Value of phosphodiesterase 5 inhibitors as a combination therapy for treating erectile dysfunction: A literature review

Abstract

Erectile dysfunction (ED) is increasing in prevalence, with estimates that 50% of men between 40 and 70 years of age suffer from the disease. Due to a wide array of available medical interventions, significant focus has been put on combination therapies that can treat ED refractory to first‐line treatments such as phosphodiesterase 5 inhibitors (PDE5is). However, reviews evaluating monotherapy noninferiority and patient satisfaction of monotherapy versus combination therapy are lacking. A thorough PubMed search was performed to evaluate combination therapy in ED treatment. Articles published between January 2008 and June 2023 were reviewed, including randomized control trials, retrospective analyses, and cohort studies. Combination therapies included PDE5i plus another PDE5i, testosterone supplementation, α‐blockers, vacuum erectile devices, intracavernosal injections, and low‐intensity shockwave therapy. Based on this review, PDE5i monotherapy is not inferior to combination therapy and has increased satisfaction, convenience, and ease of use for patients with ED. Limitations of current literature on combination therapy include small sample size, limited data on patient satisfaction, possible biases, and limited follow‐up time. Further studies will need larger randomized control trials with follow‐up times greater than 1 year.

Keywords

combination therapy / erectile dysfunction / intracavernosal injection / low‐intensity shockwave therapy / phosphodiesterase 5 inhibitor / vacuum erectile device

1 INTRODUCTION

Erectile dysfunction (ED) is defined as failure to achieve or maintain an erection sufficient for satisfactory sexual intercourse. Failure of proper blood flow to the corpora or leakage of venous outflow can cause ED. ED can be caused by both psychological and/or organic factors. Organic causes include increasing age, cardiovascular disease, hyperlipidemia, hypertension, diabetes mellitus, neurological disease, hormonal changes, sleep apnea, iatrogenic, and more[1].

ED is increasing in prevalence and is estimated to affect half of men between the ages of 40 and 70, with up to 150 million men affected worldwide[2]. While there is limited data on up‐to‐date healthcare cost of ED, the total cost of ED‐related healthcare is expected to rise with an aging population. Additionally, ED can have profoundly negative effects on a man's quality of life. Men with ED can experience symptoms of depression, anxiety, avoiding sexual relations, and avoiding treatment. Yafi et al.[3] report rates of depression in men with ED are as high as 56%, and nearly 70% of men deny having ED. Because of this, the problem can go untreated, with the median time to pursue treatment of more than 2 years. Furthermore, 50%–80% of men will discontinue medical interventions within 1 year due to avoidance of sexual activity secondary to fear of failure[3].

Due to increasing prevalence and significant effects on quality of life, a variety of treatment options are available for ED. Most commonly, phosphodiesterase 5 inhibitors (PDE5is) are utilized due to oral formulation and beneficial effects in a wide range of patients. PDE5i will be discussed in more detail later in this review. Other treatment options include vacuum erection devices (VEDs), intracavernosal injection (ICI), low‐intensity shockwave therapy (LiST), α‐blockers, and surgical interventions such as penile implants. For the purposes of this review, we will focus on nonsurgical interventions. VED is a mechanical suction device placed over the penis that creates negative pressure to increase blood flow to the corpora cavernosa. VED is commonly used in combination with a constriction band at the base of the penis that prevents retrograde blood flow. ICI involves injecting vasoactive agents such as prostaglandin E1 (PG‐E1) or phentolamine into the corpora cavernosa. PG‐E1 increases cyclic adenosine monophosphate (cAMP) levels, causing vasodilation. LiST is a small, wand‐like device that uses sound waves to stimulate penile tissue and promote blood flow. α‐Blockers are generally used in combination with other medical options, helping to relieve lower urinary tract symptoms and improve quality of life[3].

Relaxation of smooth muscle is a critical component of erectile function. Therefore, this has been a target for therapeutic intervention with PDE5i. PDE5 is the predominant phosphodiesterase in the corpus cavernosum. Normally, PDE5 breaks down cGMP in the corpus cavernosa, decreasing smooth muscle relaxation and facilitating resolution of the erection. PDE5i acts to decrease PDE5 activity, thus increasing the availability of cGMP and subsequent smooth muscle relaxation[4]. Numerous PDE5is are on the market, including sildenafil, tadalafil, vardenafil, and avanafil, with varying half‐lives. Both sildenafil and vardenafil half‐lives are between 3 and 5 hours and must be taken on an empty stomach. Tadalafil has a longer half‐life at 18 hours, and avanafil has a half‐life of 6 hours[3]. Side effects of PDE5is include heartburn, headache, facial flushing, and myalgia (most associated with tadalafil). All men should be counseled on the risk of dangerously low blood pressure if PDE5is are taken with nitrates, commonly used in the treatment of angina.

The purpose of this review is to evaluate the use of PDE5i as a monotherapy for ED versus combination therapy with other PDE5is, testosterone supplementation (TS), α‐blockers, shockwave therapy, PG‐E1, or use of VED. We sought to review the current literature for evidence that monotherapy may be more beneficial to patients than combination therapy.

2 MATERIALS AND METHODS

An extensive PubMed search was conducted on combination therapies for ED on July 8, 2023. Inclusion criteria were human studies evaluating men using combination therapy for ED. Exclusion criteria were studies evaluating men using combination therapy after prostatectomy, when the majority of patients had undergone prostatectomy, studies evaluating monotherapy, studies not including the use of PDE5i, non‐human subjects, non‐English language studies, and case series. All articles included PDE5i use. Literary searches were restricted to the English language and included combinations of the following terms: PDE5i combination therapy, PDE5i monotherapy, ED, PDE5i nonresponders, VED, ICI, LiST, sildenafil, and tadalafil. Articles published between January 2008 and June 2023 were reviewed. Criteria included all pertinent review articles, randomized controlled trials, cohort studies, and retrospective analyses. References from retrieved articles were also manually scanned for additional relevant publications. Outcomes of interest were efficacy of combination therapy in comparison to monotherapy and patient satisfaction with combination versus monotherapy.

3 RESULTS

Using the search terms described in the methods section, thirty articles were initially reviewed, with eleven fulfilling both the inclusion and exclusion criteria. The majority of articles reviewed evaluated combination therapies after a failure of PDE5i monotherapy.

Three RCTs were included in the review. One evaluated tadalafil monotherapy versus tadalafil and sildenafil combination therapy, and the authors only found benefits for patients with severe ED. No benefit or minimal difference was observed in patients with mild and mild‐to‐moderate ED[5]. The second RCT evaluated LiST versus LiST and PDE5i, but an International Index of Erectile Function (IIEF) score improvement was only observed at one out of three possible follow‐up visits at 6 months[6]. The third RCT compared VED versus VED and PDE5i, noting a significant IIEF score in combination therapy[7] (Table 1).

Three systematic reviews were included in this study. The first review assessed TS and PDE5i versus PDE5i monotherapy. A positive effect of combination therapy was found in uncontrolled studies, with no effect found in placebo‐controlled studies[8]. The second review evaluated PDE5i monotherapy versus PDE5i plus another agent, including VED, LiST, and tadalafil. The authors found improvement in IIEF in all categories, but the quality of evidence was downgraded due to inconsistencies[9]. The last systematic review examined PDE5i monotherapy versus PDE5i in combination with a variety of other drugs. Tadalafil alone or in combination with sildenafil showed similar IIEF‐5 score, and a superior effect on IIEF scores from the combination of androgen plus PDE5i compared with PDE5i monotherapy was observed[10] (Table 2).

Four cohort studies were included. The first prospective analysis examined tadalafil monotherapy versus tamsulosin and tadalafil, and the authors concluded that combination therapy did not have a significant impact on IIEF scores[11]. The second prospective study assessed LiST and PDE5i combination therapy, noting an improvement in IIEF scores in 71% of patients[12]. The third prospective study of VED and PDE5i observed a significant improvement in IIEF scores, nearly doubling[13]. The last cohort study, a retrospective analysis, evaluated PDE5i monotherapy versus PDE5i and PG‐E1. Monotherapy had substantially increased patient satisfaction as compared to combination therapy[14] (Table 3).

Lastly, a cross‐sectional survey was included. Tadalafil monotherapy scored significantly higher on patient satisfaction and convenience than tadalafil combined with α‐blockers and/or 5α‐reductase inhibitors (5‐ARIs)[15] (Table 3).

4 DISCUSSION

In the following paragraphs, we will outline the strengths and weaknesses of the involved studies, and most importantly, what this means for patients suffering from ED.

We will begin by examining PDE5i monotherapy versus PDE5i plus another PDE5i. Cui et al.[5] assigned 180 men in a 1:1 ratio to tadalafil monotherapy or tadalafil and sildenafil combination therapy. The study showed that combination therapy improved the IIEF‐5 scores of patients with severe ED. The treatment group was given sildenafil for only 4 weeks and follow‐up time was limited to 12 weeks. Additionally, for questions 2 and 3 on IIEF‐5, there were minimal differences in patients with mild and mild‐to‐moderate ED. For question 2, there was no difference in control and treatment arm for patients with mild ED (5.0 ± 0.0), and minimal difference in patients with mild‐to‐moderate ED (4.7 ± 0.2, 4.9 ± 0.1, respectively). Similarly, for question 3, patients with mild ED saw little difference in IIEF‐5 scores (4.7 ± 0.5, 4.9 ± 0.2, respectively). Patients with mild‐to‐moderate ED had minimal difference as well (3.5 ± 0.9, 3.8 ± 1.0, respectively). These results indicate that combination therapy of two PDE5i will not be beneficial for the majority of patients, only benefiting those with severe ED. This study did not evaluate the long‐term effects of combination therapy, bringing into question whether the beneficial effects in severe ED will last[5].

Similarly, Singh et al.[11] categorized 133 men into three groups to evaluate the effects of α‐blockers on lower urinary tract symptoms (LUTS) on benign prostatic hyperplasia (BPH): daily tamsulosin, daily tadalafil, or a combination of both. They included secondary outcomes that evaluated IIEF‐5 scores for ED. The combination therapy had a significant impact on IIEF‐5 scores when compared to tamsulosin monotherapy but did not have a significant impact when combination therapy was compared to tadalafil monotherapy. This suggests that tadalafil monotherapy will treat symptoms of ED as effectively as combination therapy, but with increased ease of use and likely decreased costs to the patient[11].

Questions of combination therapy superiority are not limited to oral medications. Labairu‐Huerta et al.[14] evaluated the efficacy of a variety of combination therapies, including PGE1 and PDE5i. A total of 1200 men were included in the study, with patients split between the monotherapy and combination therapy groups. Of these, 597 patients received PDE5i monotherapy, 124 received PDE5i and PG‐E1, and 62 received PG‐E1 monotherapy. Patients were followed for an average of 48 months. The study looked at satisfactory responses to treatment, defined as an IIEF score between 22 and 25. Satisfactory response was achieved in 72% of patients receiving PDE5i and just 47% of patients receiving combination therapy. In this case, monotherapy had a significant advantage in satisfactory response compared to combination therapy, suggesting that PG‐E1 combination therapy would not improve patient outcomes. This is another example of the efficacy of monotherapy[14].

Regarding patient satisfaction, Lee et al.[15] conducted an internet survey of 507 men with both ED and BPH. Patients were broken into three groups: those taking once‐daily tadalafil, tadalafil combination with α‐blockers and/or 5‐ARIs, or nontadalafil PDE5i with α‐blockers and/or 5‐ARIs. Once‐daily tadalafil scored nearly 10 percentage points higher than the tadalafil combination on the Treatment Satisfaction Questionnaire For Medication‐9 item effectiveness, 70.0% versus 60.8%. Once‐daily tadalafil also scored higher on convenience (83.1% vs. 74.7%). This indicates that men value ease of taking a medication, and are more in favor of taking monotherapy, likely due to easier adherence, less cost, and lack of disruption to lifestyle. Additionally, once‐daily tadalafil patients found it much easier to plan when they would take their medications compared to a tadalafil combination. The convenience and ease of taking one daily pill, rather than multiple pills, is of great importance to patients. There were also no significant differences in health‐related quality of life between the three treatment groups, again suggesting a lack of benefit to patients taking combination therapy[15].

Other combinations, including androgen supplementation and PDE5i, have also been studied. Corona et al.[8] evaluated efficacy of TS versus TS and PDE5i combination. Five of the studies included in the analysis looked at TS monotherapy versus TS and PDE5i. The authors found a positive effect of combination therapy only in uncontrolled studies. Placebo‐controlled studies did not have a positive effect. Additionally, they used the Begg adjusted rank correlation test between studies of TS and TS plus PDE5i, which suggested the presence of publication bias. The studies involved in the review had variations in basal testosterone levels and definitions of hypogonadism. The lack of positive effect in control trials, in addition to possible publication bias, does not suggest that TS and PDE5i combination therapy should be used for ED without further evaluation[8].

Mykoniatis et al.[9] evaluated PDE5i monotherapy versus many different combination treatments. They included studies on adding daily tadalafil, shockwave therapy, vacuum erectile devices (VED), folic acid, metformin, and angiotensin‐converting enzyme inhibitors to existing PDE5i treatment. In each category, they concluded there was a significant IIEF score improvement. However, each category was based on limited number of studies, and in many cases, only one study. They also further subclassified patients into a variety of groups, including those with LUTS, hypogonadism, prostatectomy‐induced ED, and others. Many variables were included. The authors stated that evidence quality was downgraded for the mean IIEF score change due to serious inconsistency and indirectness, which they attributed to high levels of heterogeneity in the involved studies and highly variable study selection criteria. The authors also noted limited follow‐up time in all studies included in the review. It seems that very limited conclusions can be drawn from this study regarding the original question of whether combination therapy treated ED better than PDE5i monotherapy alone. It is likely that stronger evidence could have been compiled if one or two types of combination therapy were analyzed, with less heterogeneity between involved studies[9].

The following year, Mykoniatis et al.[6] had 25 patients receiving combination therapy and 25 patients receiving LiST and placebo. To be included in the study, patients had to have previous, regular use of any PDE5i. Patients received six total sessions of LiST over 3 weeks. Patients were further split into those with mild ED and those with mild‐to‐moderate ED. They followed patients for 6 months, but only had statistically significant differences in IIEF scores at the 6‐month follow‐up. No significant differences were seen at 1 month and 3 months follow‐up. They also only observed a clinical difference between the two groups at 3 months. The authors acknowledged that the findings were not robust at all timepoints. This study had a very small cohort, with limited treatment duration. These study limitations do not give strong evidence for use of combination therapy without further large‐scale RCTs. Additionally, Palmieri et al. evaluated LiST in combination with PDE5i in PDE5i nonresponders. 106 patients received 6 weeks of treatment. They had 4 total weeks of follow‐up, with 71% of patients showing an improvement in IIEF scores. Again, this is a relatively small cohort and does not have a control group. The limited follow‐up time does not evaluate any long‐term treatment outcomes, specifically how long the 6 weeks of LiST will have a beneficial effect on ED symptoms. Undoubtedly, this type of combination therapy would be very difficult for many patients to access and would likely be a reasonable option for a small subset of patients. Many patients would have lost work time, increased transportation costs, and many clinic visits in a short period of time while receiving this therapy[12].

Continuing the evaluation of devices for ED, some studies looked at combination therapy involving VED. Sun et al.[7] specifically focused on men with diabetes. 66 patients were included, all of whom had previously failed PDE5i monotherapy, defined as 4 to 6 unsuccessful attempts using a maximum dose of 100 mg of sildenafil for at least 3 months. All patients had moderate or severe ED. Half of the patients were given VED and sildenafil, and the other half were given VED monotherapy. The authors saw a significant increase in IIEF scores for combination therapy. However, the follow‐up time was limited to 3 months, the cohort size was small, and this was a specialized patient population. The authors acknowledged that they could not measure the frequency of VED use during the study period. These factors suggest limited strength of evidence and do not strongly indicate the need for combination therapy with VED. Canguven et al.[13] had a very similar cohort size and design, with the exception that diabetes was not involved in the study. 69 men were followed over 4 weeks, all of whom received VED and PDE5i. There was an increase in IIEF from 9.0 to 17.6 over the course of the study. Again, this study had a small cohort, very limited follow‐up period, and no control. Other factors to consider with VED use are device cost, frequency of use required for efficacy, and if patients are using the device correctly. Patients would need to be taught how to use the device, another possible challenge for this combination therapy over PDE5i monotherapy[7,13].

Limitations of this review include limited number of studies fulfilling inclusion and exclusion criteria, lack of statistical analysis, and heterogeneity of reviewed articles. Nonetheless, it is important to acknowledge that entirely eliminating publication bias and dealing with selective reporting remains a formidable challenge. A common theme of articles included in this review was small sample size, limited treatment duration, and limited follow‐up time. Future studies should focus on larger, randomized control trials with treatment duration of at least 1 year and follow‐up duration of at least 1 year after treatment to provide a more comprehensive analysis of combination therapy versus monotherapy for management of ED. Additional studies could examine the overall cost to patients of combination therapy versus monotherapy.

5 CONCLUSION

PDE5i monotherapy versus combination therapy should be a shared decision between healthcare provider and patient. Many factors should go into the decision, including a discussion of cost of additional treatment, adherence, usability, satisfaction with additional treatment, and in some cases, equivalent efficacy of monotherapy. Men have been shown to have higher satisfaction, convenience, and ease of use with monotherapy, and this should be discussed with the patient depending on their needs. Studies included in this review showed limitations including small cohort size, limited follow‐up duration, and lack of generalization to the population. When all variables are considered, patients may not have significant improvement in ED symptoms with combination therapy.

References

[1] Sooriyamoorthy T, Leslie SW. Erectile dysfunction. Treasure Island, FL: StatPearls; 2023.

[2] Nunes KP, Labazi H, Webb RC. New insights into hypertension‐associated erectile dysfunction. Curr Opin Nephrol Hypertens. 2012;21(2):163–170.

[3] Yafi FA, Jenkins L, Albersen M, Corona G, Isidori AM, Goldfarb S, et al. Erectile dysfunction. Nat Rev Dis Primers. 2016;2(1):16003.

[4] Corbin JD. Mechanisms of action of PDE5 inhibition in erectile dysfunction. Int J Impot Res. 2004;16(S1):S4–S7.

[5] Cui H, Liu B, Song Z, Fang J, Deng Y, Zhang S, et al. Efficacy and safety of long‐term tadalafil 5 mg once daily combined with sildenafil 50 mg as needed at the early stage of treatment for patients with erectile dysfunction. Andrologia. 2014;47(1):20–24.

[6] Mykoniatis I, Pyrgidis N, Zilotis F, et al. The effect of combination treatment with low‐intensity shockwave therapy and Tadalafil on mild and mild‐to‐moderate erectile dysfunction a double‐blind, randomized, placebo‐controlled clinical trial. J Sex Med. 2022;19(Suppl_2):106–115.

[7] Sun L, Peng F‐L, Yu Z‐L, Liu C‐L, Chen J. Combined sildenafil with vacuum erection device therapy in the management of diabetic men with erectile dysfunction after failure of first‐line sildenafil monotherapy. Int J Urol. 2014;21(12):1263–1267.

[8] Corona G, Isidori AM, Buvat J, Aversa A, Rastrelli G, Hackett G, et al. Testosterone supplementation and sexual function: a meta‐analysis study. J Sex Med. 2014;11(6):1577–1592.

[9] Mykoniatis I, Pyrgidis N, Sokolakis I, Ouranidis A, Sountoulides P, Haidich AB, et al. Assessment of combination therapies vs monotherapy for erectile dysfunction. JAMA Network Open. 2021;4(2):e2036337.

[10] Munk NE, Knudsen JS, Comerma‐Steffensen S, Simonsen U. Systematic review of oral combination therapy for erectile dysfunction when phosphodiesterase type 5 inhibitor monotherapy fails. Sex Med Rev. 2019;7(3):430–441.

[11] Singh DV, Mete UK, Mandal AK, Singh SK. A comparative randomized prospective study to evaluate efficacy and safety of combination of tamsulosin and tadalafil vs. tamsulosin or tadalafil alone in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. J Sex Med. 2014;11(1):187–196.

[12] Palmieri A, Arcaniolo D, Palumbo F, Verze P, Liguori G, Mondaini N, et al. Low intensity shockwave therapy in combination with phosphodiesterase‐5 inhibitors is an effective and safe treatment option in patients with vasculogenic ED who are PDE5i non‐responders: a multicenter single‐arm clinical trial. Int J Impot Res. 2020;33(6):634–640.

[13] Canguven O, Bailen J, Fredriksson W, Bock D, Burnett AL. Combination of vacuum erection device and PDE5 inhibitors as salvage therapy in PDE5 inhibitor nonresponders with erectile dysfunction. J Sex Med. 2009;6(9):2561–2567.

[14] Labairu‐Huerta L, Padilla‐Fernández B, Arrondo‐Arrondo JL, Valverde‐Martínez LS, Martín‐Rodríguez A, Silva‐Abuín JM, et al. PDE‐5 inhibitors in monotherapy versus combination therapy in a sample of 1200 patients with erectile dysfunction. Arch Ital Urol Androl. 2015;87(3):204–209.

[15] Lee L, Goren A, Boytsov N, Donatucci C, McVary K. Treatment satisfaction among men with concurrent benign prostatic hyperplasia and erectile dysfunction treated with tadalafil or other phosphodiesterase type‐5 inhibitor combinations. Patient Prefer Adherence. 2016;10:1205–1215.

Rights & permissions

2024 The Authors. UroPrecision published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.