24 Current Diabetes Reviews, 2008, 4, 24-30 1573-3998/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Redefining the Role of Long-Acting Phosphodiesterase Inhibitor Tadalafil in the Treatment of Diabetic Erectile Dysfunction Roberto Bruzziches, Emanuela A. Greco, Marcello Pili, Davide Francomano, Giovanni Spera and Antonio Aversa* Chair of Internal Medicine, Dept. Medical Pathophysiology, Sapienza University of Rome, Italy Abstract: Diabetes mellitus (DM) is an established risk factor predisposing to male erectile dysfunction (ED), and it has been calculated that more than 50% of diabetic men develop ED within ten years of diagnosis. It has been suggested that the risk of ED increases with metabolic indices of inadequate diabetes control and with a longer duration of disease. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the pathogenesis of diabetic ED. Coronary and peripheral atherosclerosis are frequent complications of DM and diabetic patients have an increased risk of future cardiovascular events comparable to that of pa- tients with coronary artery disease. The prolonged half-life of tadalafil (17.5 hours) and its prolonged period of responsiveness (36- hours), constitute an ideal pharmacokinetic profile for once-a-day dosing and makes it an ideal candidate for rehabilitative therapy in DM patients, whereas a poor compliance with on-demand schedule is reported. The aim of this review will be to give an update on clinical overall efficacy and safety of tadalafil trials, i.e in diabetic population, and fi- nally provide evidences for redefining the role of chronic treatment in selected group of patients. Keywords: Endothelial dysfunction, Phosphodiesterase type-5 inhibitors, Diabetes mellitus, Cardiovascular disease, Once-a-day dosing. INTRODUCTION Erectile dysfunction (ED) is defined as the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual performance [1]. In the new millennium, male ED often represents the “tip of the iceberg” of a systemic vascular disorder; about 50–85% of ED pa- tients is estimated to have an organic cause by modern methods of examination [2]. Many diseases which are commonly encountered in the aging male (diabetes, metabolic syndrome, hypogonadism, hyper- tension, atherosclerosis, cardiovascular and neurological disease) as well as chronic diseases (arthritis, renal and hepatic failure, pulmo- nary disease) represent a frequent cause of organic ED and are often treated with medications that can interfere with sexual function at central and/or peripheral level. In addition, incorret lifestyle – i.e. high fat meals, cigarette smoking, alcool or drug abuse – may all contribute to the onset of ED. It is now well understood that male ED is a symptom of specific, systemic or relational pathologies rather than a disease itself; for this reason in the near future both general practitioners and specialists in internal medicine would have to inter- play with sexual medicine. ED may constitute the first manifestation of important systemic pathologies and is considered as a possible marker of atherosclerotic, metabolic and neurological pathologies which remain clinically undiagnosed. ED is more common in men with diabetes mellitus (DM) and is often associated with vascular disease. Coronary and peripheral atherosclerosis are frequent compli- cations of diabetes. Patients with DM have an increased risk of future cardiovascular events comparable to that of patients with coronary artery disease (CAD) [3, 4]. Therefore, regarding the risk of cardio- vascular events, DM can be considered equivalent to established CAD [5]. The incidence of DM is increasing at an alarming rate, and diabetic men already make up a quarter of the men in the overall population of ED. As already outlined, impotence occurs in almost 50% of men with DM, and the rate of sexual dysfunction is only slightly lower in diabetic women [1]. The onset of ED occurs at an earlier age in patients with DM. In more than 50% of patients with ED and DM, the former is noted within ten years of the onset of DM; it may present as the first sign of diabetes in as much as 10% of pa- tients [6]. Temporary ED may be due to poorly controlled diabetes, although this point is debatable. ED seems to occur at an earlier age in type-1 than in type-2 diabetic patients, although probably occurs *Address correspondence to this author at the Dip. to Fisiopatologia Medica, Room 37, Viale Policlinico 155, 00161 Rome, Italy; Tel: +390649970721, Fax: +39064461450; E-mail: antonio.aversa@uniroma1.it with equal frequency in the two types. Ageing, cigarette smoking and the presence of diabetic complications (neuropathy, vascular diseases, retinopathy and nephropathy) show a significant relationship with the occurrence of ED in both type-1 and type-2 diabetes [7]. A large body of evidence has accumulated to suggest that the im- pairment of vascular endothelial function is an initial step towards the development of atherosclerosis; also, endothelial function is impaired in patients with overt atherosclerotic disease as well as in those at increased cardiovascular risk and it is often present in diabetic pa- tients even without clinically evident atherosclerotic diseases [8, 9]. In addition to blunted endothelium-dependent and –independent re- sponses diabetic patients are reported to have a reduced response to vasoactive agents [10]. The recent discovery that chronic, not on-demand administration of phosphodiesterase type-5 inhibitors (PDE5-i) may improve erectile and endothelial response in men previously unresponding to on- demand regimes, opens a new scenario in the treatment of men with ED and comorbidities. PDE5-i are a group of on-demand drugs li- censed for ED treatment and appear to offer advantages over past therapies in terms of ease of administration and cost, and they are now widely advocated as first-line therapy. These drugs have been shown to improve erectile function, penetration and maintenance of erection, resulting in more successful intercourses. Sildenafil and vardenafil are short-acting agents, while tadalafil has a longer half- life allowing the user more flexibility in sexual activity. Although the various classes of PDE5-i differ with respect to selectivity and phar- macokinetic profiles, efficacy and safety of these agents are compa- rable in broad populations of men with ED. PDE5-i facilitate erection by increasing nitric oxide (NO) availability through the inhibition of cyclic guanosine monophosphate (cGMP) breakdown in endothelial cells [11]. Efficacy of PDE5-i is reported to be lower in men with ED and DM compared with those without DM [12]. Similarly the endo- thelial effectiveness of drugs known to improve endothelial function is lower in patients with diabetes compared with patients without diabetes [13]. It has been suggested that chronic PDE5-i administra- tion may regulate the transduction pathway leading to the activation of endothelial-NO synthase (eNOS) with no effect on NO bioavail- ability or on the cGMP pathway, thereby eliminating a possible con- cern for tachyphylaxis [14] and that chronic administration of PDE5-i may improve endothelial function long term [15]. Aim of the present article will be to review the efficacy and safety data of long-term therapy with tadalafil in patients with DM and to provide an up-date on endothelial function effects determined by its chronic use in this special sub-population of patients. Not For Distribution Not For Distribution