Prevention of progression from prediabetes to diabetes in hypogonadal men treated with testosterone for up to 12 years 


A Yassin, D-J Yassin, G Doros, A Traish, F Saad



Background: Hypogonadism is a predictor of type 2 diabetes mellitus (T2DM) (Laaksonen et al. Diabetes Care 2004; 27:1036-1041). 

Aim: To study long-term effectiveness and safety of testosterone undecanoate injections (TU) in a hypogonadal men from a registry study in a urological institute.

Method: 
In a real-life, ongoing, cumulative, observational registry study, 505 hypogonadal men with total testosterone levels ≤12 nmol/L were enrolled at the time of analysis. 
253 (50.1%) had prediabetes at baseline, defined by HbA1c between 5.7 and 6.4%, according to ADA definition. 175 received treatment with TU 3-monthly injections up to 12 years (T-group). In 76/175 men, testosterone treatment had been temporarily interrupted for a mean of 16 month, due to reimbursement problems. All men continued testosterone therapy after this intermission period. 78 patients opted against testosterone therapy and served as controls (CTRL). At each or each other visit, anthropometric and metabolic parameters were measured.
Mean changes over time between groups were compared by mixed effects model for repeated measures with random effect for intercept and fixed effects for time, group and their interaction and adjusted for age, weight, waist circumference, fasting glucose, blood pressure and lipids. 

Results:
Mean age at baseline was 59.2±9.6 years in the T-group and 66.6±7.2 years in CTRL (p<0.0001). Mean follow-up: 99 months in the T-group, 68 in CTRL.

In the T-group, mean HbA1c decreased from 5.9±0.2 to 5.4±0.2% after 12 years (p<0.0001). In CTRL, mean HbA1c increased from 5.9±0.2 to 6.2±0.6% after 8 years (p<0.0001). The mean difference at 8 years was -0.8% (p<0.0001).

Not a single patient in the T-group progressed from prediabetes to T2DM. Only 23 men (13%) still fulfilled prediabetes criteria, 152 (87%) had HbA1c <5.7% and were no longer prediabetic. In CTRL, 30 men (38.5%) progressed to T2DM during the observation time. The mean difference between groups at 8 years was -0.7 (p=0.0549).

Mean glucose decreased from 5.3±0.9 to 4.6±0.5 mmol/L (p<0.0001) at 12 years in the T-group. In CTRL, glucose increased from 4.9±1.4 to 5.0±0.9 mmol/L at 8 years. The mean difference between groups at 8 years was -0.7 (p=0.0549).

The triglyceride:HDL ratio, a surrogate parameter for insulin resistance, decreased in the T-group from 6.3±2.9 to 4.4±2.3 at 8 and 3.1±1.2 at 12 years (p<0.0001). In CTRL, the ratio increased from 4.0±2.5 to 6.2±2.4 at 8 years. The mean difference between groups at 8 years was -1.9 (p<0.01) 

The TyG index, another surrogate parameter for insulin resistance, decreased in the T-group from 9.3±0.4 to 9.0±0.4 at 8 and 8.8±0.3 at 12 years (p<0.0001). In CTRL, the TyG index increased from 8.9±0.6 to 9.3±0.4 at 8 years. The difference between groups at 8 years was -0.3 (p<0.05).

Mean weight decreased from 96±11.7 to 89.3±9.8  at 8 and 87.1±7.5 kg at 12 years in the T-group (p<0.0001). In CTRL, weight increased from 92.1±9.9 to 98.2±6.3 at 8 years. The difference between groups at 8 years was -14.6 kg (p<0.0001). 

Mean waist circumference decreased from 104.7±7.1 to 98.4±6.6  at 8 and 94.1±2.2 cm at 12 years in the T-group (p<0.0001). In CTRL, waist circumference increased from 99.9±9.0 to 106±3.2 at 8 years. The difference between groups at 8 years was -12.2 cm (p<0.0001).

In the T-group, all injections were administered in the doctor’s office and documented, therefore the adherence to testosterone treatment was 100%. 

Discussion: 
Limitations: The study was not designed to investigate effects of testosterone on prediabetes. Patients were not randomized as this was not possible in a regular medical office. There was no structured lifestyle advice. The untreated control patients were approximately 6.5 years older at baseline. The reason is that the T-group contained a number of young men with primary hypogonadism (Klinefelter’s syndrome, orchiectomy after testicular cancer). However, baseline HbA1c was equal in both groups. 

Strengths: The long duration of follow-up, the excellent medication adherence to testosterone. All patients were treatment-naïve regarding diabetes medications.

This primary preventive effect may have been mediated by sustained weight loss in the testosterone-treated group and by the well-documented increase in lean body mass that invariably occurs when hypogonadal men are treated with testosterone.

Conclusion: 
Testosterone therapy prevented progression from prediabetes to T2DM in hypogonadal men while more than one third of untreated hypogonadal men developed T2DM.