madman
Super Moderator
Abstract
Erectile dysfunction (ED) is a long-term complication of type 2 diabetes (T2D) widely known to affect the quality of life. Several aspects of altered metabolism in individuals with T2D may help to compromise the penile vasculature structure and functions, thus exacerbating the imbalance between smooth muscle contractility and relaxation. Among these, advanced glycation end-products and reactive oxygen species derived from a hyperglycaemic state are known to accelerate endothelial dysfunction by lowering nitric oxide bioavailability, the essential stimulus of relaxation. Although several studies have explained the pathogenetic mechanisms involved in the generation of erectile failure, few studies to date have described the efficacy of glucose-lowering medications in the restoration of normal sexual activity. Herein, we will present current knowledge about the main starters of the pathophysiology of diabetic ED and explore the role of different anti-diabetes therapies in the potential remission of ED, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting.
1. Introduction
Erectile dysfunction (ED) is a commonly underestimated complication of diabetes mellitus that affects more than 50% of people with diabetes [1,2]. Diabetes dramatically raises the risk of developing ED by 2.5-fold. Additionally, ED represents an early sentinel of a cardiovascular event preceding a coronary event by at least three years [3], and thus warrants remarkable consideration by clinicians so as to prevent one of the main causes of death among subjects with type 2 diabetes (T2D) [4].
Several mechanisms related to the onset of diabetes may explain the high prevalence of ED among subjects with T2D. Hyperglycaemia and insulin resistance promote several biochemical derangements in the vascular and neurological systems, leading to an improper induction of erection. Moreover, obesity and visceral fat accumulation, typically observed in subjects with T2D, collectively represent one of the main risk factors for secondary hypogonadism [5]. Indeed, almost 40% of subjects with T2D are obese [6], and roughly 50% of these individuals have a hemoglobin A1c (HbA1c) concentration higher than 7% [7]. Therefore, the association of visceral obesity with the hyperglycaemic/dyslipidaemic milieu and the combination of low circulating testosterone levels and the development of endothelial dysfunction, macrovascular and microvascular disease, and diabetic neuropathy can significantly alter the fine mechanisms involved in regular erectile function.
Several hypoglycaemic agents are commonly prescribed to subjects with T2D to reduce HbA1c levels and, thus, the incidence and progression of diabetic complications. Therefore, a significant impact of these drugs on erectile function is to be expected. However, substantial differences in the mechanism of action, glucose-lowering efficacy, and effects on body weight and other cardiovascular risk factors of each drug may explain a potential variable impact on erectile function.
.
This review sought to report on the selective effects demonstrated by glucose-lowering medications on erectile function and explore the potential mechanisms involved.
2. Pathophysiology of ED
Erection results from nerve impulses that produce vascular and cavernosal smooth muscle relaxation, which leads to increased arterial inflow to the penile corpora cavernosa. This is predominantly mediated by nitric oxide (NO), which is mainly produced by parasympathetic noradrenergic and noncholinergic neurons and cholinergic neurons, which, in turn, stimulate endothelial cells. After the release of NO, vascular smooth muscle responds with a cyclic guanosine monophosphate (cGMP)-mediated dilatation of the corpora cavernosa, facilitating the supply of blood. Increasing the blood flow impedes venous return through passive compression of the subtunical venules, maintaining the erection. However, a lack of NO due to endothelial dysfunction triggers insufficient relaxation of the vascular smooth muscle of the corpora cavernosa, resulting in ED [8]. In this setting, several biological contributors are known to interfere with sexual performance, particularly in the context of metabolic illness (e.g., diabetes, obesity). We henceforth discuss current advances concerning the effects of endogenous mediators and related molecular mechanisms that affect erectile functionality and suggest potential therapeutic strategies that may restore metabolic control along with improved sexual function.
2.1. Hyperglycaemia
2.2. Hypogonadism
3. Glucose-Lowering Medications
3.1. Insulin
3.2. Sulfonylureas
3.3. Metformin
3.4. Acarbose (ACA)/α-Glucosidase Inhibitors
3.5. Thiazolidinediones
3.6. GLP-1RAs and DPP-4i
3.7. SGLT2is
4. Conclusions
To date, several glucose-lowering medications are available to treat subjects with T2D. Importantly, several experimental and clinical data have highlighted the ability of glucose-lowering drugs to improve endothelial dysfunction and preserve endothelial cell viability. In addition, since endothelial dysfunction represents a key event in the development of atherosclerosis, as well as of ED, the potential role of these agents in ED and the related molecular mechanisms are under investigation. Several lines of experimental evidence suggest the potential effects of specific glucose-lowering medications in the therapy of ED. Metformin, TZDs, and GLP-1RAs could represent the best choice to favor a partial recovery of normal erectile function in individuals with T2D (Table 1). Nevertheless, a multidrug intervention may potentially be associated with an additive effect, even though this has not yet been demonstrated. Further in vitro and in vivo studies, as well as high-quality clinical trials are still needed both to define the mechanisms of action of such drugs and to validate their use in the management of ED. Furthermore, another important aspect relates to the need to evaluate the pharmacological interactions between glucose-lowering agents and other drugs used in the treatment of sexual dysfunctions. The treatment or, more importantly, the prevention of this complication in individuals with T2D must become fundamental since it both represents an early predictor of cardiovascular complications and affects the quality of life of these patients.
Erectile dysfunction (ED) is a long-term complication of type 2 diabetes (T2D) widely known to affect the quality of life. Several aspects of altered metabolism in individuals with T2D may help to compromise the penile vasculature structure and functions, thus exacerbating the imbalance between smooth muscle contractility and relaxation. Among these, advanced glycation end-products and reactive oxygen species derived from a hyperglycaemic state are known to accelerate endothelial dysfunction by lowering nitric oxide bioavailability, the essential stimulus of relaxation. Although several studies have explained the pathogenetic mechanisms involved in the generation of erectile failure, few studies to date have described the efficacy of glucose-lowering medications in the restoration of normal sexual activity. Herein, we will present current knowledge about the main starters of the pathophysiology of diabetic ED and explore the role of different anti-diabetes therapies in the potential remission of ED, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting.
1. Introduction
Erectile dysfunction (ED) is a commonly underestimated complication of diabetes mellitus that affects more than 50% of people with diabetes [1,2]. Diabetes dramatically raises the risk of developing ED by 2.5-fold. Additionally, ED represents an early sentinel of a cardiovascular event preceding a coronary event by at least three years [3], and thus warrants remarkable consideration by clinicians so as to prevent one of the main causes of death among subjects with type 2 diabetes (T2D) [4].
Several mechanisms related to the onset of diabetes may explain the high prevalence of ED among subjects with T2D. Hyperglycaemia and insulin resistance promote several biochemical derangements in the vascular and neurological systems, leading to an improper induction of erection. Moreover, obesity and visceral fat accumulation, typically observed in subjects with T2D, collectively represent one of the main risk factors for secondary hypogonadism [5]. Indeed, almost 40% of subjects with T2D are obese [6], and roughly 50% of these individuals have a hemoglobin A1c (HbA1c) concentration higher than 7% [7]. Therefore, the association of visceral obesity with the hyperglycaemic/dyslipidaemic milieu and the combination of low circulating testosterone levels and the development of endothelial dysfunction, macrovascular and microvascular disease, and diabetic neuropathy can significantly alter the fine mechanisms involved in regular erectile function.
Several hypoglycaemic agents are commonly prescribed to subjects with T2D to reduce HbA1c levels and, thus, the incidence and progression of diabetic complications. Therefore, a significant impact of these drugs on erectile function is to be expected. However, substantial differences in the mechanism of action, glucose-lowering efficacy, and effects on body weight and other cardiovascular risk factors of each drug may explain a potential variable impact on erectile function.
.
This review sought to report on the selective effects demonstrated by glucose-lowering medications on erectile function and explore the potential mechanisms involved.
2. Pathophysiology of ED
Erection results from nerve impulses that produce vascular and cavernosal smooth muscle relaxation, which leads to increased arterial inflow to the penile corpora cavernosa. This is predominantly mediated by nitric oxide (NO), which is mainly produced by parasympathetic noradrenergic and noncholinergic neurons and cholinergic neurons, which, in turn, stimulate endothelial cells. After the release of NO, vascular smooth muscle responds with a cyclic guanosine monophosphate (cGMP)-mediated dilatation of the corpora cavernosa, facilitating the supply of blood. Increasing the blood flow impedes venous return through passive compression of the subtunical venules, maintaining the erection. However, a lack of NO due to endothelial dysfunction triggers insufficient relaxation of the vascular smooth muscle of the corpora cavernosa, resulting in ED [8]. In this setting, several biological contributors are known to interfere with sexual performance, particularly in the context of metabolic illness (e.g., diabetes, obesity). We henceforth discuss current advances concerning the effects of endogenous mediators and related molecular mechanisms that affect erectile functionality and suggest potential therapeutic strategies that may restore metabolic control along with improved sexual function.
2.1. Hyperglycaemia
2.2. Hypogonadism
3. Glucose-Lowering Medications
3.1. Insulin
3.2. Sulfonylureas
3.3. Metformin
3.4. Acarbose (ACA)/α-Glucosidase Inhibitors
3.5. Thiazolidinediones
3.6. GLP-1RAs and DPP-4i
3.7. SGLT2is
4. Conclusions
To date, several glucose-lowering medications are available to treat subjects with T2D. Importantly, several experimental and clinical data have highlighted the ability of glucose-lowering drugs to improve endothelial dysfunction and preserve endothelial cell viability. In addition, since endothelial dysfunction represents a key event in the development of atherosclerosis, as well as of ED, the potential role of these agents in ED and the related molecular mechanisms are under investigation. Several lines of experimental evidence suggest the potential effects of specific glucose-lowering medications in the therapy of ED. Metformin, TZDs, and GLP-1RAs could represent the best choice to favor a partial recovery of normal erectile function in individuals with T2D (Table 1). Nevertheless, a multidrug intervention may potentially be associated with an additive effect, even though this has not yet been demonstrated. Further in vitro and in vivo studies, as well as high-quality clinical trials are still needed both to define the mechanisms of action of such drugs and to validate their use in the management of ED. Furthermore, another important aspect relates to the need to evaluate the pharmacological interactions between glucose-lowering agents and other drugs used in the treatment of sexual dysfunctions. The treatment or, more importantly, the prevention of this complication in individuals with T2D must become fundamental since it both represents an early predictor of cardiovascular complications and affects the quality of life of these patients.
