Losartan Improves Erectile Dysfunction in Diabetic Patients

A Clinical Trial

Y Chen; S Cui; H Lin; Z Xu; W Zhu; L Shi; R Yang; R Wang; Y Dai

Int J Impot Res. 2012;24(6):217-220. 

Abstract and Introduction

Abstract

The activation of cavernous local renin-angiotensin system has an important role in pathogenesis of diabetic erectile dysfunction (ED). In our primary study, we found that angiotensin Type 1 receptor blocker improved the erectile function of diabetic rats. Therefore we explored the losartan in clinical treatment for diabetic patients suffering with ED. A total of 124 diabetic patients with ED were included in this study and treated with losartan or tadalafil or losartan plus tadalafil or watch for waiting as control for 12 weeks. Erectile function was assessed by International Index of Erectile Function (IIEF-5) questionnaire, the percentage of positive responses to sexual encounter profile questions 2 (SEP2), 3 (SEP3) and the global assessment question (GAQ). Losartan or tadalafil or losartan plus tadalafil significantly improved the mean IIEF-5 scores, the percentage of successful penetrations (SEP2), the successful intercourse completions (SEP3) and GAQ (P<0.05). The combination of losartan and tadalafil is more effective than the single-use of losartan or tadalafil (P<0.05). The patients with moderate and mild ED had better response rates to losartan than patients with severe ED. This is the first clinical trial in losartan therapy on diabetic patients suffering from ED. Losartan seems to be effective and well-tolerated in diabetic ED patients, especially for mild to moderate ones. The combination therapy of losartan and tadalafil appeared to be more effective than monotherapy.

Introduction

Erectile dysfunction (ED) is a common complication for diabetic patients. The pathogenesis of diabetic ED is multifactorial, involving the neural, vascular, endocrine and metabolic systems.[1,2] The first-line treatment for diabetic ED is phosphodiesterase Type 5 inhibitors. However, the efficacy of phosphodiesterase Type 5 inhibitors on diabetic ED is only about 51–62%.[3–5] Therefore, it is necessary to search for more effective medical therapies for this difficult condition.

Our previous study showed that the angiotensin II (Ang II) level in the cavernosum of diabetic rats was much higher than that in normal controls.[6] Kifor et al.[7] reported that exogenous Ang II by ICI could terminate spontaneous erection in dogs, whereas administration of losartan, an Ang II receptor antagonist, resulted in smooth-muscle relaxation and erection. The inhibitor of local renin-angiotensin system (RAS) (angiotensinogen, (pro)renin receptor, angiotensin-converting enzyme, and angiotensin Type I (AT1) receptor) of cavernosum in diabetic rats was obtained by administration of the angiotensin Type 1 receptor blocker (ARB), losartan.[8] Administration of losantan could also regulate human penile smooth muscle tone[9] and HO-1 gene expression[10] and improves erectile function in diabetic rats.[8]

ARBs, a class of selective inhibitors of AT1, such as losartan, valsartan and irbesartan, are medications commonly used for cardiovascular disease. There is increasing clinical evidence showing that ARBs are effective on non-diabetic ED. The use of losartan[11] and valsartan[12] was reported to improve erectile function in hypertensive patients. The study with irbesartan also showed an improvement in sexual desire, frequency of sexual contacts and erectile function in hypertensive patients with the metabolic syndrome.[13] However, there is no clinical report on ARBs for the treatment of diabetic ED. So we designed this clinical trial with the use of losartan for the treatment of diabetic ED.

Methods

Study Design and Inclusion Criteria

This is a prospective randomized clinical trial with a total of 124 patients and a duration of 12 weeks. The patients were diagnosed with diabetes by endocrinologists.

The inclusion criteria were: male gender with ED, age >18 years, a definite diagnosis of Type 2 diabetes for at least 3 months and blood glucose well-controlled, complaining for ED, agree to participate and sign the informed consent and able to answer a self-applied questionnaire. Exclusion criteria were: recently diagnosed coronary artery disease (CAD), poorly controlled blood pressure or orthostatic hypotension, congestive heart failure, arrhythmia, significant renal or hepatic dysfunction or anemia, prostate disease with or without previous surgical treatment, any penile abnormal anatomy, Pyronie's disease or using intracavernosal injection and vacuum erectile device for the ED treatment already. The study protocol was approved by the University and performed in accordance with the Declaration of Helsinki Principles.

All patients were treated with insulin to control the blood glucose with normal hemoglobin A1c level by endocrinologists as a standard in this study. The patients were randomized into four groups: diabetic-ED patients watching for waiting as control (n=30), diabetic-ED patient treated with tadalafil 5 mg once daily (n=31)[14–16] diabetic-ED patient treated with losartan 50 mg once daily (n=32)[17] and diabetic-ED patient treated with losartan 50 mg and tadalafil 5 mg once daily (n=31) for 12 weeks. All patients were followed up in the clinic on fourth and eight weeks of treatment for safety assessment and twelth weeks of treatment after one week wash-out period for evaluation of erectile function. A self-administered questionnaire was completed about the time and number of drugs used, sexual quality and any adverse effects occuring.

Evaluation of Erectile Function

Efficacy of treatment was evaluated by the International Index of Erectile Function (IIEF-5) questionnaire, the percentage of positive responses to SEP-2 (SEP-2:'Were you able to insert your penis into your partner's vagina?') and 3 (SEP3: 'Did your erection last long enough for you to have successful intercourse?') and the global assessment question (GAQ) ('Has the treatment you have been taking over the past study interval improved your erection?') at baseline and at the end of the study. We used the scores of IIEF-5 to divide the patients into three degrees: mild (12<=IIEF-5<=21), moderate (8<=IIEF-5<=11) and severe (IIEF-5<=7) respectively.

Statistical Analysis

Statistical Program for Social Sciences for Windows 17.0 statistics package program was used for statistical analysis of the data. Results were expressed as mean± s.d. for all continuous variables. Differences between baseline and end point measurements were assessed using one-way analysis of variance. For each SEP question and GAQ, the scores of pre-treatment and post-treatment were considered the percentage of 'yes' responses relative to the number of sexual encounters, respectively. Chi-square tests were used in SEP and GAQ data. P<0.05 was considered the threshold for statistical significance.

Results

Baseline characteristics for patients in each group are presented in . There are no statistical significance for mean age, blood pressure, fasting blood glucose, diabetic duration and ED duration among all groups (P>0.05).

Table 1.  Baseline data of each group

Characteristic Control (n=30) Tadalafil 5 mg (n=31) Losartan 50 mg (n=32) Losartan 50 mg plus tadalafil 5 mg (n=31)
Age (years) 48.1±12.6 46.1±12.9 46.7±10.2 45.4±14.9
Systolic BP (mm Hg) 132.3±21.0 134.7±18.2 130.7±19.3 135.1±20.1
Diastolic BP (mm Hg) 79.6±10.9 80.1±10.3 78.8±10.5 83.9±10.1
Fasting blood glucose (mmol l−1) 6.9±2.5 7.0±2.0 7.3±2.3 7.2±2.1
Diabetes duration (years) 6.4±4.2 6.2±4.1 6.1±4.7 5.8±4.8
ED duration (months) 28.4±12.5 26.9±11.8 25.1±12.3 25.6±11.7

Data presented as mean±s.d. All data of each groups have no statistical difference (P>0.05).

The mean IIEF-5 scores were significantly improved with the treatment of tadalafil (9.40±3.66 vs 16.00±4.55) or losartan (9.68±3.46 vs 13.28±4.92) or losartan plus tadalafil (9.94±4.02 vs 18.61±4.83) (P<0.05) as compared with baseline, respectively. The details are presented in Figure 1. The combination of losartan and tadalafil is more effective than losartan alone (P<0.05). There were no significant changes of IIEF-5 scores in control group (P>0.05) from the baseline to the endpoint of the study.

Figure 1.

 

Mean IIEF-5 (International Index of Erectile Function) scores at baseline and endpoint of each group. * P<0.05 for end point vs baseline of each group. The treatment of tadalafil, losartan or losartan plus tadalafil were effective on increasing the mean IIEF-5 scores. # P<0.05 for tadalafil or losartan vs losartan plus tadalafil at end point. The treatment of the combination of losartan and tadalafil were more effective than single-use.

According to the baseline of the IIEF-5 scores, each treatment group (tadalafil, losartan and tadalafil plus losartan) was divided into 3 sub-groups: mild (12<=IIEF-5<=21), moderate (8<=IIEF-5<=11) and severe (IIEF-5<=7) respectively. A total of nine sub-groups variance of IIEF-5 scores between baseline and the scores of twelth12th week are presented and re-analysed. The details are presented in Figure 2. The patients with moderate and mild ED had better response rates to losartan than patients with severe ED.

Figure 2.

 

The variance of IIEF-5 (International Index of Erectile Function) scores between baseline and end point of nine sub-groups. *P<0.05 for severe and moderate vs mild erectile dysfunction (ED). There has been no significant difference of the variance scores among severe, moderate and mild-ED treated by tadalafil or tadalafil plus losartan. The diabetic patients with moderate or mild ED had more effect on single-use of losartan.

In the tadalafil, losartan and losartan plus tadalafil treatment groups, the percentages of positive answers to SEP-2 increased from 32.3 to 80.7% and 34.4 to 65.6% and 35.5 to 90.3% as compared with 33.3 to 40.0% in the control group (P<0.05) (Figure 3). The percentages of positive answers to the SEP-3 questions of four groups were 26.7, 25.8, 25.0 and 25.8% at baseline. There was no change of positive answer to SEP-3 in control group (Figure 4). The percentage of SEP-3 to tadalafil, losartan treatment and losartan plus tadalafil treatment significantly increased (67.7%, 59.4% or 77.4%, respectively) as compared with 33.3% in the control group (P<0.05). tadalafil, losartan or losartan plus tadalafil significantly improved the percentage of successful penetrations (SEP-2) and successful intercourse completions (SEP-3) as compared with control group.

Figure 3.

 

The percentage of positive answers to the sexual encounter profile questions-2 (SEP-2) in diabetic patients with erectile dysfunction (ED) at baseline and following 12 weeks of treatment. *P<0.05 for end point vs baseline.

Figure 4.

 

The percentage of positive answers to the sexual encounter profile questions-3 (SEP-3) in diabetic patients with (erectile dysfunction) ED at baseline and following 12 weeks of treatment. *P<0.05 for end point vs baseline.

The GAQ used to assess the overall effect of the treatment indicated that tadalafil, losartan and losartan plus tadalafil were all superior to control (P<0.05) in improving erections (tadalafil 74.2%, losartan 62.5% and losartan plus tadalafil 83.9% vs control 16.7%) (Figure 5). However, there was no statistical difference between tadalafil, losartan and losartan plus tadalafil in GAQ.

Figure 5.

 

The percentage of positive answers to the (GAQ) in diabetic patients with erectile dysfuction (ED) at the end of treatment with control, losartan or tadalafil or losartan plus tadalafil. *P<0.05 for losartan or tadalafil or losartan plus tadalafil vs control.

Safety Assessment

The common adverse events with losartan were postural hypotension (9.4%), mild giddiness (12.5%) and allergy (3.1%), whereas tadalafil caused headache (3.2%) and rhinorrhagia (3.2%). The administration of tadalafil plus losartan did not increase the adverse events (hypotension 6.5%, giddiness 6.5%, headache 3.2%). These adverse events were mostly mild and did not affect the patients' participation and completion of the study.

Discussion

Our primary studies proved that cavernous local RAS existed in the penis and played an important role in pathogenesis of ED.[7,8] The most active factor of RAS components, Ang II, binding to the AT1, can cause contraction of cavernous smooth muscles. The overexpression of Ang II and upregulation of RAS in cavernous tissue of diabetic ED rats were studied in our primary work.[8] Downregulation of RAS, such as decreasing the production of RAS components and disturbing the binding between the active factors of RAS and its specific receptor, may be the most useful method for diabetic-ED treatment.

Angiotensin I-converting enzyme inhibitors block the activity of Angiotensin I-converting enzyme and prevent Ang I from transforming to Ang II. ARB obstruct the combination of Ang II to AT1R and subsequently cause a similar physiological effect. Losartan is an AT1 antagonist, chemically described as 2-butyl-4-chloro-1-[p- (o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Losartan is widely used for hypertension, heart disease and nephropathy of diabetes. Our primary animal studies showed that ARB treatment of diabetic rats could improve erectile function.[7,8] However, there is no clinical report regarding losartan treatment for patients with diabetic ED.

In this study, we found that diabetic patients suffering from ED were responsive to the losartan treatment. The IIEF-5 scores, the percentage of positive answers to the SEP-2, SEP-3 and GAQ after treatment are all significantly increased as compared with baseline and the end point of control groups. The analysis of our study also indicated that losartan worked better in mild and moderate ED than severe cases. It is consistent with our previous studies, which shows that losartan can downregulate the local expression of AT1 and Ang II, but it cannot elevate the reduced smooth muscle/collagen ratio in diabetic rats[7,8] We believe that the losartan may not completely reverse the severe damaged penile tissues due to diabetes.

The complex pathogenesis of diabetic ED indicates that targeting a single pathway may not obtain the best-treatment effect. With an uncontrolled hyperglycemic situation, the endothelial cells, smooth muscle cells and nerves are persistently damaged and finally ED is aggravated. The appropriate use of insulin to control the blood glucose is considered as the first step, especially for Type 1 diabetes.

PDE5 inhibitor is now widely used as the first-line therapy for majority of patients suffering from ED. Chronic PDE5 inhibitor therapy has become increasingly popular.[18] There might be two major mechanisms involved: the first one is to connect organic etiology, such as improving endothelial function,[19] decreasing corporal fibrosis and veno-occlusive dysfunction.[20] The second mechanism may be the psychogenic factor. The routine administration of PDE5 inhibitor, similar to the antihypertensive drugs daily, makes sexual life routinely and relieves the anxiety and depression of ED. tadalafil with long half-life is the ideal agent for chronic once daily therapy.

In our study, the combination therapy with daily losartan and tadalafil seems to be more effective than losartan alone (from Figure 1). This is further evidence of the effectiveness of combination therapy in diabetic ED. There were still be some patients who did not benefit from the combination therapy with losartan and tadalafil, particularly the patients with severe diabetic ED. It is necessary to search for novel medical therapies for these difficulties to treat patients in further study. This clinical trial had the limitation that there had been no truly placebo-controlled group in this study. We should design the multi-centre double-blind placebo-controlled clinical study in the future (Figures 2, 3, 4, 5).

Conclusions

This is the first clinical trial in losartan therapy on diabetic patients suffering from ED. Losartan seems to be effective and well-tolerated in diabetic-ED patients, especially for mild to moderate ones. The combination therapy of losartan and tadalafil appeared to be more effective than monotherapy.

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