Tadalafil 5 mg once daily for the treatment of erectile dysfunction during a 6-month observational study (EDATE): impact of patient characteristics and comorbidities

Men with erectile dysfunction (ED) have several comorbid conditions such as cardiovascular disease (CVD) and associated risk factors including diabetes, hypertension, dyslipidemia, smoking, obesity, sedentary lifestyle, and others such as depression, premature ejaculation, lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), and overactive bladder [ 1– 4]. In the Men’s Attitudes to Life Events and Sexuality (MALES) study, 64 % of the men reported having at least 1 comorbid condition including hypertension (36 %), dyslipidemia (29 %), depression (25 %), CVD (17 %), and diabetes (14 %) [ 1].

Given these prevalence rates of comorbidities in men with ED, it is important to choose an appropriate treatment that maintains its efficacy and tolerability in the presence of the comorbidities [ 5]. Oral phosphodiesterase type 5 (PDE5) inhibitors including avanafil, sildenafil, tadalafil, and vardenafil are proven to be safe and effective for managing ED [ 6– 14]. Furthermore, these drugs have demonstrated efficacy in men with ED who have comorbid cardiovascular risk factors including hypertension, dyslipidemia, and/or diabetes [ 5], and tadalafil once daily (OaD) has shown efficacy in the treatment of BPH/LUTS [ 15– 17].

It has been suggested that appropriate treatment of concomitant ED may help in improving the adherence and management of associated comorbidities, which may eventually decrease healthcare costs and improve the overall health of the affected men [ 18]. However, some pharmacological drugs used for treating these comorbid conditions have sexual side effects. For example, antihypertensive drugs such as thiazide diuretics increase the risk of ED; 5α-reductase inhibitors, used for treating LUTS linked to symptomatic BPH, are associated with sexual disorders; and α-blockers tamsusolin and silodosin, used for treating BPH, are frequently responsible for ejaculatory disorders like anejaculation and reduced ejaculate volume [ 19]. This further underscores the significance of choosing an efficacious medication for treating ED in these subpopulations, if required.

The EDATE study was the first multinational, observational study in patients with ED, with or without previous exposure to PDE5 inhibitors, that documented the effectiveness and tolerability of tadalafil 5 mg OaD under routine conditions. The study highlighted that more than 85 % of men who choose to be treated with tadalafil OaD maintained the treatment in the next 6 months [ 20]. In this article, we present results of secondary analyses for the impact of patient characteristics and relevant comorbidities on treatment continuation rates as well as treatment effectiveness and satisfaction in patients with ED who had started with or switched to tadalafil OaD and were followed for a period of 6 months.

Currently, there are few observational studies in patients with ED that assess the impact of baseline characteristics and presence of comorbid conditions on PDE5 inhibitor treatment continuation rates. In particular, few existing studies assess treatment satisfaction and effectiveness beyond the IIEF-EF domain. The primary analysis of the EDATE observational study demonstrated high treatment continuation rates (86.3 %) over a period of 6 months in 778 patients with ED who initiated or switched to PDE5 inhibitor treatment with tadalafil OaD at baseline (Additional file 6) [ 20].

Here in this cohort with high frequency of comorbidities and use of concomitant medications, we found that continuation rates over 6 months of treatment with tadalafil OaD were comparable across subgroups. Furthermore, continuation rates were over 80 % regardless of the presence of comorbidities, pretreatment with PDE5 inhibitors, or ED severity. Even in the subgroup of older patients (>65 years), the continuation rate was 75 % at Month 6. IIEF was affected by some baseline characteristics including ED severity, pretreatment with PDE5 inhibitors, and the presence or absence of diabetes and BPH. However, treatment satisfaction remained predominantly unaffected by any comorbid condition or baseline characteristic except for age, with patients aged 18–65 years reporting significantly higher satisfaction scores vs those aged >65 years.

In our study, younger patients (18–65 years) had higher chances of continuing tadalafil OaD vs older patients. This finding resonates with that from the DETECT observational study in which age less than 60 years was one of the factors associated with continuation of tadalafil on-demand treatment at 12 months [ 23]. Similarly, an observational study in Latin America found that persistence and adherence rates for PDE5 inhibitor treatment at 6 months were generally higher in younger men with ED (mean age, 52.3 years vs 54.9 years for non-persistent patients and 52.1 years vs 55.5 years for non-adherent patients) [ 24]. In a Korean study, the most common reason for discontinuing PDE5 inhibitor treatment given by older men (>70 years) with ED was concerns about the side effects, possibly due to higher prevalence of comorbidities in this subgroup [ 25].

We observed significant improvement from baseline in all the IIEF domain scores and EDITS total score at the second (1–3 months) and third (4–6 months) visits in the overall tadalafil OaD cohort. In particular, the LS mean IIEF-EF domain score increased by 7.1 points from baseline to 4 to 6 months after initiation of tadalafil OaD, exceeding the minimal clinically important difference (MCID) of 4 points [ 26]; this observation aligns with the 9.4-point increase observed with tadalafil OaD in a previous randomised controlled trial [ 27].

We found that PDE5 inhibitor pretreatment had a significant impact on IIEF scores, i.e. pretreated patients showed less improvement during tadalafil OaD treatment compared with treatment-naïve patients, in the domains of EF, orgasmic function, intercourse satisfaction, and overall satisfaction. In the EDATE cohort, 36.7 % of patients switched to tadalafil OaD due to lack of efficacy of previous PDE5 inhibitor treatment [ 20]. Thus, we believe that some of the patients in the tadalafil OaD cohort who were pretreated with PDE5 inhibitors may have been insufficient responders to any PDE5 inhibitor treatment, leading to a negative effect on their IIEF domain scores. In real-life clinical practice, men with inadequate response to ED treatment will usually keep seeking for a better treatment option to improve their erection. A large observational study in Middle Eastern countries among men with ED receiving tadalafil on-demand ( N = 1,080) also found significantly higher mean IIEF-EF domain scores in treatment-naïve patients vs those who were pretreated (13.26 vs 9.28; p < 0.0001) [ 28].

ED etiology had no significant effect on IIEF in our study. This is in keeping with findings from an integrated analysis of 6 randomised studies which showed that tadalafil OaD was consistently efficacious across disease etiologies in men with ED [ 29].

In this study, there were significant effects of ED severity on the IIEF-EF, orgasmic function, sexual desire, and overall satisfaction domains. Mild ED reduced the change from baseline for IIEF-EF, sexual desire, and overall satisfaction, while severe ED meant an increased change in orgasmic function relative to moderate ED. This aligns with findings from an analysis of 6 randomised studies of tadalafil 2.5 and 5 mg OaD in patients with ED. Placebo-adjusted LS mean changes in IIEF-EF from baseline for both doses of tadalafil were numerically higher in patients with severe ED (4.6 and 5.8) vs those in patients with mild (2.3 and 4.5) and moderate (4.4 and 5.5) ED [ 29]. This may be explained by the possibility of greater changes from baseline in patients with more severe disease compared with those with mild or moderate disease. Furthermore, Rosen and colleagues have demonstrated that the MCID in the IIEF-EF domain increases significantly with higher baseline severity of ED ( p < 0.0001) [ 26].

We observed a significant impact of reported BPH on IIEF-EF, orgasmic function, and sexual desire domain scores, i.e., the presence of BPH reduced improvement during tadalafil OaD treatment. However, BPH can be accompanied by other comorbidities and the estimated reduction in efficacy from our model is unlikely to define the differences between BPH and non-BPH patients alone. It is worth noting that patients with BPH in our study did show improvement from baseline to Month 6 in unadjusted mean (SD) IIEF-EF domain score (5.7 [6.7]); Additional file 5). However, self-reported prevalence of BPH was small (6.3 %), and a full baseline assessment of LUTS/BPH was not actively performed. Thus, our findings in the small number of patients with BPH should be interpreted with caution.

In our study, diabetes significantly impacted the changes in IIEF domains of EF, orgasmic function, intercourse satisfaction, and overall satisfaction, i.e., patients with diabetes showed more improvement than patients without diabetes. This may have occurred because patients with diabetes had more severe ED at baseline. According to the MALES study, men with diabetes were more likely to perceive their ED to be severe and permanent vs those without diabetes [ 30]. The efficacy of tadalafil OaD for ED treatment in males with diabetes has been previously evaluated in a placebo controlled, randomised multicentre study, showing statistically significant improvements in the IIEF-EF ( p ≤ 0.005), intercourse satisfaction ( p = 0.033), and overall satisfaction ( p < 0.001) domain scores vs placebo [ 31].

There was no significant effect of CVD, dyslipidemia, and hypertension on any of the IIEF domain scores, similar to results from previous studies. In an integrated analysis of data from 6 randomised controlled trials, patients with ED receiving tadalafil 2.5 and 5 mg OaD experienced IIEF-EF LS mean improvements reaching or exceeding the MCID (≥4) regardless of CVD, diabetes, hypertension, or hyperlipidemia [ 29]. Furthermore, in an analysis of 11 placebo-controlled randomised studies, tadalafil on-demand significantly improved IIEF-EF domain score from baseline ( p < 0.005 vs placebo) in all subpopulations regardless of age, disease etiology, severity and duration, and presence of comorbid conditions such as diabetes, hypertension, CVD, hyperlipidemia, depression, and BPH [ 32].

Treatment satisfaction, as assessed by EDITS, was not affected by pretreatment with PDE5 inhibitors, ED etiology, ED severity, or presence of relevant comorbidities in this study. This is consistent with data from a previous randomised study in which patients receiving fixed-dose tadalafil on-demand were significantly more satisfied with their treatment vs placebo ( p < 0.001) despite high incidence of severe, organic ED and presence of comorbid conditions [ 33].

Large overall sample size, longitudinal nature, real life setting, and including patients with ED from several countries were important strengths of this study. In addition, to increase the external validity of the study, study sites were selected randomly from a list of investigators who expressed interest in participation and by asking sites to enroll patients consecutively. However, results may still be biased as only sites and investigators with interest were selected. As patients had to pay for their treatment, the study may also be biased towards those with higher education and economic status. The prevalence of comorbidities was based on patient-reported data, and was not confirmed by active baseline assessment by investigators. Thus, results may have been biased by false positive or missed diagnoses, and should be interpreted with caution.

Being an observational study, the patient population within subgroups was not well-defined. The small number of discontinuation events additionally limits the subgroup analysis of time to discontinuation. Nevertheless, this study provides valuable data on the impact of baseline characteristics and presence of comorbidities on continuation rates, and effectiveness and satisfaction of treatment with tadalafil OaD in a naturalistic setting and therefore has implications for everyday clinical practice. Furthermore, ED and CVD have common pathogenic pathways mediated via endothelial dysfunction [ 34], and it is suggested that tadalafil may potentially provide beneficial effects in patients with coronary artery disease, hypertension, heart failure, pulmonary arterial hypertension, diabetes mellitus, and Raynaud’s phenomenon [ 35].

This observational study found that under routine clinical conditions, the presence of comorbidities did not have any significant impact on treatment continuation rates and treatment satisfaction among men with ED who choose treatment with tadalafil OaD. Continuation rates and treatment satisfaction were comparatively lower in men older than 65 years. Pretreatment with PDE5 inhibitors, ED severity, and presence or absence of diabetes and BPH had an impact on treatment effectiveness; however, age and presence of hypertension, CVD, dyslipidemia, or ED etiology did not affect IIEF in this cohort. These findings have clinical implications for counseling patients with ED, particularly for discussing expectations after PDE5 inhibitor treatment, as comorbidities are common in these patients, especially in older men.