Testosterone treatment in obese hypogonadal men with type 2 diabetes

Testosterone treatment in obese hypogonadal men with type 2 diabetes

Effects of long-term testosterone therapy on patients with “diabesity”: Results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Haider A, Yassin A, Doros G, et al. Int J Endocrinol 2014; Article ID: 683515.

Obesity is a chronic disease of increasing concern in developing and developed countries. It is associated with many comorbidities, including insulin resistance, type 2 diabetes mellitus (T2DM), and hypogonadism (testosterone deficiency [TD]).1 Patients who present with obesity and T2DM, termed “diabesity”,2 have an increased risk of cardiovascular disease (CVD). This summary discusses the key findings from a report1 using pooled data from two long-term, observational, prospective, cumulative registry studies to investigate the use of parenteral testosterone undecanoate (TU) 1,000 mg in obese hypogonadal men with T2DM.

Key Points

  • The present study investigated the use of long-term TU 1,000 mg for up to 6 years, the longest follow-up period to date1
  • Use of TU 1,000 mg was investigated in 156 obese hypogonadal men with T2DM and dyslipidemia, aged between 41–73 years1

    • All 156 patients had body mass index (BMI) ≥30 kg/m2
    • Mean age, 61.17 ± 6.18 years; mean total testosterone levels, 8.9 ± 1.99 nmol/L
  • Treatment with TU 1,000 mg produced significant, progressive improvements in anthropometric parameters associated with obesity1

    • Waist circumference (WC) decreased from 114 ± 8.69 to 102.52 ± 7.93 cm, with a mean reduction of 11.56 ± 0.34 cm over 6 years (p<0.0001)
    • Decreases in actual body weight each year were significantly improved compared with the previous year, with a mean loss of 17.49 ± 0.58 kg at 6 years (p=0.0041 for year 6 versus 5)
    • By 6 years follow-up, body weight change (%) was significantly reduced by 15.04 ± 0.48% versus baseline (p<0.0001)
    • BMI progressively declined over 6 years, with a mean reduction of 5.59 ± 0.18 kg/m2 (p<0.0001)
    • By study end, seven men (4.5%) attained a WC <94 cm, 48 men (30.8%) were overweight, and one man (0.6%) achieved normal weight
  • TU 1,000 mg progressively and significantly decreased levels of HbA1c after 6 years, suggesting that hyperglycemia and insulin resistance were ameliorated by TU1

    • HbA1c decreased from 8.08 ± 0.09 to 6.14 ± 0.71%, with a mean change of 1.93 ± 0.06% after 6 years (p<0.0001)
    • By study end, more men achieved HbA1c levels of ≤7.0% (123 [79%] versus 25 [16%]) and ≤6.5% (92 [59%] versus 12 [8%]) compared with baseline (Figure)
  • TU 1,000 mg significantly improved BP, lipid profiles, liver enzymes, and blood levels of an inflammatory biomarker, suggesting an improvement in liver function and fat content, and inflammatory response1

    • Significant, gradual improvements were seen in systolic and diastolic BP over 3 years (mean decreases of 23.15 ± 0.83 and 15.07 ± 0.8 mmHg, respectively, both p<0.0001), which were sustained over 6 years
    • Levels of HDL-C (+35.03 ± 5.11%), total cholesterol (–32.12 ± 1.41%), LDL-C (–25.93 ± 1.63%), and triglycerides (–29.91 ± 2%) were gradually and significantly improved by 3–4 years and sustained at 6 years (all p<0.0001)
    • TU 1,000 mg significantly reduced blood levels of the liver transaminases (AST and ALT) over 6 years (mean changes 12.01 ± 1.33 U/L and 12.46 ± 1.83 U/L, respectively, both p<0.0001)
    • Blood levels of an inflammatory biomarker C-reactive protein (CRP), were significantly decreased by a mean of 2.88 ± 0.28 U/L over 6 years (p<0.0001)

What is known

In 2006, the prevalence of obesity and diabetes was reported to have increased by 7.8% and 7.3%, respectively, over the preceding decade.3 Increases in body weight and obesity are associated with an increased risk of insulin resistance and T2DM.4 Conversely, the risk of T2DM is decreased by 50–60% following a loss in body weight of 5–7%.5 Of clinical importance, patients with both obesity and T2DM exhibit higher risks of CVD6 and mortality.7,8 Thus, obesity and T2DM are associated with a number of comorbidities, and the combination of both diseases in a single patient represents a clinical therapeutic challenge.

The bidirectional relationship between TD, obesity, and T2DM is complex, and TD itself may be a risk factor for development of obesity and T2DM.1 Levels of testosterone are inversely related to obesity, and TD is associated with T2DM.9 Furthermore, TD was significantly associated with BMI and WC in a study of 355 men with T2DM.10 Testosterone is known to regulate many metabolic functions. Several studies have shown that testosterone therapy in men with T2DM improved parameters of both conditions, including body weight, WC, fasting blood glucose, and HbA1c.10-12

What this study adds

Findings from this 6-year study in obese, diabetic men with TD demonstrate that TU significantly improves a number of anthropometric parameters associated with obesity and T2DM. Improvements in weight loss and WC were independent of diet and exercise or behavioral counseling, and were sustained over 6 years. These results complement findings from a study in 20 hypogonadal men with metabolic syndrome, in which treatment with TU for 60 months significantly improved both WC (–9.6 ± 3.8 cm) and body weight (–15 ± 2.8 kg, both p<0.0001).13 These reductions in WC are important as this measure has previously been suggested as a risk factor of all-cause mortality,14 incident CVD, and diabetes.7 These findings suggest that TU may be an effective option in managing weight in obese, diabetic men with TD.

Despite poor control of T2DM at baseline (mean HbA1c, 8.08%), treatment with TU significantly reduced fasting blood glucose and HbA1c levels, and a large proportion of patients achieved target HbA1c levels (Figure). These findings support results from a study by Hackett et al., where adding TU to existing diabetic (and antihypertensive or lipid-lowering) therapy resulted in marked reductions in HbA1c of 0.41% within 6 weeks in poorly controlled patients (HbA1c >7.5) that were maintained at 30 weeks.15 This suggests that normalizing testosterone levels improves hyperglycemia and insulin resistance in obese, diabetic men with TD. Importantly, TU maintained improvements in glycemic control for 6 years,1 a target which is difficult to attain despite a modern generation of intensive diabetic treatments.16,17

Of equal importance, TU significantly reduced levels of CRP over the observation period in obese, diabetic men with TD, which may be linked to concurrent reductions in WC and blood pressure. Markers of liver function improved over 6 years, suggesting that TU reduces liver fat content and inflammation and, consequently, risks of cardiometabolic diseases are reduced. Significant benefits in lipid profile over 6 years were also observed; in particular, levels of LDL-C were significantly reduced and sustained over the observation period. Overall, these findings suggest that TU may improve cardiometabolic function and reduce CVD risk in obese, diabetic men with TD.

Whilst the findings of this study merit further exploration, there are some limitations to the study. Being a long-term, open-label, observational, and uncontrolled study some bias may have been introduced. Furthermore, improvements in weight and diabetic measures were not foreseen at study design. As a result, behavioral and lifestyle changes, duration of T2DM, and changes in co-medications were not assessed.

Figure: Proportion of Patients attaining HbA1c

References

1. Haider A, Yassin A, Doros G, et al. Effects of long-term testosterone therapy on patients with ‘‘diabesity’’: Results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Int J Endocrinol 2014
2. Sims EA, Danforth E, Jr., Horton ES, et al. Endocrine and metabolic effects of experimental obesity in man. Recent Prog Horm Res 1973;29:457-496.
3. Haffner SM. Relationship of metabolic risk factors and development of cardiovascular disease and diabetes. Obesity (Silver Spring) 2006;14 Suppl 3:121S-127S.
4. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006;444(7121):840-846.
5. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344(18):1343-1350.
6. Astrup A, Finer N. Redefining type 2 diabetes: 'diabesity' or 'obesity dependent diabetes mellitus'? Obes Rev 2000;1(2):57-59.
7. Balkau B, Deanfield JE, Despres JP, et al. International Day for the Evaluation of Abdominal Obesity (IDEA): A study of waist circumference, cardiovascular disease, and diabetes mellitus in 168,000 primary care patients in 63 countries. Circulation 2007;116(17):1942-1951.
8. Casanueva FF, Moreno B, Rodriguez-Azeredo R, et al. Relationship of abdominal obesity with cardiovascular disease, diabetes and hyperlipidaemia in Spain. Clin Endocrinol (Oxf) 2010;73(1):35-40.
9. Rao PM, Kelly DM, Jones TH. Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. Nat Rev Endocrinol 2013;9(8):479-493.
10. Kapoor D, Goodwin E, Channer KS, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006;154(6):899-906.
11. Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: Results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med 2010;7(10):3495-3503.
12. Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011;34(4):828-837.
13. Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. Int J Endocrinol 2014; Article ID 527470.
14. Czernichow S, Kengne AP, Stamatakis E, et al. Body mass index, waist circumference and waist-hip ratio: Which is the better discriminator of cardiovascular disease mortality risk?: Evidence from an individual-participant meta-analysis of 82 864 participants from nine cohort studies. Obes Rev 2011;12(9):680-687.
15. Hackett G, Cole N, Bhartia M, et al. Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: The BLAST study. J Sex Med 2013
16. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355(23):2427-2443.
17. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):854-865.

Last updated: 2018
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