Effects of diet and antihyperglycemic drugs on erectile dysfunction: A systematic review

Abstract Background Erectile dysfunction is recognized as one of the complications of diabetes mellitus. To date, a wide gap of knowledge is present on the efficacy of pharmacological treatments of diabetes mellitus on erectile function, acting not only through metabolic control. Similarly, the effects of different diet regimens on erectile dysfunction are still debated. Objectives We aimed to explore the effects of diet and antihyperglycemic drugs, considering both old and novel therapeutic approaches, on erectile function. Materials/methods We performed a systematic review, following the PRISMA guidelines. The research was conducted on studies reporting erectile dysfunction assessment in subjects with diabetes and the relationship with diet and antihyperglycemic drugs. Results The Mediterranean diet was effective in most studies for the protection of erectile function. Furthermore, antihyperglycemic drugs seem to show an overall protective role on erectile function. Discussion/conclusion Although encouraging results are present for all classes of antihyperglycemic drugs, several studies are needed in humans, mainly on acarbose, pioglitazone, dipeptidyl‐peptidase‐4 inhibitors, and sodium‐glucose cotransporter‐2 inhibitors.

F I G U R E 1 PRISMA guidelines insulin resistance, 14 play an important role in the pathogenesis of ED. [14][15][16] DM is one of the most common chronic diseases due to impaired carbohydrate metabolism. Alongside insulin therapy, which is the gold standard in T1DM patients, or educational therapy for all subjects with DM, 17 new antihyperglycemic drugs have been introduced in recent decades for the treatment of DM. 18 Therefore, along with diet, metformin, sulfonylureas, glinides, and thiazolinediones (TZD), the following drugs are now widely used for the management of DM: dipeptidyl-peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. 18 To date, some studies evaluated the effects of DM management on sexual dysfunction in males and females, 19,20 but the data are still limited on ED.
The aim of this work was to systematically review the effect of diet and antihyperglycemic drugs, both considering old and new therapeutic approaches, on ED.

MATERIALS AND METHODS
We followed the PRISMA guidelines in this systematic review ( Figure 1).

Article identification
We searched the PubMed, Science Direct, and Google Scholar databases for studies reporting ED assessment in diabetic patients and the relationship with diet and antihyperglycemic drugs up to February 20, 2022.
The inclusion criteria were: (1) articles reporting data on the effect of diet on ED; (2) articles reporting data on the effect of antihyperglycemic drugs on ED; (3) studies on humans. The exclusion criteria were: (1) non-English-language articles; (2) non-human studies.
Studies on animal were only considered to describe the possible effect of drugs on erectile function (EF).

Diet
Dietary habits may have a beneficial or detrimental impact on EF through several mechanisms. The most investigated and solid benefits derived from a healthy diet are antioxidant and anti-inflammatory mechanisms.
Diets rich in plant foods, and the Mediterranean diet in particular, are characterized by significant intake of polyphenols, which are capable of increasing nitric oxide (NO) availability. 21 An increase in endothelial progenitor cells could also be involved. 22 NO availability may also be increased by fish-derived omega-3 fatty acids, possibly another mechanism mediating improved EF by the Mediterranean diet. 23 Moreover, plant-based diets are rich in antioxidants, exerting protective roles against reactive oxygen species (ROS). 24 The microbiome may also play a role: a healthy microbiome in fact leads to reduced inflammation, gut permeability, and overall to metabolic improvement, with expected amelioration of ED symptoms. 25 (Table 1). Overall, a higher intake of fruits and/or vegetables was associated with lower odds of having or developing ED in most, [34][35][36][37][38] but not all studies. 39,40 Interestingly, a study conducted by Chen et al. 41 reported that a higher intake of vegetables was also associated to worse ED. These findings could be explained by the high use of pesti-

Metformin
Metformin is an oral biguanide and the first-line therapy in patients with T2DM; the antihyperglycemic effect is obtained by increasing peripheral insulin sensitivity and through the inhibition of hepatic gluconeogenesis. 59  observed that rats with obesity and insulin resistance have impaired vasomotor function which is improved after metformin administration.
In particular, metformin restores the increase in intracavernosal pressure (ICP), improves the relaxation of the corpus cavernosum in response to acethylcoline, and restores the contractile responses to phenylephrine. 63 The importance of insulin resistance in endothelium function impairment has also been studied by Kim et al. 64 In particular, the authors observed adipose visceral tissue in the penis of obese rats.
Consequently, endothelial (e) and neuronal (n)NOS are decreased. On the other hand, after metformin administration, the adipose tissue decreases/disappears, while nNOS and eNOS levels are restored. 64 The authors also observed an increase in adenosine monophosphate (AMP)-activated protein kinase after metformin treatment, 64 which enhances both nNOS and eNOS. 64 Regarding the effect of metformin on EF in humans, only a few studies are available ( showed an improvement of ED and insulin resistance. 65 The authors concluded that the combination of metformin and Phosphodiesterase type 5 inhibitors (PDE5i) improves ED in patients with severe obesity and insulin resistance, 65 probably due to the effect of metformin on insulin resistance. 65 Indeed, PDE5i needs sufficient levels of NO to be effective, which are decreased in an insulin resistance milieu. 15

Insulin
Insulin therapy is the most effective treatment for DM. Studies in diabetic rats showed an improvement of EF after insulin treatment due to its activity on an eNOS-related pathway, although insulin alone was unable to completely restore EF in basal conditions and after the administration of PDE5i. 67 However, the addition of simvastatin to insulin treatment completely restored basal and PDE5i-stimulated erectile response due to the stronger activation of RhoA/Rho kinase pathway, which has a crucial role in corporal apoptosis. 67 Improved glycemic control can be insufficient to restore EF in some conditions. In fact, some studies showed that subjects with T1DM still show endothelial dysfunction, after glycemic control has been achieved, possibly because of oxidative stress. 68 To date, only a few studies were conducted on the effect of insulin treatment in men with ED (  74 observed that the prevalence of ED in T1DM was lower in patients with intensive treatment versus patients in conventional therapy; intensive insulin treatment was associated with a decreased incidence of ED in patients with microalbuminuria or non-proliferative retinopathy, whereas no difference was observed between conventional therapy versus intensive in patients in primary prevention. In this direction, there are a few studies in subjects using CSII. In one of these studies, the effect of insulin therapy on EF was evaluated in 164 subjects with T1DM versus 60 control subjects: insulin improved ED in the diabetic group; among this group, CSII was associated with an ED prevalence rate higher than the MDI rate (39% vs. 36%); this difference was not statistically significant. 73 Finally, Kesavadev et al. 75 compared CSII and MDI therapies, reporting a significant reduction in ED severity and an increase in IIEF-5 scores in the CSII group. 75,76 In conclusion, promising results, depending also on the type of insulin administration, could be in favor of protection of EF.

Acarbose
Acarbose is an oral antidiabetic drug that inhibits the enterocyte αglucosidase enzyme, slowing glucose intestinal absorption. However, its efficacy on ED has been poorly studied. Only one study was conducted on animals and none in humans. Specifically, Oyeleye et al. 77 observed an improvement in biomarkers of ED in diabetic rats treated with acarbose, particularly when it is associated with Moringa oleifera leaves.

Sulfonylureas and glinides
Sulfonylureas and glinides are oral antihyperglycemic drugs that stimulate the release of insulin from pancreatic cells, acting on adenosine triphosphate (ATP)-sensitive potassium (K) channels. 78 A study conducted by Ruiz Rubio et al. 79 (Table 2).

Thiazolidinediones
TZDs are synthetic agonists of peroxisome proliferator-activated receptor-γ and are used in the treatment of T2DM, belonging to the class of insulin sensitizers. Among TZDs, the most commonly used is pioglitazone, as rosiglitazone was withdrawn in some countries because of the higher risk of myocardial infarction found in treated patients. 81 Several studies evaluated the sexual function in diabetic and aged rats, highlighting an improvement in EF after the treatment with TZDs. [82][83][84][85][86] In particular, Kovanecz et al. 82,83 demonstrated that the treatment with pioglitazone ameliorates the corporal veno-occlusive dysfunction, and corporal smooth muscle detriment in type 2 diabetic rats. The effect was observed with low-dose and long-term treatment, with inhibition of the Rho-kinase pathway. 83 Furthermore, Katz et al. 84 demonstrated a protective effect of TZDs on pelvic ganglion neurons in rats undergoing bilateral cavernosal nerve crush injury (BCNI).
Similar results were obtained by Aliperti et al. 85 : specifically, they found an improvement in EF in rats, mediated by an increase in the expression of eNOS and nNOS. Finally, Heidenberg et al. 86 also found an improvement in EF in rats with BCNI, mediated by the insulin-like growth factor-1 pathway.
Only one study was conducted to evaluate the effect of pioglitazone on sexual function in men 87 (Table 2). Specifically, the authors conducted a prospective, randomized, placebo-controlled, double-blind trial, enrolling 38 men with ED, assessed through the IIEF-6 as poor responders to sildenafil. Patients received pioglitazone 30 mg once daily or placebo for 9 weeks, in association with sildenafil on demand.
The authors found an improvement in sexual function in patients treated with pioglitazone compared with the control group, evidenced by an increase in the IIEF-6 total score only in the former group, but not in the latter. However, these results were not related to changes in blood glucose and testosterone levels, except for a statistically significant reduction in total cholesterol levels in the group of subjects treated with pioglitazone compared with placebo.
In conclusion, several studies are needed to evaluate the effect of pioglitazone in humans; however, the vasculoprotective and antifibrotic properties in animals are promising. In this regard, Aliperti and Hellstrom 88 speculated that pioglitazone could be a safe and effective treatment for ED in men undergoing radical prostatectomy. Animal studies highlighted that GLP-1 RAs have a protective effect on corpus cavernosum endothelial cells and improve the EF in diabetic rats by regulating the Akt/eNOS signaling pathway. 99 Yuan et al. 100 showed that liraglutide improves EF in rats with T1DM through the inhibition of the Ras homolog gene family (RhoA)-Rho-associated protein kinase pathway, which is responsible for penile flaccidity status. These data have also been confirmed for exenatide, which appears to have a positive impact on sexual function by inhibiting the NADPH oxidase. 101 Furthermore, liraglutide and exenatide have been correlated with the levels of Sirtuin1, which is implicated in endothelial dysfunction and in the development of diabetic micro-and macrovascular complications and ED. 102 Few studies have been conducted to evaluate the effect of GLP-1

Dipeptidyl-peptidase-4 inhibitors
RAs on sexual function in men (

Sodium-glucose cotransporter-2 inhibitors
SGLT-2 inhibitors have hypoglycemic activity working through the inhibition of glucose reabsorption in the proximal convoluted tubule of the kidney, increasing glycosuria. 107,108 To date, the role of SGLT-2 inhibitors on ED is not sufficiently investigated; in fact, only data from a study on a T2DM rat model are available, the Goto-Kakizaki rat treated with empagliflozin, with or without acute intravenous injection of sildenafil 109 : rats treated with empagliflozin showed an improvement of EF versus the placebo group, due to a better response of corpora cavernosa to the NO effect, limiting oxidative activity.
The well-known beneficial role of SGLT-2 on cardiovascular protection 18 led to speculation on this effect on ED too; however, a potential detrimental effect due to a higher risk for genitourinary effect and male accessory gland inflammation should also be considered. 110 Finally, the use of SGLT-2 has been recognized as cause of secondary erythrocytosis of increasing relevance in general practice, 111 mainly in association with testosterone replacement therapy. 112

CONCLUSIONS
Erectile dysfunction is recognized as one of the complications arising from steady hyperglycemia in diabetes mellitus. 7 The treatment of diabetes mellitus, using healthy nutrition or lifestyle and specific antihyperglycemic drugs, is the best hurdle to progression of diabetic erectile dysfunction, as for any other diabetic complications. Nevertheless, a wide knowledge gap is present with regard to whether pharmacological treatments have a direct impact on erectile function, besides ameliorating the glycemic control. In fact, this is a crucial point to reach: several studies have demonstrated the efficacy of a well-balanced glycemic control as a key to slow down complications.
Starting with dietary habits, we reported the potentially protective or deleterious impact on erectile function, depending on the specific diet. In particular, the Mediterranean diet was effective in most studies in preserving erectile function, thanks to the extensive use of plant foods as vegetables; conversely, western diets, those high in fats and/or hypercaloric, may hamper erectile function.
With regard to antihyperglycemic drugs, a limited number of studies focused on men, and metformin was the most studied. In synthesis, a several studies showed that metformin can improve erectile function, acting on endothelial function, blood pressure, and atherosclerosis.
GLP-1 RAs were explored in some studies on subjects with erectile dysfunction, with some showing promising effects.
The main limitation of this work is the shortage of trials on humans; in this regard, the section about the use of antihyperglycemic drugs in subjects with diabetes and erectile dysfunction is short and the poor information led to speculate the useful effects of these drugs on erectile function. However, the strength of this study is represented by the fact that these speculations could highlight a gap of knowledge to fill, leading to new studies, and the role of new antidiabetic drug association could be a point to focus for future evaluations, to support a "tailor made" therapy for subjects with diabetes mellitus.
In conclusion, although there are some encouraging results in favor of their protective role on erectile function, more studies are needed for acarbose, pioglitazone, DPP-4i, and SGLT-2i to be recommended in diabetes mellitus patients affected with erectile dysfunction.

FUNDING INFORMATION
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CONFLICT OF INTEREST
None.