madman
Super Moderator
ABSTRACT
Introduction. Erectile dysfunction (ED) is associated with diabetes mellitus with an estimated prevalence of 52.5% in the diabetic population. The first-line therapy for ED is phosphodiesterase type 5 inhibitors (PDE5i), but data suggest that diabetic men may be less responsive than non-diabetic men. Thus, other treatments, including intracavernosal injections, intraurethral prostaglandin, vacuum erection devices, and penile prosthetic surgery, should be considered in the management of diabetic men with ED refractory to PDE5i. Furthermore, combination therapy of PDE5i and other oral treatments such as arginine or L-carnitine may have synergistic effects resulting in better outcomes. In addition, there are novel therapies such as low-intensity shockwave therapy and stem cell therapy which may also be effectively targeted treatment modalities. Furthermore, studies suggest that ED can be improved by targeting concurrent comorbidities or metabolic diseases such as depression, hypertension, hypogonadism, and dyslipidemia. We present an evidence-based narrative review focusing on the management of ED in diabetic men who have not responded to PDE5i.
Conclusions Both clinicians and patients should be aware of the different management options for Diabetic patients who have responded to PDE5i.
INTRODUCTION
Erectile dysfunction (ED) has a prevalence of 52.5% in diabetic male patients, as described in a metanalysis of 145 studies, including 88 577 men with type 1 and Type 2 diabetes. 1 In the same metanalysis, a significant association was found between diabetes mellitus (type 1 and type 2 diabetes, n = 863) and the odds of having ED (OR 3.6, 95% CI, 2.5- 5.6, P < 0.0001) compared with healthy controls (n = 5385) 1. Furthermore, in the Massachusetts Male Aging Study, the age-adjusted probability of ED was 3 times greater in diabetic patients than in those without diabetes2.
The first-line therapy for ED in diabetes mellitus (DM) is PDE5 inhibitors (PDE5i). However, DM patients appear to be less responsive to these pharmacological agents compared to men without DM. This is supported in an in vitro study by Angulo et al. where relaxation of human corpus cavernosum strips from diabetic and non-diabetic patients with ED was compared and lower basal and stimulated levels of cGMP (cyclic guanosine-monophosphate) were found in strips of corpus cavernosum from men with DM3. Therefore, a patient-centered and tailored approach with an understanding of the pathophysiological mechanisms and the pharmacology of each therapy will optimize outcomes and patient satisfaction
*This narrative review is focused on the pathophysiology of ED in diabetic patients and the main treatment options in men who have not responded to PDE5i.
PATHOPHYSIOLOGY
In order to understand the optimal management of ED in diabetic men, one must appreciate the pathophysiological mechanisms of ED in men with DM and also the common comorbidities associated with ED and DM.
ED in DM patients can be caused by vascular, neuropathic, psychological, and endocrine factors. Moreover, ED and DM share common risk factors including metabolic syndrome, hypertension, cardiovascular disease, obesity, and depression (Figure 1)4-7
ATHEROSCLEROSIS
DM causes the accelerated formation of atherosclerotic plaques10,11 through endothelial dysfunction, inflammation, oxidative stress, and immune response11. Hence DM is associated with both peripheral vascular and cardiovascular disease. A number of studies have demonstrated impaired endothelial dysfunction in the corpora cavernosum of diabetic men and animals. Given that the arterial vasculature of the penis is much smaller than other vessels (such as coronary arteries) 12, ED often precedes cardiovascular disease and is recognized as a warning sign of occult cardiovascular disease13. Therefore, men presenting with ED should be screened for atherosclerotic risk factors (DM, HTN, High cholesterol) 14
NEUROPATHY
DM leads to decreased medicated smooth muscle relaxation of the corpus cavernosum, as a result of impaired NO (Nitric oxide) production15,16. This has clinical implications because severe neuropathy can affect PDE5i efficacy, which requires a minimum level of NO to function effectively17 and is likely to be one mechanism for a reduced response to PDE5i in diabetic compared to nondiabetic men3.
In addition to this, recent cohort studies showed the predictive capability of diabetic neuropathy in the development of ED. For example, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications Study (DCCT/EDIC) observed that patients with Type 1 DM with cardiovascular autonomic neuropathy had an OR of 2.65(95% CI 1.47-4.79) for developing erectile dysfunction and lower urinary tract symptoms18
MICROANGIOPATHY
DM can affect both corpus cavernosum relaxation and oxidative stress regulation. DM results in lower baseline Nitric oxide (NO) levels in the corpus cavernosum, irrespective of cGMP stimulation, and combined with impaired endothelium-dependent relaxation of the corpus cavernousum results in impaired smooth muscle relation 3.
The penile expression of VEGF (Vascular Endothelial Growth Factor) is diminished in diabetic models. For example, in rat models of type 2 diabetes, using immunohistochemistry and quantitative PCR, the protein and mRNA expression of penile VEGF was reduced compared to control animals; mRNA levels of VEGF were 58% less than levels in control animals19. Given that VEFG regulates endothelial cell proliferation, angiogenesis, and anti-apoptosis, this may be another mechanism for ED in DM19.
Data shows that chronic hyperglycemia can increase oxidative stress due to inflammation, elevated production of reactive oxygen species (ROS), hyperhomocysteinemia, and reduced cellular antioxidants. 20-23 Morano et al. demonstrated higher levels of oxidative activity in circulating monocytes of patients with DM and ED than in diabetic patients without ED (mean± standard error of mean oxidation index, 9.3±1.6 vs 4.8±0.5, p <0.03, respectively) 21.
COMMON DIABETIC COMORBIDITIES ASSOCIATED WITH ERECTILE DYSFUNCTION
*METABOLIC SYNDROME AND OBESITY
*DYSLIPIDAEMIA
*HYPOGONADISM
*HYPERTENSION
*DEPRESSION
FAILURE TO RESPOND TO PDE5i
A minimal or absent response to PDE5i is not an uncommon scenario in diabetic patients. Therefore, PDE5i needs to be taken appropriately to ensure optimal use, and physicians must consider all the factors modulating the drug's maximum effect (Table 1). McCullough et al. studied the impact of counseling on patient satisfaction with sildenafil use in 867 patients with ED. The authors reported that appropriate dose adjustment and tailored instructions increased patient satisfaction by 64%54. As a general recommendation, the patient should try PDE5i 6 to 8 times before declaring failure to PDE5i55.
Treatment modalities to treat erectile dysfunction
*OPTIMISATION OF COMORBIDITIES
*ANTIOXIDANT SUPPLEMENTATION
*INTRACAVERNOSAL INJECTION THERAPY
The penile injection of erectogenic agents was one of the first available pharmacological treatments for ED, and its early use was described in the 1980s with papaverine and phenoxybenzamine77. Nowadays, Intracavernosal injections (ICI) have remained a valuable treatment option in men not responding to PDE5i or where the side effects of PDE5i are not tolerated or contraindicated.
The available Intracavernosal Injections (ICI) formulations are prostaglandin E1 (PGE1) monotherapy, bimix (papaverine 30 mg/mL and phentolamine 1mg/mL), trimix (papaverine 30 mg/mL, phentolamine 1 mg/mL, and PGE1 10 µg/mL) or invicorp (aviptadil 25 µg and phentolamine mesilate 2mg). Although there are few studies specific to the diabetic population, Table 2 summarises the efficacy of these different treatment options.
*INTRAURETHRAL/TOPICAL ALPROSTADIL
Synthetic forms of PGE1 have been used as an intraurethral medical therapy for ED treatment and take advantage of the high absorption rate of the urethral mucosa (<10 minutes)83. PGE1 causes vasodilation of the erectile tissue and increases cavernosal artery blood flow, thereby facilitating penile erection83.
The maximum efficacy in terms of the Erection Assessment Score (EAS) is achieved with 1000 µg 84,85. However, meaningful clinical response (defined as complete rigid erections or sufficient for intercourse) is lower than in ICI, as demonstrated in multiple clinical trials86-88. A common adverse effect is penile pain (9 to 18%) without risk of priapism or plaque formation. Regarding discontinuation rates, a systematic review investigating the use and barriers of different ED treatments found a dropout rate from 32% to 70%.89
*VACUUM ERECTION DEVICES
Vacuum erection devices (VED) increase blood flow into the penile corpora through a soft constriction ring around the penile base generating negative pressure. There are manual or electrical pumps available commercially, and lubricant is applied to enhance sealing.
*PENILE PROSTHESIS
The insertion of a penile prosthesis (IPP) represents an end-stage treatment of ED in diabetic patients as a PP is reserved for refractory cases to ICI or VED, given the potential risks, complications, and irreversibility of the procedure. Comprehensive patient counseling is recommended to ensure appropriate expectations97.
Both malleable and inflatable prostheses are suitable alternatives for diabetic patients. However, choosing between these options depends on other factors such as the history of retropubic surgeries, pelvic radiotherapy, or manual dexterity.
NOVEL TREATMENTS
*STEM CELL THERAPY
Stem cells are undifferentiated cells that can differentiate into several cell lineages and are classified depending on their origin and potency. Stems cells have multiple characteristics that could improve ED in diabetic patients, such as differentiation in multiple cell lines, self-regeneration, and multiplying capability102. Most of the evidence on stem cells regarding ED is based on animal models of diabetic erectile dysfunction where there were improvements in functional and structural changes103.
*The limitation to contemporary data is the lack of randomized, controlled trials and the small number of existing studies105,107,108. Therefore, until more high-level evidence is available, stem cell therapy in ED should be considered experimental and should only be recommended in clinical trials.
LOW-INTENSITY EXTRACORPOREAL
*SHOCK WAVE THERAPY
Low-intensity extracorporeal shock wave therapy (LI-ESWT) delivers low-intensity acoustic energy to the penile corpora resulting in neovascularisation of the erectile tissue, which theoretically should enhance and restore erectile function109,110. A meta-analysis including 7 RCT reported an increase in the IIEEF-EF score in men with ED who had LI-ESWT compared to sham groups (MD: 2.54; 95% CI, 0.83-4.25; p= 0.004) 111. A limitation to the current literature is the lack of consensus regarding the ideal LI-ESWT protocol. However, better outcomes have been reported if more than >18000 total shock waves, 6 weeks length course duration, and a low density of energy111.
LIMITATIONS TO CURRENT LITERATURE AND NEED FOR FUTURE WORK
In summary, the level of evidence of different treatments for treating ED in diabetic men is limited, despite DM being one of the most common comorbidities associated with ED. Therefore, there is a need for further randomized controlled trials investigating the utility of vacuum erection devices, Intracavernosal injections, intraurethral alprostadil, and shockwave therapy in diabetic patients.
However, the current evidence supports the options discussed in this review as clinically safe and comparatively effective in this population. In addition, emerging options such as LI-SWT have promising results in this population. However, stem cell therapy is still not ready for clinical utility and should not be offered outside clinical trials. Therefore, more robust evidence and standardized protocols are needed before its implementation
DISCUSSION
Despite the current limitations in contemporary literature, there is still data to support the use of several therapies individually or combined with PDE5i in men who have not responded to PDE5i alone.
*The authors recommend the following treatment algorithm for the management of ED in men with DM refractory to PDE5i (Figure two).
CONCLUSION
The quality of the evidence is heterogeneous for diabetic patients not responding to PDE5i. The management of all DM with ED should be holistic and patient-centered with consideration of optimization of concurrent comorbidities. In those who have not responded to PDE5i, several treatment options can be trialed as an adjunct or alternative therapy to PDE5i. Whilst the use of stem cell therapy and low-intensity shockwave therapy is emerging, randomized controlled trials are required prior to their routine use in clinical practice.
Introduction. Erectile dysfunction (ED) is associated with diabetes mellitus with an estimated prevalence of 52.5% in the diabetic population. The first-line therapy for ED is phosphodiesterase type 5 inhibitors (PDE5i), but data suggest that diabetic men may be less responsive than non-diabetic men. Thus, other treatments, including intracavernosal injections, intraurethral prostaglandin, vacuum erection devices, and penile prosthetic surgery, should be considered in the management of diabetic men with ED refractory to PDE5i. Furthermore, combination therapy of PDE5i and other oral treatments such as arginine or L-carnitine may have synergistic effects resulting in better outcomes. In addition, there are novel therapies such as low-intensity shockwave therapy and stem cell therapy which may also be effectively targeted treatment modalities. Furthermore, studies suggest that ED can be improved by targeting concurrent comorbidities or metabolic diseases such as depression, hypertension, hypogonadism, and dyslipidemia. We present an evidence-based narrative review focusing on the management of ED in diabetic men who have not responded to PDE5i.
Conclusions Both clinicians and patients should be aware of the different management options for Diabetic patients who have responded to PDE5i.
INTRODUCTION
Erectile dysfunction (ED) has a prevalence of 52.5% in diabetic male patients, as described in a metanalysis of 145 studies, including 88 577 men with type 1 and Type 2 diabetes. 1 In the same metanalysis, a significant association was found between diabetes mellitus (type 1 and type 2 diabetes, n = 863) and the odds of having ED (OR 3.6, 95% CI, 2.5- 5.6, P < 0.0001) compared with healthy controls (n = 5385) 1. Furthermore, in the Massachusetts Male Aging Study, the age-adjusted probability of ED was 3 times greater in diabetic patients than in those without diabetes2.
The first-line therapy for ED in diabetes mellitus (DM) is PDE5 inhibitors (PDE5i). However, DM patients appear to be less responsive to these pharmacological agents compared to men without DM. This is supported in an in vitro study by Angulo et al. where relaxation of human corpus cavernosum strips from diabetic and non-diabetic patients with ED was compared and lower basal and stimulated levels of cGMP (cyclic guanosine-monophosphate) were found in strips of corpus cavernosum from men with DM3. Therefore, a patient-centered and tailored approach with an understanding of the pathophysiological mechanisms and the pharmacology of each therapy will optimize outcomes and patient satisfaction
*This narrative review is focused on the pathophysiology of ED in diabetic patients and the main treatment options in men who have not responded to PDE5i.
PATHOPHYSIOLOGY
In order to understand the optimal management of ED in diabetic men, one must appreciate the pathophysiological mechanisms of ED in men with DM and also the common comorbidities associated with ED and DM.
ED in DM patients can be caused by vascular, neuropathic, psychological, and endocrine factors. Moreover, ED and DM share common risk factors including metabolic syndrome, hypertension, cardiovascular disease, obesity, and depression (Figure 1)4-7
ATHEROSCLEROSIS
DM causes the accelerated formation of atherosclerotic plaques10,11 through endothelial dysfunction, inflammation, oxidative stress, and immune response11. Hence DM is associated with both peripheral vascular and cardiovascular disease. A number of studies have demonstrated impaired endothelial dysfunction in the corpora cavernosum of diabetic men and animals. Given that the arterial vasculature of the penis is much smaller than other vessels (such as coronary arteries) 12, ED often precedes cardiovascular disease and is recognized as a warning sign of occult cardiovascular disease13. Therefore, men presenting with ED should be screened for atherosclerotic risk factors (DM, HTN, High cholesterol) 14
NEUROPATHY
DM leads to decreased medicated smooth muscle relaxation of the corpus cavernosum, as a result of impaired NO (Nitric oxide) production15,16. This has clinical implications because severe neuropathy can affect PDE5i efficacy, which requires a minimum level of NO to function effectively17 and is likely to be one mechanism for a reduced response to PDE5i in diabetic compared to nondiabetic men3.
In addition to this, recent cohort studies showed the predictive capability of diabetic neuropathy in the development of ED. For example, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications Study (DCCT/EDIC) observed that patients with Type 1 DM with cardiovascular autonomic neuropathy had an OR of 2.65(95% CI 1.47-4.79) for developing erectile dysfunction and lower urinary tract symptoms18
MICROANGIOPATHY
DM can affect both corpus cavernosum relaxation and oxidative stress regulation. DM results in lower baseline Nitric oxide (NO) levels in the corpus cavernosum, irrespective of cGMP stimulation, and combined with impaired endothelium-dependent relaxation of the corpus cavernousum results in impaired smooth muscle relation 3.
The penile expression of VEGF (Vascular Endothelial Growth Factor) is diminished in diabetic models. For example, in rat models of type 2 diabetes, using immunohistochemistry and quantitative PCR, the protein and mRNA expression of penile VEGF was reduced compared to control animals; mRNA levels of VEGF were 58% less than levels in control animals19. Given that VEFG regulates endothelial cell proliferation, angiogenesis, and anti-apoptosis, this may be another mechanism for ED in DM19.
Data shows that chronic hyperglycemia can increase oxidative stress due to inflammation, elevated production of reactive oxygen species (ROS), hyperhomocysteinemia, and reduced cellular antioxidants. 20-23 Morano et al. demonstrated higher levels of oxidative activity in circulating monocytes of patients with DM and ED than in diabetic patients without ED (mean± standard error of mean oxidation index, 9.3±1.6 vs 4.8±0.5, p <0.03, respectively) 21.
COMMON DIABETIC COMORBIDITIES ASSOCIATED WITH ERECTILE DYSFUNCTION
*METABOLIC SYNDROME AND OBESITY
*DYSLIPIDAEMIA
*HYPOGONADISM
*HYPERTENSION
*DEPRESSION
FAILURE TO RESPOND TO PDE5i
A minimal or absent response to PDE5i is not an uncommon scenario in diabetic patients. Therefore, PDE5i needs to be taken appropriately to ensure optimal use, and physicians must consider all the factors modulating the drug's maximum effect (Table 1). McCullough et al. studied the impact of counseling on patient satisfaction with sildenafil use in 867 patients with ED. The authors reported that appropriate dose adjustment and tailored instructions increased patient satisfaction by 64%54. As a general recommendation, the patient should try PDE5i 6 to 8 times before declaring failure to PDE5i55.
Treatment modalities to treat erectile dysfunction
*OPTIMISATION OF COMORBIDITIES
*ANTIOXIDANT SUPPLEMENTATION
*INTRACAVERNOSAL INJECTION THERAPY
The penile injection of erectogenic agents was one of the first available pharmacological treatments for ED, and its early use was described in the 1980s with papaverine and phenoxybenzamine77. Nowadays, Intracavernosal injections (ICI) have remained a valuable treatment option in men not responding to PDE5i or where the side effects of PDE5i are not tolerated or contraindicated.
The available Intracavernosal Injections (ICI) formulations are prostaglandin E1 (PGE1) monotherapy, bimix (papaverine 30 mg/mL and phentolamine 1mg/mL), trimix (papaverine 30 mg/mL, phentolamine 1 mg/mL, and PGE1 10 µg/mL) or invicorp (aviptadil 25 µg and phentolamine mesilate 2mg). Although there are few studies specific to the diabetic population, Table 2 summarises the efficacy of these different treatment options.
*INTRAURETHRAL/TOPICAL ALPROSTADIL
Synthetic forms of PGE1 have been used as an intraurethral medical therapy for ED treatment and take advantage of the high absorption rate of the urethral mucosa (<10 minutes)83. PGE1 causes vasodilation of the erectile tissue and increases cavernosal artery blood flow, thereby facilitating penile erection83.
The maximum efficacy in terms of the Erection Assessment Score (EAS) is achieved with 1000 µg 84,85. However, meaningful clinical response (defined as complete rigid erections or sufficient for intercourse) is lower than in ICI, as demonstrated in multiple clinical trials86-88. A common adverse effect is penile pain (9 to 18%) without risk of priapism or plaque formation. Regarding discontinuation rates, a systematic review investigating the use and barriers of different ED treatments found a dropout rate from 32% to 70%.89
*VACUUM ERECTION DEVICES
Vacuum erection devices (VED) increase blood flow into the penile corpora through a soft constriction ring around the penile base generating negative pressure. There are manual or electrical pumps available commercially, and lubricant is applied to enhance sealing.
*PENILE PROSTHESIS
The insertion of a penile prosthesis (IPP) represents an end-stage treatment of ED in diabetic patients as a PP is reserved for refractory cases to ICI or VED, given the potential risks, complications, and irreversibility of the procedure. Comprehensive patient counseling is recommended to ensure appropriate expectations97.
Both malleable and inflatable prostheses are suitable alternatives for diabetic patients. However, choosing between these options depends on other factors such as the history of retropubic surgeries, pelvic radiotherapy, or manual dexterity.
NOVEL TREATMENTS
*STEM CELL THERAPY
Stem cells are undifferentiated cells that can differentiate into several cell lineages and are classified depending on their origin and potency. Stems cells have multiple characteristics that could improve ED in diabetic patients, such as differentiation in multiple cell lines, self-regeneration, and multiplying capability102. Most of the evidence on stem cells regarding ED is based on animal models of diabetic erectile dysfunction where there were improvements in functional and structural changes103.
*The limitation to contemporary data is the lack of randomized, controlled trials and the small number of existing studies105,107,108. Therefore, until more high-level evidence is available, stem cell therapy in ED should be considered experimental and should only be recommended in clinical trials.
LOW-INTENSITY EXTRACORPOREAL
*SHOCK WAVE THERAPY
Low-intensity extracorporeal shock wave therapy (LI-ESWT) delivers low-intensity acoustic energy to the penile corpora resulting in neovascularisation of the erectile tissue, which theoretically should enhance and restore erectile function109,110. A meta-analysis including 7 RCT reported an increase in the IIEEF-EF score in men with ED who had LI-ESWT compared to sham groups (MD: 2.54; 95% CI, 0.83-4.25; p= 0.004) 111. A limitation to the current literature is the lack of consensus regarding the ideal LI-ESWT protocol. However, better outcomes have been reported if more than >18000 total shock waves, 6 weeks length course duration, and a low density of energy111.
LIMITATIONS TO CURRENT LITERATURE AND NEED FOR FUTURE WORK
In summary, the level of evidence of different treatments for treating ED in diabetic men is limited, despite DM being one of the most common comorbidities associated with ED. Therefore, there is a need for further randomized controlled trials investigating the utility of vacuum erection devices, Intracavernosal injections, intraurethral alprostadil, and shockwave therapy in diabetic patients.
However, the current evidence supports the options discussed in this review as clinically safe and comparatively effective in this population. In addition, emerging options such as LI-SWT have promising results in this population. However, stem cell therapy is still not ready for clinical utility and should not be offered outside clinical trials. Therefore, more robust evidence and standardized protocols are needed before its implementation
DISCUSSION
Despite the current limitations in contemporary literature, there is still data to support the use of several therapies individually or combined with PDE5i in men who have not responded to PDE5i alone.
*The authors recommend the following treatment algorithm for the management of ED in men with DM refractory to PDE5i (Figure two).
CONCLUSION
The quality of the evidence is heterogeneous for diabetic patients not responding to PDE5i. The management of all DM with ED should be holistic and patient-centered with consideration of optimization of concurrent comorbidities. In those who have not responded to PDE5i, several treatment options can be trialed as an adjunct or alternative therapy to PDE5i. Whilst the use of stem cell therapy and low-intensity shockwave therapy is emerging, randomized controlled trials are required prior to their routine use in clinical practice.
