Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome (the TIMES2 Study)

The Robert Hague Centre for Diabetes and Endocrinology, Barnsley Hospital, Barnsley, UK.
Diabetes care (Impact Factor: 8.42). 03/2011; 34(4):828-37. DOI: 10.2337/dc10-1233
Source: PubMed


This study evaluated the effects of testosterone replacement therapy (TRT) on insulin resistance, cardiovascular risk factors, and symptoms in hypogonadal men with type 2 diabetes and/or metabolic syndrome (MetS).
The efficacy, safety, and tolerability of a novel transdermal 2% testosterone gel was evaluated over 12 months in 220 hypogonadal men with type 2 diabetes and/or MetS in a multicenter, prospective, randomized, double-blind, placebo-controlled study. The primary outcome was mean change from baseline in homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were measures of body composition, glycemic control, lipids, and sexual function. Efficacy results focused primarily on months 0-6 (phase 1; no changes in medication allowed). Medication changes were allowed in phase 2 (months 6-12).
TRT reduced HOMA-IR in the overall population by 15.2% at 6 months (P = 0.018) and 16.4% at 12 months (P = 0.006). In type 2 diabetic patients, glycemic control was significantly better in the TRT group than the placebo group at month 9 (HbA(1c): treatment difference, -0.446%; P = 0.035). Improvements in total and LDL cholesterol, lipoprotein a (Lpa), body composition, libido, and sexual function occurred in selected patient groups. There were no significant differences between groups in the frequencies of adverse events (AEs) or serious AEs. The majority of AEs (>95%) were mild or moderate.
Over a 6-month period, transdermal TRT was associated with beneficial effects on insulin resistance, total and LDL-cholesterol, Lpa, and sexual health in hypogonadal men with type 2 diabetes and/or MetS.

Download full-text


Available from: Eric Meuleman
  • Source
    • "Regarding the cardiovascular system, low testosterone has been associated with increased blood pressure, dyslipidemia, atherosclerosis, arrhythmia, thrombosis, endothelial dysfunction, as well as with impaired left ventricular function; however, TRT has not been proven so far to be beneficial with respect to cardiovascular disease; neither has it been definitely shown to have specific adverse cardiovascular effects [29]. Additional data from recent studies suggest a beneficial effect of TRT in special populations, such as men with testosterone deficiency and type 2 diabetes mellitus as far as survival [30], glycemic control, cholesterol concentrations, body composition, libido and sexual function [31], as well as patient-reported quality of life (QoL) [32] are concerned. According to the BLAST-study [33], achieving threshold serum concentrations seems to be of significant importance for the response to TRT. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Late-onset hypogonadism (LOH) represents a common clinical entity in aging males, characterized by the presence of symptoms (most usually of a sexual nature, such as decreased libido, decreased spontaneous erections and erectile dysfunction) and signs, in combination with low serum testosterone concentrations. Whether testosterone replacement therapy (TRT) should be offered to those individuals is still under extensive debate. Aims: The aim of this position statement is to provide and critically appraise evidence on TRT in the aging male, focusing on pathophysiology and characteristics of LOH, indications for TRT, available therapeutic agents, monitoring and treatment-associated risks. Materials and methods: Literature review and consensus of expert opinion. Results and conclusions: Diagnosis and treatment of LOH is justified, if a combination of symptoms of testosterone deficiency and low testosterone is present. Patients receiving TRT could profit with regard to obesity, metabolic syndrome, type 2 diabetes mellitus, sexual function and osteoporosis and should undergo scheduled testing for adverse events regularly. Potential adverse effects of TRT on cardiovascular disease, prostate cancer and sleep apnea are as yet unclear and remain to be investigated in large-scale prospective studies. Management of aging men with LOH should include individual evaluation of co-morbidities and careful risk versus benefit assessment.
    Full-text · Article · Nov 2015 · Maturitas
    • "glucose and lipid metabolism and ED (Isidori et al., 2005; Corona et al., 2011; Jones et al., 2011; Hackett et al., 2013,2014), while Met, beside its universally well-known antiglycaemic role, is generally considered as a drug with weightneutral effect (Handelsman et al., 2015; Inzucchi et al., 2015), and as not having an intrinsic positive effect on the lipid profile (Wulffel e et al., 2004), it is necessary to point out that we were not able to identify each drug (T or Met) and/or lifestyle changes (or all together those factors) as predominantly having caused those clinical and metabolic improvements. However , in our experience, although that treatment regimen and serum T and its bioavailable fractions (FT and BioT) were in the normal range for adult men (Wang et al., 2008; Bhasin et al., 2010), neither clinical signs (BMI), metabolic parameter (HbA1c, TC and LDL) nor the IIEF score reached those values that were considered as appropriate targets for the treatment in young adult obese subjects affected by T2DM without severe complications (Apovian et al., 2015; Handelsman et al., 2015; Inzucchi et al., 2015; Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, Cheng AY, 2013; Rosen et al., 2002) (Tables 1 and 4). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this retrospective observational study was to evaluate whether adding liraglutide to lifestyle changes, metformin (Met) and testosterone replacement therapy (TRT), by means of improving weight and glycaemic control, could boost erectile function in type 2 diabetic obese men with overt hypogonadism and erectile dysfunction (ED) in a 'real-life setting'. Forty-three obese, diabetic and hypogonadal men (aged 45-59 years) were evaluated because of complaining about the recent onset of ED. They were subdivided into two groups according to whether hypogonadism occurred after puberty (G1; n = 30: 25 with dysfunctional hypogonadism and 5 with acquired hypogonadotropic hypogonadism) or before puberty (G2; n = 13: 10 with Klinefelter's syndrome and 3 with idiopathic hypogonadotropic hypogonadism). Both G1 and G2 patients were given a combination of testosterone (T) [testosterone undecanoate (TU) 1000 mg/every 12 weeks] and Met (2000-3000 mg/day) for 1 year. In the poor responders (N) to this therapy in terms of glycaemic target (G1N: n = 16; G2N: n = 10), liraglutide (L) (1.2 μg/day) was added for a second year, while the good responders (Y) to T + Met (G1Y: 14/30 and G2Y: 3/13) continued this two drugs regimen therapy for another year. All patients were asked to fill in the International Index of Erectile Function (IIEF 15) questionnaire before starting TU plus Met (T1) and after 12 months (T2) and 24 months (T3) of treatment. Patients underwent a clinical examination and a determination of serum sex hormone binding globulin (SHBG), total testosterone (T) and glycosylated haemoglobin (HbA1c) at T1, T2 and T3. At T2, each patient obtained an improvement of ED (p < 0.01) and of the metabolic parameters without reaching, however, the glycaemic goals [HbA1c = >7.5% (>58 mmol/mol)], while T turned out to be within the range of young men. L added to TU and Met regimen in G1N and G2N allowed these patients to reach not only the glycaemic target [HbA1c = <7.5% (<58 nmol/mol)] and a significant reduction in body weight (p < 0.01), but also a further increase in SHBG (p < 0.05) and T (p < 0.01) plasma levels as well as a significant increment of IIEF score (T3). Conversely, at T3 G1Y and G2Y, who received the combined therapy with TRT and Met for the second year, showed a partial failure of that treatment given that there was no improvement of the IIEF score and they showed a significant rise in serum HbA1c (p < 0.05) and weight (p < 0.04) compared with the assessments at T2. These results suggest that TRT could improve clinical and metabolic parameters in obese, type 2 diabetic men with ED and overt hypogonadism (independently of when T deficit occurred). Furthermore, in case of insufficient metabolic control the addition of L to TRT and Met regimen allows to achieve serum T levels in the range of healthy men, as well as to reach glycaemic target and to lower weight, leading to a considerable improvement of ED.
    No preview · Article · Oct 2015 · Andrology
    • "Other potential drivers of DM consistent with the same observation of greater vulnerability to DM at lower body mass index in Asians, such as lower muscle mass [6], which is a sink for glucose disposal, are rarely considered. Experimental evidence from randomized controlled trials shows that increasing muscle mass through exercise or through testosterone administration improves glucose metabolism [7] [8], consistent with some observational evidence [9]. Peak lifetime muscle mass is acquired in adolescence. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hong Kong, in common with other Asian settings, has high rates of diabetes mellitus (DM) despite a relatively nonobese population. Given the rapid economic development in the region, most Asians grew up in limited living conditions. We examined the longitudinal mortality trends of DM. We assessed whether the first generation (birth cohorts in the 1930s) with late adolescence in a more economically developed environment had a lower risk of DM. We used DM deaths and population figures in Hong Kong, 1976 to 2010. We fitted age-period-cohort models to decompose mortality rates into effects for age at mortality, calendar period of mortality, and birth cohort. The risk of death from DM fell for the first generation (births in the early 1930s) with late adolescence in Hong Kong, but possibly the risk rose again for the first generation (birth 1960s) affected by the obesity epidemic. Adiposity might contribute to diabetes in Hong Kong, and similar Asian settings, however current vulnerability of many older Asians to DM in plentiful environments may be the result of limited living conditions until adulthood. Furthermore, our findings are more consistent with limited adolescent conditions than fetal undernutrition playing a role in vulnerability to DM. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jan 2015 · Annals of Epidemiology
Show more