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Treatment with testosterone improves cardiovascular risk factors in obese hypogonadal men, with or without type 2 diabetes mellitus

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Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study
Haider A, Saad F, Doros G, and Gooren L. Obesity Research & Clinical Practice 2014;8:e339–49

Obesity is a well-known risk factor for the development of cardiovascular disorders. Globally, obese patients have a higher risk of morbidity1,2 and mortality3; risk of type 2 diabetes, cardiovascular mortality, and premature death is increased by ~30% in obese patients.4 In addition, obesity leads to a decrease in serum testosterone and vice versa. This summary discusses the effects of normalising testosterone levels in obese hypogonadal men, with and without type 2 diabetes mellitus (T2DM). Based on a registry of 255 hypogonadal men5 this was a long-term observational analysis of a subgroup of obese men (n=181).6

Key Points

  • In a prospective, observational, long-term study, 181 obese (BMI ≥30kg/m2) hypogonadal men, with and without type 2 diabetes mellitus (T2DM), were treated with testosterone undecanoate (TU) over 5 years. 40% (72 patients) also had T2DM

    • Patients were aged between 33–67 years (mean 59.11±6.06 years) with serum testosterone <12.1 nmol/L
  • After 5 years treatment with TU, there were significant anthropometric improvements, with all patients having lost weight (mean reduction 18.86±0.36 kg), mean waist circumference decreased by 8.87% and BMI reduced by 16.44%

    • All patients lost weight, 99% of patients lost ≥5 kg, 90% lost ≥10 kg, 70% lost ≥15 kg, and 40% lost ≥20 kg. Mean weight significantly decreased from 114.71±11.59 kg at baseline to 93.2±8.49 kg over the 5 year study period (p<0.0001). Reduction in body weight was continual and sustained over the 5 year treatment period (Figure 1)
    • Waist circumference decreased significantly (p<0.0001 vs baseline and previous year) from 111.20±7.54 cm at baseline to 100.46±7.10 cm after 5 years (Figure 1)
    • A significant decrease (p<0.0001) in BMI occurred over the 5 year study period from 36.72±3.72 to 30.2±2.59 kg/m2
  • There were similar reductions in anthropometric parameters in the diabetic subgroup. Mean body weight and BMI decreased by 15.97%, weight circumference decreased by 10.31 cm

    • Mean body weight decreased from 116.94±11.62 to 94.42±9.42 kg over 5 years (p<0.0001 vs baseline and previous year)
    • Waist circumference significantly decreased by 10.31±0.29 cm from 112.93±7.16 to 101.48±7.24 cm (p<0.0001 compared with baseline and previous year)
    • In addition, a significant decrease in BMI was observed (p<0.0001) over the 5 year treatment period. BMI decreased by 6.02±0.18 kg/m2 from 37.71±3.50 to 30.95±2.96 kg/m2
  • In the total study population there was an improvement in all cardiovascular risk factors and metabolic state. Significant improvements were seen in lipid profile, blood pressure, fasting glucose, HbA1c and liver function

    • Fasting blood glucose significantly decreased from 5.84±0.84 to 5.41±0.12 mmol/L (p<0.0001) and HbA1c decreased from 7.4±1.47 to 6.02±0.61% (p<0.0001)
    • Significant improvement were seen in the lipid profile of patients (p<0.0001 vs baseline for all). Reductions were seen in total cholesterol from 7.63±0.95 to 4.9±0.28 mmol/L, LDL cholesterol from 4.47±1.02 to 2.93±0.93 mmol/L, and triglycerides from 3.32±0.56 to 2.17±0.13 mmol/L. HDL cholesterol increased from 1.58±0.44 to 1.61±0.44 mmol/L
    • Both systolic (SBP) and diastolic blood pressure (DBP) improved over 5 years. SBP decreased from 159.17±15.9 to 139.04±10.96 mmHg and DBP from 96.5±11.01 to 80.36±7.52 mmHg
    • A reduction was seen in serum levels of C-reactive protein from 4.03±4.80 to 0.77±1.53 mg/dL
  • In the diabetic subgroup there were significant improvements in fasting glucose and HbA1c with comparatively greater decreases seen in the diabetic subgroup than in the general population. Fasting glucose decreased by 1.35 mmol/L and HbA1c decreased by 2.01%

    • HbA1c declined steadily over 5 years from 8.35±0.70% to 6.21±0.6% (p<0.0001). Fasting glucose declined from 6.58±0.79 to 5.42±0.16 mmol/L
  • Treatment with TU was well tolerated. Increases in both haemoglobin (3.37%) and haematocrit (5.32%) remained within the normal range. Both parameters reached a plateau after 3 years of treatment with minor fluctuations thereafter

    • Haemoglobin increased from 14.54±0.62 to 15.03±.04 g/dL over 2 years and then remained stable. Haematocrit increased from 43.71±2.51 to 49.03±1.65%
  • Prostate volume increased slightly (<10%) over three years then stabilised, and mean prostate specific antigen increased over the 5 years by 0.18 ng/dL6

What is known

In obese and overweight patients, diet and exercise have been shown to reduce weight and improve obesity parameters, however, these patients have a higher risk of reverting back after an initial weight loss. It has been well documented that normalising circulating testosterone in obese hypogonadal patients is efficacious7,8 and well tolerated.9 Improvements in diet and exercise lead to improvements in the management of diabetes, but even further improvements may be achieved after the administration of testosterone.10

It is now recognised that waist circumference is a better identifier of weight loss than BMI.11 Indeed, waist circumference provides a better measure of (abdominal) body fat and is a better predictor of diabetes mellitus and cardiovascular risk in obese patients.11

What this study adds

In this population of hypogonadal obese men, in a real-life setting, treatment with TU was associated with a significant decrease in both anthropometric parameters and cardiovascular risk factors in patients both with and without T2DM.6

Throughout the study period patients did not experience low levels of testosterone; serum testosterone was maintained in a range >17–19 nmol/L over the 5 year treatment period. Normalising testosterone levels in obese hypogonadal men in this long-term study resulted in continuous and sustained decreases in waist circumference, body weight and BMI. Fasting blood glucose decreased over the first year and then remained steady. Total cholesterol, LDL, and triglycerides significantly decreased (p<0.0001 compared with baseline) following a similar pattern to fasting blood glucose. HDL cholesterol had a significant increase compared with baseline (p<0.0001).

Patients in the diabetic subgroup experienced similar reductions in anthropometric and cardiovascular parameters, however percent decrease in HbA1c was more pronounced in the diabetic subgroup than in the full study population, falling by a mean 2.01±0.07%. Blood pressure is a major risk factor for cardiovascular diseases; in this study both SBP and DBP decreased over the first two years of the study, before levelling off. Further decreases were seen in SBP after 4 years of treatment, falling to 139.04 mmHg.

One remarkable finding from this study is the continuous weight loss over the 5 year treatment period. Weight loss associated with pharmacological treatments usually reaches a plateau after 1–2 years of treatment, with a similar effect seen after bariatric surgery.6 However, in this study, treatment with TU was associated with a continuous and sustained decrease in weight over 5 years.

TU was found to be well tolerated; both haematocrit and haemoglobin increased but remained within normal ranges. Prostate volume increase slightly but prostate-specific antigen levels decreased and there was no indication for increased risk of prostate cancer in this population.

Despite the benefits shown, this study was associated with a number of limitations. As the study was performed in patients who sought treatment at an urologist’s office for a number of urological conditions, the study was not designed to monitor the effect of normalising serum testosterone levels on weight loss, and therefore the population of men were different to those enrolled to weight loss trials.

The promising results from this study need to be confirmed in larger, controlled studies, and future studies should consider the inclusion of free living, physical activity and exercise which have been shown to have clinical benefit in improvements of glucose control and HbA1c.

Figure 1. Percent decrease in mean waist circumference and mean weight in obese hypogonadal men over 60 months of treatment6

Figure 1. Percent decrease in mean waist circumference and mean weight in obese hypogonadal men over 60 months of treatmen

References

1. Astrup A, Rossner S, Finer N, et al. Obesity in Europe - does anybody care? Expert opinion on pharmacotherapy 2013;14(8):971-973.
2. Mathus-Vliegen EM, Obesity Management Task Force of the European Association for the Study of O. Prevalence, pathophysiology, health consequences and treatment options of obesity in the elderly: a guideline. Obesity facts 2012;5(3):460-483.
3. Flegal KM, Kit BK, Orpana H, et al. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. Jama 2013;309(1):71-82.
4. Schmidt M, Johannesdottir SA, Lemeshow S, et al. Obesity in young men, and individual and combined risks of type 2 diabetes, cardiovascular morbidity and death before 55 years of age: a Danish 33-year follow-up study. BMJ open 2013;3(4)
5. Saad F, Haider A, Doros G, et al. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity 2013;21(10):1975-1981.
6. Haider A, Saad F, Doros G, et al. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: an observational study. Obesity research & clinical practice 2014;8(4):e339-349.
7. Saad F. Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease? Diabetes/metabolism research and reviews 2012;28 Suppl 2:52-59.
8. Saad F, Aversa A, Isidori AM, et al. Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Current diabetes reviews 2012;8(2):131-143.
9. Morgentaler A. Testosterone and prostate cancer: what are the risks for middle-aged men? The Urologic clinics of North America 2011;38(2):119-124.
10. Heufelder AE, Saad F, Bunck MC, et al. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. Journal of andrology 2009;30(6):726-733.
11. Klein S, Allison DB, Heymsfield SB, et al. Waist circumference and cardiometabolic risk: a consensus statement from Shaping America's Health: Association for Weight Management and Obesity Prevention; NAASO, The Obesity Society; the American Society for Nutrition; and the American Diabetes Association. The American journal of clinical nutrition 2007;85(5):1197-1202.

Last updated: 2018
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