Long-Term Testosterone Therapy in Type 2 Diabetes Is Associated with Decreasing Waist Circumference and Improving Erectile Function.

PURPOSE: To describe the 4-year metabolic follow-up results from the BLAST study. MATERIALS AND METHODS: Baseline hemoglobin A1c (HbA1c), weight, and waist circumference (WC) data were recorded in 185 men recruited for the BLAST randomised controlled trial (RCT) and erectile function (EF) scores were also available in an additional 48 men screened for the RCT. Intra/inter-group associations between these parameters and testosterone replacement therapy (TRT) were assessed at 1) end of the RCT (30 weeks), 2) open-label phase (82 weeks), and 3) final assessment via non-parametric statistics. RESULTS: Improvement in HbA1c and weight at the end of the RCT and open-label phase in men on TRT was not maintained long-term. The convergence in HbA1c could have been due to incentivised care with HbA1c targets. Interestingly those on TRT at final assessment required fewer anti-diabetic agents. The weight increase in routine care may have been due to changes in diabetes medication or an increase in lean muscle mass. WC continued to decrease in men on TRT indicating possible reduction in visceral fat. Improvement in EF scores continued with long-term TRT, this was abolished when TRT was discontinued. CONCLUSIONS: This study hints at benefits in glycaemic control, weight and WC, and long-term RCTs studying mechanisms of benefit and clinical outcomes are necessary. Our results also show that EF scores continued to improve with long-term TRT, even beyond the 6 months that we previously reported in the BLAST RCT.

Long-term testosterone therapy in type 2 diabetes is associated with reduced mortality without improvement in conventional cardiovascular risk factors.

OBJECTIVES: To further characterize the beneficial impact of testosterone replacement therapy (TRT) on the association between mortality and hypogonadism (HG) in men with type 2 diabetes (T2DM), by determining, firstly, if changes in cardiovascular disease (CVD) risk factors after TRT play a role, secondly, whether the reduction in mortality is lost when TRT is discontinued and, finally, the presence of subgroups where benefit may be greater. MATERIALS AND METHODS: We studied 857 men with T2DM, screened for the BLAST randomized controlled trial, over 3.8 years of follow-up. The men were stratified first by testosterone levels: group 1: total testosterone (TT) >12 nmol/L and free testosterone (FT) >0.25 nmol/L; Group 2: TT ≤12 nmol/L or FT ≤0.25 nmol/L. Group 2 was further stratified into those not on TRT (Group 2a) and those on TRT (Group 2b). Group 2b was further stratified by whether TRT was discontinued (Group 2b1) or not (Group 2b2). The principal outcome, mortality, was studied using Cox regression. RESULTS: We found that TRT was not associated with improvements in CVD risk factors. CVD risk factors (baseline and changes during follow-up) were not associated with mortality. Men in Group 1 and Group 2b were found to have lower mortality (reference: Group 2a), even with CVD risk factors included in the regression models. Mortality was lower in men in Group 2b1 (6.2%) and Group 2b2 (0%) compared with those in Group 2a (16.9%). The lower mortality associated with Group 1 and Group 2b was observed primarily in older (>64.6 years) and less overweight (≤93.8 kg) men. CONCLUSIONS: The benefits associated with normal testosterone levels and TRT (even after discontinuation) do not appear to be related to improvements in the CVD risk factors studied. In view of TRT having greater impact in men of lower weight, better outcomes may be achieved with concurrent TRT and weight reduction programmes.

Testosterone undecanoate improves sexual function in men with type 2 diabetes and severe hypogonadism: results from a 30-week randomized placebo-controlled study.

OBJECTIVE: To evaluate the sexual function response to 30 weeks' treatment with long-acting testosterone undecanoate (TU) or placebo in 199 men with type 2 diabetes and either severe or mild hypogonadism (HG). PATIENTS AND METHODS: Men with HG were identified from seven primary care type 2 diabetes registers. A 30-week randomized placebo-controlled study of TU was carried out in 199 of these men (placebo, n = 107, TU, n = 92). The patient-reported outcome measure was the 15-item International Index of Erectile Function score. Men completing the study (n=189) were stratified, firstly, by baseline total testosterone (TT) or free testosterone (FT) into mild HG (TT 8.1-12 nmol/L or FT 0.18-0.25 nmol/L) and severe HG groups (TT ≤8 nmol/L and FT ≤0.18 nmol/L), and secondly, by intervention (placebo or TU), thereby creating four groups: mild HG/placebo; mild HG/TU; severe HG/placebo and severe HG/TU. STATISTICAL ANALYSIS: Changes in sexual function score (a secondary outcome of the study) at each visit within group (from baseline) and between groups (TU vs placebo) at each assessment (6, 18 and 30 weeks) were compared using a Wilcoxon signed-rank and Wilcoxon rank-sum test, respectively. RESULTS: Significant improvement in erectile function was evident only in the severe HG group after 30 weeks of TU treatment; this finding persisted when TU was compared with placebo. Intercourse satisfaction and sexual desire scores were also improved at 6, 18 and 30 weeks in the severe HG group after TU treatment; this increase in scores was also evident when compared with placebo. TU did not appear to alter orgasmic function significantly in any of the patient groups. CONCLUSIONS: The present study suggests that benefit in sexual symptoms after TU treatment is evident principally in patients with HG with TT levels ≤8 nmol/L and FT levels ≤0.18 nmol/L. We also suggest that 30 weeks of treatment is necessary before evaluating improvement in erectile function.

Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study.

INTRODUCTION: The association between testosterone deficiency and insulin resistance in men with type 2 diabetes is well established and current endocrine society guidelines recommend the measurement of testosterone levels in all men with type 2 diabetes or erectile dysfunction. AIM: We report the first double-blind, placebo-controlled study conducted exclusively in a male type 2 diabetes population to assess metabolic changes with long-acting testosterone undecanoate (TU). METHODS: The type 2 diabetes registers of seven general practices identified 211 patients for a 30-week double-blind, placebo-controlled study of long-acting TU 1,000 mg followed by 52 weeks of open-label use. Because of the established impact of age, obesity, and depression on sexual function, these variables were also assessed for influence on metabolic parameters. MAIN OUTCOME MEASURE: Changes in glycated hemoglobin (HbA1c) and the level of testosterone at which response are achieved. RESULTS: Treatment with TU produced a statistically significant reduction in HbA1c at 6 and 18 weeks and after a further 52 weeks of open-label medication most marked in poorly controlled patients with baseline HbA1c greater than 7.5 where the reduction was 0.41% within 6 weeks, and a further 0.46% after 52 weeks of open-label use. There was significant reduction in waist circumference, weight, and body mass index in men without depression, and improvements were related to achieving adequate serum levels of testosterone. There were no significant safety issues. CONCLUSIONS: Testosterone replacement therapy significantly improved HbA1c, total cholesterol, and waist circumference in men with type 2 diabetes. Improvements were less marked in men with depression at baseline, and therapeutic responses were related to achieving adequate serum testosterone levels. Current advice on 3- to 6-month trials of therapy may be insufficient to achieve maximal response. Patients reported significant improvements in general health.

Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes.

INTRODUCTION: Sexual dysfunction, particularly erectile dysfunction (ED), is common in men with type 2 diabetes, occurring in up to 75% of cases. The prevalence of hypogonadism is also high in men with diabetes and low testosterone is associated with both sexual dysfunction and a reduced response to oral therapy for ED. AIM: This study aimed to determine the effect of testosterone replacement with long-acting Testosterone Undecanoate (TU) on sexual function, mood and quality of life vs. placebo over a treatment period of 30 weeks followed by 52 weeks of open-label medication. The study was conducted in a primary care population of men with type 2 diabetes attending their primary care physician for routine visits. METHODS: The male diabetic populations of seven general practices were screened at routine diabetes visits to detect symptomatic men with total testosterone levels of 12 nmol/L or less or with free testosterones of 250 pmol/L or less. Two hundred eleven men were screened. A double-blind placebo-controlled study was conducted in 199 men with type 2 diabetes and hypogonadism treated for 30 weeks with either 1,000 mg of TU or matching placebo followed by 52-week open-label follow on. MAIN OUTCOME MEASURES: The primary outcome measure, International Index of Erectile Function (IIEF), was used to evaluate sexual dysfunction, and the Ageing Male Symptom (AMS), Hospital Anxiety and Depression Scale, and Global Efficacy Question were used as secondary outcome measures to assess mood and self-reported quality of life. RESULTS: Testosterone replacement therapy with long-acting TU improved all domains of sexual function at 30 weeks (erectile function [EF], P = 0.005; intercourse satisfaction, P = 0.015; sexual desire, P = 0.001; overall satisfaction, P = 0.05; and orgasm, P = 0.04), with benefit as early as 6 weeks. Improvements in AMS score were significant in men without depression (P = 0.02) and the presence of depression at baseline was associated with marked reduction in response to both sexual function and psychological scores. All responses in sexual function continued to improve significantly up to 18 months with an improvement in EF score of 4.31 from baseline. In a small cohort of 35 men taking phosphodiesterase type 5 inhibitors, there was no change during the double-blind phase but a nine-point improvement in EF domain during 52-week open-label treatment. After 30 weeks, 46% vs. 17% of patients on active therapy vs. placebo felt that the treatment had improved their health, reaching 70% after open-label therapy. Less obese and older patients responded better to testosterone therapy. There were no significant adverse events. CONCLUSION: TU significantly improved all domains of the IIEF and patient reported quality of life at 30 weeks and more significantly after 52-week open-label extension. Improvement was most marked in less obese patient and those without coexisting depression. In men with type 2 diabetes, trials of therapy may need to be given for much longer than 3-6 months suggested in current guidelines.