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

ABSTRACT 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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Available from: Eric Meuleman, Sep 25, 2015
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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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    • "Testosterone deficiency has been blamed for worse cardiometabolic profile [33]. Testosterone treatment is beneficial in some components of MS [34]. Increased fat mass (central adiposity), reduced insulin sensitivity, impaired glucose tolerance, and unfavorable lipid profile had been reported [35]. "
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    ABSTRACT: Background Metabolic syndrome (MS) has become a pandemic in Turkey, as is the case globally. Increase in carotid artery intima-media thickness (CIMT) and erectile dysfunction (ED) may be evident before the clinical signs of cardiovascular disease appear. We aimed to investigate the prevalence of increased CIMT and ED as markers of atherosclerotic disease in patients with MS. Material/Methods Thirty-two patients with MS and 29 healthy controls were included. Anthropometric and biochemical parameters, along with total testosterone (TT), high sensitive C-reactive protein (hs-CRP), were recorded. Carotid artery intima-media thickness was measured. Erectile dysfunction was assessed with International Index of Erectile Function. Results Patients with MS had higher BMI, fasting plasma glucose, post-prandial plasma glucose, insulin, HOMA-IR, total cholesterol, triglycerides, hs-CRP, and CIMT, whereas TT levels were lower (p<0.0001). The prevalence and severity of erectile dysfunction were higher in patients with MS (p<0.0001). Erectile dysfunction scores correlated inversely with CIMT. MS patients with ED were older and had higher CIMT compared to those without ED. Increase in age and HOMA and decrease in TT increased the risk of ED. When KIMT exceeding the 95th percentile of healthy controls was accepted as a risk factor for CVD, presence of ED was the only determinant for this increase. Conclusions Erectile dysfunction was more prevalent and severe in patients with MS and correlated with subclinical endothelial dysfunction. Total testosterone deficiency was prominent among MS patients. Presence of ED points to an increased risk of cardiovascular disease when MS is present.
    Medical science monitor: international medical journal of experimental and clinical research 05/2014; 20:884-8. DOI:10.12659/MSM.889771 · 1.43 Impact Factor
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    • "The only double-blind, randomized, placebo-controlled study reported to date was conducted in 36 centers in Europe80 (Table 2). Men aged ≥ 40 years with TT ≤11 nmol l−1 or FT ≤255 pmol l−1 on two occasions with T2DM and/or metabolic syndrome were randomized to 2% transdermal testosterone gel for 12 months. "
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    ABSTRACT: Testosterone levels are lower in men with metabolic syndrome and type 2 diabetes mellitus (T2DM) and also predict the onset of these adverse metabolic states. Body composition (body mass index, waist circumference) is an important mediator of this relationship. Sex hormone binding globulin is also inversely associated with insulin resistance and T2DM but the data regarding estrogen are inconsistent. Clinical models of androgen deficiency including Klinefelter's syndrome and androgen deprivation therapy in the treatment of advanced prostate cancer confirm the association between androgens and glucose status. Experimental manipulation of the insulin/glucose milieu and suppression of endogenous testicular function suggests the relationship between androgens and insulin sensitivity is bidirectional. Androgen therapy in men without diabetes is not able to differentiate the effect on insulin resistance from that on fat mass, in particular visceral adiposity. Similarly, several small clinical studies have examined the efficacy of exogenous testosterone in men with T2DM, however, the role of androgens, independent of body composition, in modifying insulin resistance is uncertain.
    Asian Journal of Andrology 01/2014; 16(2). DOI:10.4103/1008-682X.122589 · 2.60 Impact Factor
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