madman
Super Moderator
PDE5 inhibitors can lower mortality and morbidity in men with type 2 diabetes and erectile dysfunction, but they are underused in this group.
ED: An autonomous risk factor
- PDE5 inhibitors (PDE5Is) can reduce mortality and morbidity in men with type 2 diabetes (T2DM) and erectile dysfunction.
- Erectile dysfunction is an independent risk factor for cardiovascular events and mortality and is now included in risk calculators.
- PDE5Is are the first-line treatment for erectile dysfunction and are associated with a significant reduction in all-cause mortality and morbidity.
- Recent studies show that PDE5Is provide cardiovascular benefits and reduce major adverse cardiovascular events (MACE) and overall mortality.
- Higher exposures to PDE5Is are associated with greater reductions in myocardial infarction and stroke.
- Tadalafil, a PDE5I, has been linked to a decreased risk of MACE or venous thromboembolism in men with lower urinary tract symptoms (LUTS) and benign prostatic hypertrophy (BPH).
- Prescribing of PDE5Is is often avoided in higher-risk patients, despite their benefits, and dosing is still often restricted.
LUTS and BPH guidance
- Men with type 2 diabetes (T2DM) have a higher prevalence (32%) of lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH) due to shared mechanisms of chronic inflammation, insulin resistance, endothelial dysfunction, pelvic atherosclerosis, and sympathetic overactivity.
- First-line NICE advice for men with minimal prostate enlargement is an alpha blocker, which may adversely affect ejaculation, especially since autonomic neuropathy already affects ejaculation in men with T2DM.
- Co-prescribing an on-demand PDE5 inhibitor (PDE5I) with an alpha blocker is more likely to cause symptomatic hypotensive episodes in men with T2DM due to comorbid autonomic neuropathy, co-administered antihypertensives, and hypoglycemia.
- Alpha blockers may potentially precipitate heart failure, as indicated by recent evidence.
- European Association of Urology (EAU) and other guidelines recommend daily tadalafil as first-line treatment for men with erectile dysfunction (ED) and LUTS, but this strategy is not advised by NICE, and diabetes specialists are unlikely to follow urology or sexual medicine guidelines.
- Various guidelines, such as those from the American Urological Association (AUA), American Diabetes Association (ADA), and others, recommend testosterone measurement in men with T2DM, with or without ED. However, testosterone is not considered in NICE guidance on T2DM, and there is no NICE guidance on erectile dysfunction, even after 22 years of PDE5Is.
Daily tadalafil is advocated
- Cardiovascular risk strategies focus on reducing modifiable risk factors.
- Erectile dysfunction (ED) should be addressed as an independent risk factor using similar approaches.
- Endothelial dysfunction is the underlying pathological process in ED.
- Use of PDE5 inhibitors (PDE5Is) has shown to improve endothelial function.
- Treatment with tadalafil showed significant improvements in IIEF, IPSS, pulse wave velocity, and ankle-brachial index.
- Daily dosing with sildenafil improved insulin sensitivity in men with prediabetes.
- Vardenafil treatment resulted in improvements in IIEF, flow-mediated dilatation, IL-6, and testosterone levels in men with hypogonadism.
- Daily tadalafil improved flow-mediated dilatation, insulin sensitivity, and lean muscle mass.
- Chronic use of PDE5Is in type 2 diabetes mellitus (T2DM) showed improved flow-mediated dilatation and reduced IL-6 levels.
- Erectile dysfunction severity was correlated with baseline hs-CRP levels.
- Tadalafil use may have long-term benefits in reducing cardiovascular risk.
Tadalafil's impact on testosterone levels when taken daily
- Men with T2DM often have low testosterone levels (up to 40%) and increased cardiovascular risk.
- Testosterone therapy can help improve sexual symptoms, quality of life, and cardiovascular risk in these men.
- Tadalafil 20mg daily for three months increased total testosterone levels without affecting semen parameters in men.
- Tadalafil 5mg for three months increased testosterone levels and IIEF-5 scores in men with metabolic syndrome and erectile dysfunction.
- Sildenafil 50–100mg for 3–7 weeks increased testosterone levels and decreased LH in men, potentially due to improved testicular blood flow.
- These findings suggest that tadalafil and sildenafil could have a beneficial effect on androgen levels, serving as alternatives or adjuncts to testosterone therapy.
PDE5 inhibitors and their impact on cardiovascular health outcomes
- PDE5Is (phosphodiesterase-5 inhibitors) were originally developed for cardiovascular disease but also improve erectile dysfunction.
- Sildenafil and tadalafil, licensed for pulmonary hypertension, show positive effects on endothelial dysfunction.
- PDE5Is have potential benefits in high-risk populations like men with T2DM, including improved endothelial function and reduced cardiovascular events.
- Tadalafil 5mg is the only PDE5I licensed for daily use.
- Men with T2DM taking PDE5Is showed a 31% reduction in all-cause mortality and a 26% reduction in myocardial infarction.
- Testosterone therapy in T2DM with PDE5Is also resulted in a significant reduction in all-cause mortality.
- Men prescribed PDE5Is after myocardial infarction had reduced all-cause and cardiovascular mortality, as well as a lower incidence of heart failure.
- Treating erectile dysfunction alongside comorbid conditions improves adherence, reduces healthcare costs, and manages comorbid medical conditions.
Diabetic neuropathy prevention
- Diabetic peripheral neuropathy affects around 30% of men with T2DM.
- Tight glycaemic control is the primary method of prevention for this condition.
- PDE5 inhibitors (PDE5Is) have shown improvements in neuropathic pain and paraesthesia.
- Nitric oxide, a neurotransmitter of the vasa nervorum, may play a preventive role in microvascular complications.
- Current drugs used to treat established diabetic peripheral neuropathy block pain pathways but may worsen erectile dysfunction.
- Preventing complications of diabetic peripheral neuropathy has the potential for significant cost savings.
Severe COVID-19 infection can lead to vasculitis
- Daily PDE5Is (phosphodiesterase-5 inhibitors) have been suggested to play a significant role in acute COVID infection.
- They have beneficial effects on pulmonary hypertension, acute inflammation, and endothelial dysfunction.
- A recent study showed that seven days of sildenafil (a PDE5I) in acutely ill COVID-19 patients led to a five-fold decrease in mortality and a 50% reduction in ITU (intensive care unit) admissions.
- These findings indicate the importance of PDE5Is in the treatment of acute COVID infection and highlight the need for additional research.
Prescribing policies for T2DM are decided by diabetes specialists, prioritizing glycaemic control. Urologists manage comorbid conditions like erectile dysfunction and BPH. Erectile dysfunction, a risk factor for coronary heart disease, should be considered in risk reduction strategies. Testosterone measurement is suggested but not routinely done in diabetes practice, despite its prevalence. Routine diabetes care should mandate accurate assessment of erectile dysfunction and hypogonadism. Evidence supports routine prescribing of PDE5Is in diabetes care as they offer multiple benefits, including increased testosterone levels. NICE guidelines on daily dosing with tadalafil need revision due to availability of cheaper generic alternatives.
