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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 2
| Issue : 2 | Page : 53-57 |
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Statins versus PDE-5 inhibitors: A comparative study in controlled diabetes mellitus patients with erectile dysfunction
Pradeep Chakaravarthy1, Bharat Vadlamani1, Ravi Kant2, Udit Chauhan3, Meenakshi Kapre4, Ankur Mittal5
1 Department of Internal Medicine, All India Institute of Medical Sciences Rishikesh, Rishikesh, Uttarakhand, India
2 Division of Diabetology & Metabolism, Department of Internal Medicine, All India Institute of Medical Sciences Rishikesh, Rishikesh, Uttarakhand, India
3 Department of Radiology, All India Institute of Medical Sciences Rishikesh, Rishikesh, Uttarakhand, India
4 Department Community & Family Medicine, All India Institute of Medical Sciences Rishikesh, Rishikesh, Uttarakhand, India
5 Department of Urology, All India Institute of Medical Sciences Rishikesh, Rishikesh, Uttarakhand, India
| Date of Submission | 31-May-2023 |
| Date of Acceptance | 24-Jun-2023 |
| Date of Web Publication | 25-Aug-2023 |
Correspondence Address:
Ravi Kant
Level 6, Academic Block, All India Institute Of Medical Sciences, Rishikesh, Virbhadra Marg, Uttarakhand 249203
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/JCDM.JCDM_5_22
Background: Atherosclerosis of penile vasculature and endothelial dysfunction are the main causes of erectile dysfunction (ED) in diabetes. Phosphodiesterase type 5 inhibitors (PDE5i) have been playing a significant role in the management of ED for around 40 years. As there are many promising studies about the effect of statins on endothelial dysfunction and symptomatic improvement in ED, we did this study to compare the effect of statins with PDE-5i. Aim: To study and compare the effect of statins and PDE-5i in ED patients with controlled diabetes mellitus. Materials and Methods: A randomized open-label parallel noninferiority institutional and comparative study was conducted in the Department of Internal Medicine, All India Institute of Medical Sciences Rishikesh, over a period of 12 months. Clinical and objective assessment of ED was based on the International Index of Erectile Function (IIEF)-5 questionnaire and peak systolic velocity (PSV) using Doppler, respectively. The study population was divided into two groups, of which one received atorvastatin 40 mg once daily at night time and the other group received sildenafil 100 mg once daily at night time. Baseline penile Doppler before therapy and 4 weeks after therapy was done. The effects of atorvastatin and sildenafil were compared with P value and statistical values. Outcomes and Results: A total of 79 patients were enrolled, of which 19 patients were excluded from the study due to their unwillingness. Quantitative variables were compared using Independent t test/Mann–Whitney test between the two groups and Wilcoxon signed-rank test was used for comparison between preintervention and postintervention groups. Qualitative variables were correlated using Chi-square test/Fisher’s exact test. The mean preintervention PSV in the atorvastatin group was 8.94 cm/s with a standard deviation of 8.15 cm/s, and the mean preintervention PSV in the sildenafil group was 10.04 cm/s with a standard deviation of 9.21 cm/s with a P value of 0.537 and 95% confidence interval (CI). The mean postintervention PSV in the atorvastatin group was 9.15 cm/s with a standard deviation of 8.22 cm/s, and the mean postintervention PSV in the sildenafil group was 10.67 cm/s with a standard deviation of 9.28 cm/s with a P value of 0.327 and 95% CI. Conclusions: Sildenafil has already been recognized as efficacious in ED and has been in use for almost 4 decades. In our study, we compared the effect of sildenafil and atorvastatin among diabetic patients between 40 and 70 years of age. Sildenafil has already shown significant subjective benefits to patients, as assessed through questionnaires. However, it did not reach a statistically significant value (PSV) within a one-month period. Nonetheless, when compared with statins, PDE5 inhibitors (PDE5i) demonstrated a positive subjective and objective response, as observed by the mean PSV difference between the two groups. Statins on the other hand have recently been studied for its pleiotropic effects on vascular smooth muscle. The role of statins is comparatively not up to the mark for PDE5i. Hence, we conclude this study with the finding that neither statins nor PDE5 inhibitors (PDE5i) demonstrated a significant increase in PSV at the end of the one-month period. Furthermore, it is evident that additional future studies and data collection are necessary to investigate the long-term effects of these treatments, as well as the combined effects of statins and PDE5i. Additionally, further research is needed to explore novel drugs and therapies for the treatment of erectile dysfunction (ED). Keywords: IIEF-5, penile Doppler ultrasonography, randomized control trial, sildenafil, statins
How to cite this article:
Chakaravarthy P, Vadlamani B, Kant R, Chauhan U, Kapre M, Mittal A. Statins versus PDE-5 inhibitors: A comparative study in controlled diabetes mellitus patients with erectile dysfunction. J Cardio Diabetes Metab Disord 2022;2:53-7 |
How to cite this URL:
Chakaravarthy P, Vadlamani B, Kant R, Chauhan U, Kapre M, Mittal A. Statins versus PDE-5 inhibitors: A comparative study in controlled diabetes mellitus patients with erectile dysfunction. J Cardio Diabetes Metab Disord [serial online] 2022 [cited 2023 Sep 22];2:53-7. Available from: http://www.cardiodiabetic.org/text.asp?2022/2/2/53/384339 |
| Introduction | |  |
Erectile dysfunction (ED) is defined as persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual intercourse and as a score of less than 22 on the five-item version of the International Index of Erectile Function (IIEF-5).[1] The etiology of ED can be vascular, neurogenic, hormonal, or psychological factors, or can be drug-induced.[1],[2] Of these, vascular insufficiency is the most common underlying pathology, mirroring the atherosclerotic process,[3] which forms the close link between dyslipidemia and ED, with endothelial dysfunction as a common mechanism.[3] Both ED and dyslipidemias are rising in prevalence. Men with diabetes tend to develop ED 10–15 years earlier than those without diabetes.[2]
The introduction of phosphodiesterase type 5 inhibitors (PDE5i) had immense medical help for erectile function problems but has also altered dramatically the medical management of pulmonary hypertension.[4] More clinicians are treating ED, especially in the primary care setting, with minimal patient work-up and prescription of PDE5i due to their proven efficacy and safety profile. Sildenafil, the first available PDE5i, revolutionized ED treatment in more than 30 million men and had vast experience and research with more than 2600 papers published in Medline as of July 2006.[3] It then has been recently approved for the treatment of idiopathic pulmonary hypertension, and numerous articles have proved that PDE5i may improve endothelial function.
The hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (statins) had significant low-density lipoprotein lowering effects and many pleiotropic effects such as direct effects on vascular tissue, kidney, bone, and glucose metabolism.[5],[6] In fact, statins were being studied in pulmonary arterial hypertension patients for their pleiotropic effects expressed by inhibiting Rho signaling pathways.[4] The protective effect of statins on diabetic vascular disease may be due to the suppression of Rho kinase cascades, resulting in increased nitric oxide (NO) production and decreased vascular tone.
Phases of penile erection are as follows:
- Phase Ia: damped systolic flow and no diastolic flow,
- Phase Ib: abrupt increase in both systolic and diastolic flow,
- Phase II: decrease in diastolic flow with a dicrotic notch,
- Phase III: diastolic flow decreases to zero and may reverse.[7]
The IIEF, a 10-item questionnaire, has been developed and validated as a brief and reliable self-administered scale for assessing erectile function.[8]
Aims and objectives
The study aimed to study and compare the effect of statins and PDE-5i in ED patients with controlled diabetes mellitus.
Primary objectives
- Assessment of PSV values and IIEF-5 questionnaire and their correlation in both atorvastatin and sildenafil groups before and after medication.
- Comparison of the change in peak systolic velocity (PSV) in both atorvastatin and sildenafil groups and their statistical relevance.
Secondary objectives
- To compare and contrast any significant effects of statins on ED with sildenafil.
- To find whether a 1-month duration of atorvastatin is significant.
Eligibility criteria
The inclusion criteria are as follows: men aged 18–60 years, controlled diabetes mellitus, and untreated ED (score <22 on the IIEF-5).
The exclusion criteria are as follows: chronic liver disease and/or abnormal liver function test (alanine aminotransferase >3 times upper normal limit [UNL]); severe renal disease or evidence deranged serum creatinine (>2 mg/dL); myositis or evidence of any muscle problems (creatine kinase >3 times UNL); patients taking drugs associated with increased risk of myopathy/rhabdomyolysis: cyclosporine, danazol, and fusidic acid; uncontrolled diabetes mellitus; androgen insufficiency; and contraindications to PDE-5 therapy.
| Materials and Methods | | |
The study was conducted in the Department of Internal Medicine, All India Institute of Medical Sciences Rishikesh, over a period of 12 months. Subjects were recruited from medicine outpatient department (OPD), urology OPD with a primary diagnosis of ED with diabetes mellitus and after obtaining informed and written consent. Ethical clearance for study obtained vide infra AIIMS/IEC/18/106.
Study protocol
The assessment of ED was based on the IIEF-5 questionnaire study.
Study population was divided into two groups. Group A with controlled diabetes with ED was given atorvastatin 40 mg once daily at night time and Group B with controlled diabetes with ED was kept as control and was given sildenafil 100 mg once daily at night time. Baseline penile Doppler ultrasonography before intervention was done, subjects with a cutoff value of PSV of 25 cm/s or lesser were included in the study, and postintervention penile ultrasonography 4 weeks after the intervention was done by a trained radiologist.
This study was a randomized controlled, open-label, non-inferiority, parallel institutional study conducted from July 2018 to June 2019.
Eligibility criteria for participants are as follows: all males aged 18–60 years with diabetes mellitus and ED after fulfilling inclusion criteria.
The interventions were as follows: After optimizing diabetes with appropriate medications, Group A received 40mg of atorvastatin once daily for a period of 4 weeks. Control Group B received 100mg of sildenafil once daily for a period of 4 weeks.
The primary outcome was an improvement in ED, assessed by postintervention penile Doppler ultrasonography and defined as >2 standard deviation (SD) or 3 cm/s increment in PSV.
| Results | | |
Categorical variables were presented in number and percentage (%), and continuous variables were presented as mean ± SD and median [Table 1]. The patients were matched for age, FBS, PPBS, HbA1c. The normality of data was tested by Kolmogorov–Smirnov test. If the normality was rejected, then nonparametric tests were used. Quantitative variables were compared using the Independent t test/Mann–Whitney test (when the datasets were not normally distributed) between the two groups, and Wilcoxon signed-rank test was used for comparison between preintervention and postintervention groups. Qualitative variables were correlated using Chi-square test/Fisher’s exact test.
| Discussion | | |
In 1994, Feldman et al.[9] reported the findings of the Massachusetts Male Aging Study (MMAS), which evaluated impotence and its medical and psychosocial correlates among men aged 40–70 years. Using the MMAS instrument scale, there was a combined prevalence of minimal, moderate, and complete ED of 52%.[10] In our study, all patients were diabetics, and the majority of patients with ED were in the age group between 40 and 60 years.
In the meta-analysis conducted by Seftel et al.,[11] 48.4% had a diagnosis of organic ED; 17.4% had nonorganic ED; and 38.8% were not specifically diagnosed but had received therapy for ED. Patients with ED had at least one of four of the following comorbidities: hypertension (41.6%), hyperlipidemia (42.4%), diabetes mellitus (20.2%), and depression (11.1%).[10],[12]
In our study, all patients enrolled were diabetics having ED as assessed objectively by the IIEF-5 questionnaire. The mean age in the atorvastatin group was 43.83 years and in the sildenafil group was 46.93 years [Table 2]. The proportion of patients having hypertension and dyslipidemia are as shown in [Table 3] and [Table 4]. The mean IIEF-5 score in the atorvastatin group was 12.71 and in the sildenafil group was 13.93.
In the study of Wassmann et al., beneficial effects of intensive statin therapy on endothelial function occur as soon as 3 days after treatment and are independent of lipid levels suggesting a role for the nonlipid-lowering pleiotropic effects of statins.[13] Although higher doses of sildenafil may improve efficacy, doses greater than 100 mg are not approved and may be limited by side effects.[13] For these reasons, we chose atorvastatin, and the duration of treatment was kept as minimum as 1 month to investigate and prove the pleiotropic effects of atorvastatin on the endothelium. For the control group, sildenafil 100 mg once daily is used.
In our study, neither sildenafil nor atorvastatin showed significant improvement that is statistically defined as >2 SD or >3 cm/s increment in PSV [Figure 1]. Still in our study, statins had a minimal role in ED revealed by a mild reduction in PSV and IIEF-5 questionnaire, which was not up to the significant level. There are not many studies about the combined effect of statins and PDE5i except one study conducted on animals (rats) by Zhao et al.,[4] which revealed that a combination of sildenafil and simvastatin lowered pulmonary artery pressure and produced a significantly greater reduction in the right ventricular hypertrophy and pulmonary arterial hypertension than either drug alone. Moreover, the combination augmented significantly endothelial NO synthase expression and cyclic guanosine monophosphate levels in the lung and right ventricle above that produced by either drug independently and resulted in greater inhibition of RhoA activity. | Figure 1: Graphical representation of change in PSV among subjects in both groups. PSV = peak systolic velocity
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| Conclusion | | |
Sildenafil has already been recognized as efficacious in ED and has been in use for almost 4 decades. In our study, we compared the effect of sildenafil and atorvastatin among diabetic patients between 40 and 70 years of age. Sildenafil has already established significant benefits to the patients subjectively, which was assessed with questionnaire; here, it does not meet a statistically significant value (PSV) in 1 month. However, when compared with statins, PDE5i is having good response subjectively and objectively observed by the mean PSV difference between two groups, respectively. Statins on the other hand have recently been studied for its pleiotropic effects on vascular smooth muscle. The role of statins is comparatively not up to the mark for PDE5i. Hence, we conclude this study with the fact of neither statins nor PDE5i established a significant increase in PSV at the end of 1 month, and we need many more future studies and data collection on long-term effects, combined effect of statins and PDE5i, and novel drugs and therapies for the treatment of ED.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Park JK, Park JS, Jeon SB, Cui WS, Kim SZ, Kang KK, et al. Why a combined intracavernosal injection with trimix and oral sildenafil is reliable therapy in the ultrasonographic evaluation of erectile dysfunction. BJU Int 2008;102:993-7.  |
| 2. | Bocchio M, Scarpelli P, Necozione S, Pelliccione F, Spartera C, Francavilla F, et al. Penile duplex pharmaco-ultrasonography of cavernous arteries in men with erectile dysfunction and generalized atherosclerosis. Int J Androl 2006;29:496-501. |
| 3. | Shamloul R, Ghanem H Erectile dysfunction. Lancet 2013;381:153-65. |
| 4. | Zhao L, Sebkhi A, Ali O, Wojciak-Stothard B, Mamanova L, Yang Q, et al. Simvastatin and sildenafil combine to attenuate pulmonary hypertension. Eur Respir J 2009;34:948-57. |
| 5. | McFarlane SI, Muniyappa R, Francisco R, Sowers JR Clinical review 145: Pleiotropic effects of statins: Lipid reduction and beyond. J Clin Endocrinol Metab 2002;87:1451-8. |
| 6. | Wassmann S, Faul A, Hennen B, Scheller B, Böhm M, Nickenig G Rapid effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition on coronary endothelial function. Circ Res 2003;93:e98-103. |
| 7. | Fitzgerald SW, Erickson SJ, Foley WD, Lipchik EO, Lawson TL Color Doppler sonography in the evaluation of erectile dysfunction. Radiographics 1992;12:3-17; discussion 18. |
| 8. | Maiorino MI, Ida M, Bellastella G, Esposito K Diabetes and sexual dysfunction: Current perspectives. Diabetes Metab Syndr Obes 2014;7:95-105. |
| 9. | Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J Urol 1994;151:54-61. |
| 10. | Miner M, Billups KL Erectile dysfunction and dyslipidemia: Relevance and role of phosphodiesterase type-5 inhibitors and statins. J Sex Med 2008;5:1066-78. |
| 11. | Seftel AD, Sun P, Swindle R The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction. J Urol 2004;171:2341-5. |
| 12. | Nikoobakht M, Nasseh H, Pourkasmaee M The relationship between lipid profile and erectile dysfunction. Int J Impot Res 2005;17:523-6. |
| 13. | Herrmann HC, Levine LA, Macaluso J Jr, Walsh M, Bradbury D, Schwartz S, et al.Can atorvastatin improve the response to sildenafil in men with erectile dysfunction not initially responsive to sildenafil? Hypothesis and pilot trial results. J Sex Med 2006;3:303-8. |
[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4]
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