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.

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    • "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. "

    Maturitas 11/2015; DOI:10.1016/j.maturitas.2015.11.003 · 2.94 Impact Factor
    • "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). "
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    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.
    Andrology 10/2015; DOI:10.1111/andr.12099 · 2.30 Impact Factor
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    • "Testosterone therapy ameliorated components of MetS [62▪,63▪,64,65,103▪▪,104]. Testosterone therapy significantly improved Homeostasis Model Assessment (HOMA)-insulin resistance, CIMT and hsCRP, TNF-α, weight, BMI and waist circumference [39,42,43,46▪▪,55,58▪▪,70]. "
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    ABSTRACT: Purpose of review The purpose of this article is to examine the contemporary data linking testosterone therapy in overweight and obese men with testosterone deficiency to increased lean body mass, decreased fat mass, improvement in overall body composition and sustained weight loss. This is of paramount importance because testosterone therapy in obese men with testosterone deficiency represents a novel and a timely therapeutic strategy for managing obesity in men with testosterone deficiency. Recent findings Long-term testosterone therapy in men with testosterone deficiency produces significant and sustained weight loss, marked reduction in waist circumference and BMI and improvement in body composition. Further, testosterone therapy ameliorates components of the metabolic syndrome. The aforementioned improvements are attributed to improved mitochondrial function, increased energy utilization, increased motivation and vigor resulting in improved cardio-metabolic function and enhanced physical activity. Summary The implication of testosterone therapy in management of obesity in men with testosterone deficiency is of paramount clinical significance, as it produces sustained weight loss without recidivism. On the contrary, alternative therapeutic approaches other than bariatric surgery failed to produce significant and sustained outcome and exhibit a high rate of recidivism. These findings represent strong foundations for testosterone therapy in obese men with testosterone deficiency and should spur clinical research for better understanding of usefulness of testosterone therapy in treatment of underlying pathophysiological conditions of obesity.
    Current Opinion in Endocrinology Diabetes and Obesity 08/2014; 21(5). DOI:10.1097/MED.0000000000000086 · 3.37 Impact Factor
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