEARCH—ED PHARMACOTHERAPY: Psychosocial Outcomes and Drug Attributes Affecting Treatment Choice in Men Receiving Sildenafil Citrate and Tadalafil for the Treatment of Erectile Dysfunction: Results of a Multicenter, Randomized, Open‐Label, Crossover Study

INTRODUCTION Although sildenafil citrate (sildenafil) and tadalafil are efficacious and well-tolerated treatments for erectile dysfunction (ED), preference studies have shown that patients may favor one medication over the other. AIM To determine whether psychosocial outcomes differed when men with ED received tadalafil compared with sildenafil. MAIN OUTCOME MEASURES Measures included a treatment preference question, Psychological and Interpersonal Relationship Scales (PAIRS), and Drug Attribute Questionnaire. METHODS Randomized, open-label, crossover study. After a 4-week baseline, men with ED (N = 367; mean age = 54 years; naïve to type 5 phosphodiesterase inhibitor therapy) were randomized: tadalafil for 12 weeks then sildenafil for 12 weeks or vice versa (8-week dose optimization/4-week assessment phases). During dose optimization, patients started with 10 mg tadalafil, or 25 or 50 mg sildenafil and could titrate to their optimal dose (10 or 20 mg tadalafil; 25, 50, or 100 mg sildenafil). Medications were taken as needed. Patients completing both 12-week periods chose which medication to continue during an 8-week extension. RESULTS Of 291 men completing both treatment periods, 71% (N = 206) chose tadalafil and 29% (N = 85) chose sildenafil (P < 0.001) for the 8-week extension. When taking tadalafil compared with sildenafil men had higher mean endpoint scores on PAIRS Sexual Self-Confidence (tadalafil = 2.91 vs. sildenafil = 2.75; P < 0.001) and Spontaneity (tadalafil = 3.32 vs. sildenafil = 3.17; P < 0.001) Domains and a lower mean endpoint score on Time Concerns Domain (tadalafil = 2.2 vs. sildenafil = 2.59; P < 0.001). The two most frequently chosen drug attributes to explain treatment preference were ability to get an erection long after taking the medication and firmness of erections. Tadalafil and sildenafil were well tolerated with 12 (3.3%) patients discontinuing for an adverse event. CONCLUSIONS As measured with PAIRS, men with ED had higher sexual self-confidence and spontaneity and less time concerns related to sexual encounters when treated with tadalafil compared with sildenafil. These psychosocial outcomes may help explain why more men (71%) preferred tadalafil for the treatment of ED in this clinical trial.

Erectile dysfunction and lower urinary tract symptoms: a consensus on the importance of co-diagnosis

Despite differences in design, many large epidemiological studies using well‐powered multivariate analyses consistently provide overwhelming evidence of a link between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS). Preclinical evidence suggests that several common pathophysiological mechanisms are involved in the development of both ED and LUTS. We recommend that patients seeking consultation for one condition should always be screened for the other condition. We propose that co‐diagnosis would ensure that patient management accounts for all possible co‐morbid and associated conditions. Medical, socio‐demographic and lifestyle risk factors can help to inform diagnoses and should be taken into consideration during the initial consultation. Awareness of risk factors may alert physicians to patients at risk of ED or LUTS and so allow them to manage patients accordingly; early diagnosis of ED in patients with LUTS, for example, could help reduce the risk of subsequent cardiovascular disease. Prescribing physicians should be aware of the sexual adverse effects of many treatments currently recommended for LUTS; sexual function should be evaluated prior to commencement of treatment, and monitored throughout treatment to ensure that the choice of drug is appropriate.

Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions.

To address widespread concerns regarding the medical condition of testosterone (T) deficiency (TD) (male hypogonadism) and its treatment with T therapy, an international expert consensus conference was convened in Prague, Czech Republic, on October 1, 2015. Experts included a broad range of medical specialties including urology, endocrinology, diabetology, internal medicine, and basic science research. A representative from the European Medicines Agency participated in a nonvoting capacity. Nine resolutions were debated, with unanimous approval: (1) TD is a well-established, clinically significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life; (2) symptoms and signs of TD occur as a result of low levels of T and may benefit from treatment regardless of whether there is an identified underlying etiology; (3) TD is a global public health concern; (4) T therapy for men with TD is effective, rational, and evidence based; (5) there is no T concentration threshold that reliably distinguishes those who will respond to treatment from those who will not; (6) there is no scientific basis for any age-specific recommendations against the use of T therapy in men; (7) the evidence does not support increased risks of cardiovascular events with T therapy; (8) the evidence does not support increased risk of prostate cancer with T therapy; and (9) the evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes. These resolutions may be considered points of agreement by a broad range of experts based on the best available scientific evidence.

The burden and extent of comorbid conditions in patients with erectile dysfunction

Background:  Erectile dysfunction (ED) is a common sexual problem in men. Under‐reporting of ED is widespread, largely because of the embarrassing nature of the condition.

What Do Patients Expect from Erectile Dysfunction Therapy

Abstract Erectile insufficiency can precipitate emotional distress and a negative spiral of events and feelings. Excessive focus by the patient on the penis as the dysfunctional unit may be associated with physical and psychological problems in the female partner. With the advent of effective, well-tolerated treatments for erectile dysfunction, including the phosphodiesterase type 5 (PDE5) inhibitor sildenafil citrate, the needs and expectations of patients and their partners concerning their medications, their physicians and other factors have come into focus. In addition to the effectiveness or tolerability of a medication, a number of nonmedical outcomes may influence patients and their partners when choosing between therapeutic modalities or pharmacotherapies. These include the spontaneity and naturalness of the sexual encounter, as well as the treatments acceptability to the sexual partner, onset/duration of action and potential interactions with food or alcohol. Patients of different ages, marital statuses or cultures may assign distinct values to each of these criteria. Couples should therefore be involved in formulating treatment plans and afforded wide latitude when initially selecting therapy and/or deciding how, or whether, to take medications. For the physician, erectile dysfunction represents an opportunity to diagnose and treat other comorbid diseases, including hypertension, ischemic heart disease and diabetes.