Effect of low-dose tadalafil once daily on glycemic control in patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, placebo-controlled pilot study

A randomized, double-blind, placebo-controlled pilot study was conducted to examine the glycemic and metabolic effects of 6-month treatment with tadalafil 5 mg OAD in patients with T2D and ED. Statistical criteria for sample size are not required in the pilot study. All patients were randomized to receive tadalafil or placebo and were instructed to use it OAD for 6 months at the same time every day. The allocation list was produced using dedicated software (ID-net™) via permuted-block randomization with 2:1 allocation and randomly sized blocks. The allocation details were blinded until statistical analysis was completed. All the patients were monitored during the entire study period. Treatment compliance was defined as the administration of at least 70% of the required dose between visits.

The study protocol was reviewed and approved by the institutional review board of Myongji Hospital (Approval no. MJH-16-038). Informed consent was obtained from all the participants when they were enrolled. The study was conducted following the protocol, ethical principles stated in the Declaration of Helsinki (revised in 2000), and applicable laws. This randomized clinical trial was registered at the Clinical Research Information Service (CRIS, http://​cris.​nih.​go.​kr), number KCT0005666.

Eligible men were recruited from the outpatient clinic of Myongji Hospital, Goyang-si, Gyeonggi-do, the Republic of Korea between January 2017 and November 2018. Men aged 35–75 years who had a regular sexual partner and had intercourse ≥ 1 time in the last month, patients with T2D and ED for > 1 year, patients with HbA1c level < 9%, and patients with no history of PDE-5 inhibitor use in the last 3 months were included in this study. ED was defined as a history of persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance. The exclusion criteria were as follows: use of exogenous insulin, thiazolidinediones, or nitrate; history of malignancy, high-risk cardiovascular disease, and chronic liver or kidney failure; and contraindications to tadalafil. In addition, concomitant medications (such as oral anti-hyperglycemic medications, anti-hypertensive drugs, and statins) were not permitted to change between 3 months before study initiation and 1 month after study completion.

The selection criteria were evaluated at baseline and a complete clinical record was obtained from each subject, including demographic characteristics, medical history, alcohol consumption, smoking status, and other medical conditions. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. A single examiner measured waist circumference (WC) in the standing position, and blood pressure (BP) was measured twice using a standardized sphygmomanometer with a 5-min rest period.

Venous blood samples were collected in the morning after an overnight fast of > 8-h. The concentrations of fasting plasma glucose (FPG), insulin, C-peptide, HbA1c, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), blood urea nitrogen (BUN), creatinine, aspartate transaminase (AST), and alanine transaminase (ALT) were measured. Homeostatic model assessment (HOMA) is a method for assessing β-cell function and IR from basal FPG and insulin or C-peptide concentrations [23]. The equations were simplified as HOMA-IR = (fasting plasma insulin × FPG)/22.5 [24]. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease Study equation. The hexokinase method, enzymatic method, and homogenous enzymatic colorimetric test were used to measure FPG, TC, TG, HDL-C and LDL-C levels, respectively. HbA1c levels were measured using turbidimetric inhibition immunoassay. Biochemical variables were measured using a Cobas Modular 6000 analyzer series (Roche Diagnostics, Basel, Switzerland). These variables were checked at baseline and 6 months. Weight, WC, BP, FPG, insulin, C-peptide, and HbA1c levels were measured at 3 months.

The secondary measures of efficacy of erectile and voiding function included the IIEF-5 score and the International Prostate Symptom Score (IPSS). The IIEF-5, the abridged five-item version of the IIEF, was used to evaluate erectile function [25]. The possible IIEF-5 scores ranged from 5 to 25. The IPSS is a validated seven‐item questionnaire used to assess lower urinary tract symptoms (LUTS). All participants completed self-administered questionnaires at baseline and 3 and 6 months of treatment.

Safety and tolerability were evaluated through adverse event (AE) monitoring throughout the study. The study investigators obtained and recorded all observed or self-reported AEs and their severities (mild, moderate, or severe). The relationships between AEs and study medication were established prior to breaking the blind. All patients underwent laboratory tests, vital sign examinations, physical examinations, and 12-lead electrocardiography at the baseline and end of the trial. Drug adherence was measured using the medication possession ratio, defined as the total number of days covered by filled prescriptions divided by the total number of observation days.

All analyses were prespecified. The study outcomes of both groups were compared using the Student’s t-test for continuous variables and Pearson’s Chi-square test for categorical variables. Data are expressed as mean ± SD or number (proportion). Repeated measures analysis of variance (ANOVA) was used to monitor the differences in HbA1c levels between the groups over the 6 months. Exploratory data analysis was used to investigate the absolute changes in HbA1c levels from baseline at 3 and 6 months in both groups. Absolute change in HbA1c was defined as the difference between baseline HbA1c levels and HbA1c levels at 3 and 6 months. Pearson’s correlation analysis was used to explore the correlations between absolute changes in HbA1c levels and other variables. Statistical significance was set at P < 0.05. All statistical analyses were performed using IBM SPSS (version 18.0; IBM, Armonk, NY, USA).

81 patients with T2D and ED were randomized to receive tadalafil (n = 50) or placebo (n = 25) for 6 months. Subsequently, 5 and 2 patients from tadalafil and placebo groups, respectively, discontinued treatment. In the tadalafil group, 3 patients were lost to follow-up, and two discontinued treatment. In the placebo group, one patient was lost to follow-up, and one patient was discontinued. Overall, 45 and 23 subjects in the tadalafil and placebo groups completed the trial (Fig. 1). Baseline characteristics were well-matched between the groups at randomization and study completion (Table 1).

In the tadalafil group, 3 patients were lost to follow-up and 2 patients discontinued treatment. One patient was lost to follow-up in the placebo group, while another discontinued therapy. Overall, 45 and 23 participants in the tadalafil and placebo groups, respectively, completed the trial (Fig. 1). Baseline characteristics were well-matched between groups at randomization and study completion.

Repeated-measures ANOVA revealed that the mean HbA1c levels significantly differed between groups over the 6-month study period (P = 0.021; Fig. 2). The mean absolute changes in baseline HbA1c levels were − 0.138 ± 0.527% and 0.204 ± 0.492% at 3 months (P = 0.012) and − 0.137 ± 0.52% and 0.196 ± 0.691% at 6-months (P = 0.030) in the tadalafil and placebo groups, respectively (Table 2).

Table 3 shows the changes in metabolic parameters from baseline at 3 and 6 months of treatment in both groups. At 3 and 6 months of treatment, the HOMA-IR score decreased from baseline in the tadalafil group; however, the change was not significantly different from that in the placebo group. In addition, there were no significant differences in WC, BMI, or BP between the groups at 3 and 6 months. At 6 months, the reduction in the FPG level from baseline was significantly greater in the tadalafil group than in the placebo group (− 6.40 ± 28.53 mg/dL vs. 5.35 ± 17.77 mg/dL, P = 0.046). At 6 months, the change in the ALT level was − 1.49 ± 12.01 IU/L in the tadalafil group and 6.17 ± 8.39 IU/L in the placebo group (P = 0.008). No significant differences were observed in changes in TC, TG, HDL-C, LDL-C, BUN, creatinine, or eGFR between the groups at 6 months.

The IIEF-5 and IPSS scores at baseline did not differ between the groups (Table 1). However, improvement in the IIEF-5 score was significantly greater in the tadalafil group than in the placebo group at 3 months (5.96 ± 5.26 vs. 0.78 ± 5.82; P = 0.001) and 6 months (6.56 ± 5.32 vs. 2.22 ± 5.73; P = 0.003). Moreover, we noted a numerical reduction in the IPSS of the tadalafil group; however, the difference was not statistically significant when compared with the placebo group.

Tadalafil was well tolerated, and no subject discontinued the study because of treatment-emergent AEs. Overall, a higher percentage of patients reported AEs in the placebo group (n = 2, 8.6%) than in the tadalafil group (n = 2, 4.4%). The reported AEs were myalgia and senile cataracts in the tadalafil group, while lumbar spinal stenosis, and decreased visual acuity were documented in the placebo group. AEs were mild in severity. The study population showed high medication adherence (> 80%) during the study period.