Abstract
According to numerous clinical studies, many serious health problems in men have similar pathological processes at their core. Diseases such as type 2 diabetes (T2DM), insulin resistance, erectile dysfunction (ED), benign prostatic hyperplasia (BPH) and depression are in most cases accompanied by conditions such as endothelial dysfunction and inflammation [1]. Endothelial dysfunction is an imbalance between the production of vasodilating, angioprotective, antiproliferative factors, on the one hand, and vasoconstrictive, prothrombotic, proliferative factors, on the other hand.
This work is devoted to a discussion of the beneficial effect of phosphodiesterase type 5 (PDE-5) inhibitors on endothelial function and mediators of chronic inflammation [2]. The possibility and feasibility of treatment and prevention of these common conditions of the body is being considered. Particular attention is paid to possible obstacles to this approach. The main obstacle is the lack of licenses for multiple drugs to treat each of these conditions. The need to involve the patient in making individual decisions regarding his health is discussed.
The article discusses the importance of an integrated approach to medical examinations and consultations. Often, patients with multiple comorbidities are assigned to narrow specialists who are primarily interested in one specific problem within their area of interest and lack sufficient motivation to treat or prevent conditions beyond their competence.
This paper explores how these health care issues might be related to physician time and funding constraints, and a lack of awareness of evidence published in journals in other areas of medicine. Many professionals are proud of the fact that they provide personalized, patient-centered care and treatment, but this can only be truly achieved if the needs of each individual patient are assessed in different settings. Patients with type 2 diabetes usually receive statins, angiotensin-converting enzyme inhibitors and metformin as part of therapy, often with poor tolerance. This article explores whether licensed PDE-5 inhibitor tadalafil should be added on a daily basis to this list [3]. According to a number of researchers, tadalafil has the potential to improve and prevent unpleasant symptoms and improve compliance with other medications.
Keywords: Cardiovascular diseases, Diabetes mellitus, type 2, Erectile dysfunction, ED, Lower urinary tract symptoms, Phosphodiesterase type 5 inhibitors, Prostatic hyperplasia, PDE-5 inhibitors, Tadalafil
Introduction
Type 2 diabetes mellitus is a disease that represents one of the most serious health problems for the citizens and economies of the Western world, including the most developed. As of 2019, in the UK, 25% of the population over 65 was diagnosed with T2DM, with 55% of them being men. The prevalence of T2DM is especially high in men from Southeast Asia and in men of Afro-Caribbean origin. In the United States, two-thirds of men over 65 have been diagnosed with diabetes. An increase in the incidence of T2DM in the population by only 1% increases the risk of death associated with diabetes by 21%, increases the risk of death from myocardial infarction (MI) by 14% and increases the risk of peripheral vascular disease by 45%. Currently, according to the standard of treatment for T2DM, all men with this diagnosis over the age of 40 years are recommended to prescribe metformin, a statin and an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) as preventive strategies. In this study, in the era of personalized diabetes care, we analyze the history of a well-informed patient with a newly diagnosed T2DM to assess the available evidence of the ongoing use of phosphodiesterase 5 (PDE-5) inhibitors [4].
Experience of a Patient
The described case is fictitious and is based on the experience of the authors and the information they collected from various sources. All names are fictitious and any coincidences with real faces are accidental.
Robert, an experienced lawyer, was diagnosed with T2DM at the age of 50 during a routine medical examination. He demonstrated a hemoglobin A1C of 6.6 mmol/mol. Among the deviations in the main indicators, he was slightly overweight (body mass index 28.6 kg/m2), blood pressure 125/80 mm hg. art., total cholesterol 5 mg/dl and high density lipoproteins 1.7 mg/dl. For the rest, he did not complain of any health problems, kept himself in good physical shape and was happily married for 20 years. His father was diagnosed with T2DM at the age of 52, he suffered from leg ulcers and died of a heart attack at the age of 65. Robert’s sex life is currently satisfactory, but not as good as it used to be. He has certain symptoms of the lower urinary tract, namely he complains of frequent urination, especially at night, and a weak urine flow. According to Robert, his father also suffered from prostate adenoma, kidney failure, and had two transurethral resections of the prostate.
As part of standard therapy for T2DM, Robert was prescribed 5 mg ramipril, 20 mg atorvastatin, and 500 mg metformin twice a day. He was not informed about the effect of the disease and medications against it on erection, so he asked the nurse what the T2DM diagnosis would mean for his sex life. Both she and the therapist were surprised by this question and offered him a flyer for newly diagnosed patients in which erectile dysfunction (ED) was not mentioned at all.
Erectile Dysfunction (ED)
Robert found this suspicious, and he carried out his own little research on the connection between T2DM and erectile dysfunction (ED). He easily found that diabetes leads to a 70% chance of developing ED over the next ten years, and an adequate response to oral therapy is achieved in only 52% of cases, even if treatment is started immediately after diagnosis. Robert asked the therapist why he needed to take three drugs aimed at preventing complications that usually occur at a much lower frequency, and none for preventing ED. He found that ED in diabetes occurs due to a combination of several mechanisms, primarily endothelial dysfunction. Endothelial dysfunction is a chronic condition that affects all blood vessels in the body. Erectile dysfunction is one of the earliest manifestations of endothelial dysfunction in diabetes mellitus, since small arteries are responsible for the appearance of an erection, which are primarily affected by endothelial dysfunction. Erectile dysfunction combined with diabetes increases the risk of heart disease by 50% within 2-5 years. Robert believes that a drug like ARB is better than an ACE inhibitor to support his erection, and wonders why this drug has not even been discussed. As a middle-aged man recently diagnosed with T2DM, he has a 30% risk of developing diabetic peripheral neuropathy (DPN) and a 33% risk of developing lower urinary tract symptoms and benign prostatic hyperplasia (LUTS and BPH, also known as prostate adenoma) [5].
Robert concluded that soon the state of his potency would seriously deteriorate, and again turned to the therapist with a request for treatment. He was advised to take 25 mg of Sildenafil if necessary and was given 4 pills to test the result. Robert’s request to measure his testosterone levels, which can be low in type 2 diabetes, was rejected on the grounds that he had a normal beard. The therapist suggested that Robert had no reason to worry on this issue.
Because of the inconvenience of planning sexual intercourse in advance to achieve the effectiveness of Sildenafil, Robert and his wife began to limit their sexual activity to one time a week, although they used to have a more regular sex life. According to Robert, Sildenafil does not have a more or less pronounced effect on him. He is dissatisfied with the result of the treatment. The lower urinary tract symptoms (LUTS) that he experiences continue to worsen: the stream of urine weakens, and the number of night urinations increases up to 3-4 times. After Robert complained to his therapist about this condition, he was prescribed 50 mg of Sildenafil and was again given 4 pills to try. Robert went to another clinic, where he underwent a digital rectal examination of his prostate and a prostate-specific antigen (PSA) level test. It was found that his prostate was slightly enlarged. Robert began taking tamsulosin at a dose of 400 mcg per day, but after two weeks, he stopped taking both tamsulosin and sildenafil, because they did not have the desired effect on his body. Robert’s erection weakened greatly, and ejaculation became almost impossible. He was in a very depressed mood.
National Institute for Health and Care Excellence, American Diabetes Association, and European Urological Association Guidance
The treatment given to Robert is broadly in line with current UK BPH practice. Although NICE recommends an annual diagnosis of erectile dysfunction for all men with T2DM, less than a quarter of all men recently diagnosed with T2DM undergo testing. Studies have shown that the percentage of men with T2DM tested for ED increased only if general practitioners received a separate fee for conducting such studies, as was the case in 2013. Thus, it can be concluded that financial payments are the main driving force contributing to changes in current medical practice.
The optimal recommendation for men with T2DM in combination with ED is to prescribe one of the lowest-cost PDE-5 inhibitors, in most cases sildenafil 25 mg with a maximum frequency of 4 times a month, that is, once a week. According to the results of randomized controlled trials, this treatment strategy is effective at best in half of patients taking PDE-5 inhibitors, even without restrictions in dosage and frequency of administration. The reason for this low efficiency is that erectile dysfunction in T2DM develops mainly due to and against the background of endothelial dysfunction, which affects the entire cardiovascular system. Naturally, one tablet of sildenafil, which is eliminated from the body in 6-8 hours, cannot have a significant effect on the pathological process underlying the development of ED. In this regard, Robert’s treatment tactics are unlikely to be effective.
Factors such as chronic inflammation, insulin resistance, endothelial dysfunction, pelvic atherosclerosis, and overactive sympathetic nervous system cause an increased prevalence of LUTS and BPH in men with T2DM. However, NICE recommends that men with mild prostate enlargement take an alpha blocker, which has negative effects on ejaculation, which adds to the neuropathy that often affects men with T2DM. In addition, the combination of an alpha-blocker with one of the PDE-5 inhibitors tends to cause episodes of symptomatic hypotension against the background of comorbid autonomic neuropathy, simultaneous use of antihypertensive drugs, and hypoglycemia [6].
The European Urological Association and the British Society for Sexual Medicine recommend daily tadalafil as a first-line treatment for men with ED and LUTS. However, NICE is not considering such a strategy, and as a result, endocrinologists lack the motivation to study and follow the guidelines for urology and sexual medicine.
The American Urological Association, the American Diabetes Association, the American Association of Clinical Endocrinologists, and the BSSM recommend regular testosterone measurements in men with T2DM, whether or not they have erectile dysfunction, but NICE’s complete guide to maintaining testosterone levels and treating ED in T2DM is still absent.
The Case for Tadalafil 5 Mg Daily For Erectile Dysfunction In Men With Type 2 Diabetes
ED is a recognized risk factor that more than doubles the risk of cardiovascular disease. Regular erections and sexual activity protect against ED, so it is advisable to present these facts to the patient and consider daily treatment and early prevention. Obviously, lifestyle advice and ED treatment should be given as part of standard diabetes care.
More than two-thirds of men over 50 years of age with T2DM suffer from lower urinary tract symptoms and BPH. A number of researchers suggest that improving endothelial dysfunction and reducing inflammatory markers while taking tadalafil may reduce the progression of BPH [7].
In addition to directly affecting the genital area, PDE-5 inhibitors are used in renal failure in type 2 diabetes and help reduce ischemic reperfusion injury, improve endothelial dysfunction, reduce apoptosis and necrosis, renal inflammation, and renal fibrosis.
Type 2 diabetes is associated with an increased risk of many types of cancer, especially colon cancer. Some researchers have speculated about the role of PDE-5 inhibitors in cancer prevention.
Another important property of PDE-5 inhibitors is their ability, when taken on a daily basis, to improve cognitive functions, reduce depression and somatization, which in most cases accompany men with T2DM and ED [8]. This is due to the fact that PDE-5 inhibition by tadalafil has anti-inflammatory effects and improves cognitive function. Tadalafil may be a promising drug against other inflammatory pathologies associated with mild cognitive impairment.
Conclusions – Back to Patient Case
Robert came to see his therapist with an argument based on extensive research. He believes that ED and BPH are now much more relevant to him than a statistical reduction in the future risk of cardiovascular outcomes. In his opinion, he should take medications on a daily basis that can improve his condition within a few days. The best management strategy for T2DM is to reduce risk factors multiple, rather than selectively. Robert intends to give priority to treatment aimed at the pathological processes of prostate adenoma. Taking sildenafil on demand did not lead to severe side effects in Robert, so he believes that tadalafil on a daily basis at a dose of 5 mg will be well tolerated by his body. However, according to the NICE guidelines, the therapist could not prescribe tadalafil to him for daily use. Roger decides to stop taking vitamins and antioxidants and use the saved money to buy generic tadalafil and take it at 5 mg per day.
The focus of current T2DM treatment policy is glycemic control. There is currently a need to recognize ED as an independent risk factor for coronary heart disease. PDE5 inhibitors are beneficial and should be recommended routinely in diabetes management.
References
[1] American Diabetes Association. Statistics about diabetes [Internet] Arlington (VA): American Diabetes Association; [cited 2018 Apr 1]. Available from: http://www.diabetes.org/diabetes-basics/statistics/ [Google Scholar]
[2] Fonseca V, Seftel A, Denne J, Fredlund P. Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: analysis of data from tadalafil clinical trials. Diabetologia. 2004;47:1914 – 1923.
[3] Kirby M, Chapple C, Jackson G, Eardley I, Edwards D, Hackett G, et al. Erectile dysfunction and lower urinary tract symptoms: a consensus on the importance of co-diagnosis. Int J Clin Pract. 2013;67:606 – 618.
[4] Kloner RA, Jackson G, Emmick JT, Mitchell MI, Bedding A, Warner MR, et al. Interaction between the phosphodiesterase 5 inhibitor, tadalafil and 2 alpha-blockers, doxazosin and tamsulosin in healthy normotensive men. J Urol. 2004;172(5 Pt 1):1935 – 1940.
[5] David J, Edwards D, Wright P. Revitalise audit: erectile dysfunction and testosterone review in primary care. Diabetes Prim Care. 2017;19:67 – 72.
[6] Lee JY, Park SY, Jeong TY, Moon HS, Kim YT, Yoo TK, et al. Combined tadalafil and α-blocker therapy for benign prostatic hyperplasia in patients with erectile dysfunction: a multicenter, prospective study. J Androl. 2012;33:397 – 403
[7] Tadalafil Treatment Improves Inflammation, Cognitive Function, And Mismatch Negativity Of Patients With Low Urinary Tract Symptoms And Erectile Dysfunction. Urios A, Ordoño F, García-García R, Mangas-Losada A, Leone P, José Gallego J, Cabrera-Pastor A, Megías J, Fermin Ordoño J, Felipo V, Montoliu C Sci Rep. 2019 Nov 19; 9(1):17119.
[8] Association of depression and diabetes complications: a meta-analysis. de Groot M, Anderson R, Freedland KE, Clouse RE, Lustman PJ Psychosom Med. 2001 Jul-Aug; 63(4):619-30.