Testosterone therapy reduces liver fat in men with type 2 diabetes and NAFLD

August 2022

Non-alcoholic fatty liver disease (NAFLD) is common in patients with type 2 diabetes, and there is currently no available treatment for NAFLD beyond lifestyle modification.

Testosterone therapy improves insulin resistance and reduces total body fat, but its impact on the liver fat has not yet been thoroughly studied.

Here we summarise the results from a secondary analysis of a randomized controlled trial that aimed to evaluate the effect of treatment with testosterone undecanoate injections on liver fat in men with hypogonadism and type 2 diabetes.1

Key Points

  • A new report from a randomized controlled trial shows that treatment with testosterone undecanoate injection reduces liver fat in men with hypogonadism, type 2 diabetes and NAFLD.
  • Considering there is currently no approved treatment for NAFLD, testosterone therapy is particularly promising for men with hypogonadism, NAFLD and type 2 diabetes.

What is known about testosterone and fatty liver disease

The prevalence of NAFLD, NASH and fibrosis has been shown (using magnetic resonance and biopsy) to be 38%, 14% and 5.9% respectively, in a middle-aged Western population who have a BMI of around 30 kg/m2.2

NAFLD is associated with a 2- to 3-fold increased risk of type 2 diabetes, and patients with type 2 diabetes have a higher prevalence of steatohepatitis, liver fibrosis and end-stage liver disease,3 as well as a high prevalence of hypogonadism, informally also known as low testosterone. Vice versa, men with low testosterone have increased risk for NAFLD, even after adjustment for traditional risk factors,4, 5 as well as type 2 diabetes.6, 7 Hence, a bidirectional link exists between low testosterone, type 2 diabetes and NAFLD, where each condition worsens the other, creating a vicious circle.

The benefits of testosterone therapy for prevention of type 2 diabetes were established in the T4DM study, which showed that men receiving treatment with testosterone undecanoate injection for two years had a reduced incidence of type 2 diabetes by nearly half compared to men receiving placebo (12.4% vs 21.1%). Furthermore, a long-term real-world evidence study showed that treatment with testosterone undecanoate injections for 11 years resulted in significant improvement in glycemic control and remission of type 2 diabetes (defined as HbA1c <6.5% and discontinuation of all diabetes drugs) in a large proportion of men.

While the metabolic benefits of testosterone therapy for prevention, and possibly also treatment, of type 2 diabetes in men with hypogonadism are well established, the potential benefits of testosterone therapy for prevention and treatment of NAFLD have been less researched. A real-world evidence study showed that treatment with testosterone undecanoate injections for up to 12 years reduced fatty liver index, suggesting improvement in liver function.8 Nevertheless, results from randomized trials are conflicting, with studies showing that testosterone therapy either reduces liver fat content,9 or has no effect on liver fat.10-12

To learn more about the potential benefit of testosterone therapy on NAFLD, an analysis of data from a previous randomized controlled trial 13 was conducted, with the aim to evaluate the effect of testosterone therapy on liver fat, and to identify factors associated with changes in liver fat in a population of men with low testosterone levels and type 2 diabetes.

 

What this study adds

The study included 88 men, aged 35-70 years with type 2 diabetes and a fasting, early morning testosterone level of ≤ 12.0 nmol/L (346 ng/dL); 39 men had liver fat measured by MRI, of whom 20 men received treatment with testosterone undecanoate injection (1000 mg administered at 0, 6, 18 and 30 weeks), and the remaining 19 men received placebo. All patients were followed up for a total of 40 weeks.

Before start of the study, all patients had >5% hepatic steatosis, and 38 of 39 patients met diagnostic criteria for NAFLD. Liver fat content at baseline was 15.0% (range 11.5%-21.1%) in the testosterone group, and 18.4% (range 15.0%-28.9%) in the placebo group. ALT was 34 units/L (26-38) in the testosterone, and 32 units/L (25-52) in the placebo group.

At week 40, men receiving treatment with testosterone undecanoate injection had a reduction in liver fat content by 3.5%. In contrast, men receiving placebo had an increase in liver fat content by 1.2% in the placebo arm (figure), resulting in a significant between-group difference in liver fat content of 4.7% (p < 0.001). After controlling for baseline liver fat, testosterone therapy was associated with a relative reduction in liver fat of 38.3% (95% confidence interval 25.4%-49.0%, P < 0.001).

 

Figure: Effect of treatment with testosterone undecanoate injection vs. placebo on liver fat.

Figure : Effect of treatment with testosterone undecanoate injection vs. placebo on liver fat.

Data from: Apostolov R, Gianatti E, Wong D, et al. Testosterone therapy reduces hepatic steatosis in men with type 2 diabetes and low serum testosterone concentrations. World journal of hepatology. Apr 27 2022;14(4):754-765.

Compared to placebo, men receiving treatment with testosterone undecanoate injections also had a significant reduction in total cholesterol and significant increase in HDL levels, along with a decrease in body fat mass and increase in lean mass. Factors associated with change in liver fat were testosterone therapy, BMI, baseline liver fat, and total and free testosterone levels at week 40, with a high correlation between total and free testosterone.

A strength of this study is that the two patient groups were well matched with respect to medication use, in particular diabetes mediations that could impact hepatic steatosis, and all 39 patients maintained a stable diabetic regimen throughout the study.

 

Commentary

This study shows an association between testosterone treatment and a significant reduction in liver fat in men with low testosterone and type 2 diabetes. These data provide a strong rationale for larger and longer duration randomized trials.

Currently, the present study is the longest duration randomized controlled trial investigating the effect of testosterone therapy on liver fat, with a study period of 10 months (40 weeks). The previous studies had a study duration of only 6 months (24 weeks).9-12

Real-world evidence studies have clearly shown that a number of benefits of testosterone therapy require long-term uninterrupted treatment to fully manifest, such as improvement in erectile function, waist size, glucose control and lipids, and reduced incidence of prostate cancer, heart attack, stroke and premature death.14-19

Emerging data suggest that reduction in liver fat is an outcome that requires long-term testosterone therapy to show consistent improvement. A relatively large real-world evidence study of 505 men with hypogonadism, showed that treatment with testosterone undecanoate injection for up to 12 years significantly reduced fatty liver index, whereas men with hypogonadism who did not receive testosterone therapy had a significant worsening of fatty liver index.8

Furthermore, the improvement in liver function seen in men receiving long-term treatment with testosterone undecanoate injections was accompanied by a significantly reduced risk of heart attack, stroke and premature mortality.

References

  • Apostolov R, Gianatti E, Wong D, et al. Testosterone therapy reduces hepatic steatosis in men with type 2 diabetes and low serum testosterone concentrations. World journal of hepatology. Apr 27 2022;14(4):754-765. Return to content
  • Harrison SA, Gawrieh S, Roberts K, et al. Prospective evaluation of the prevalence of nonalcoholic fatty liver disease and steatohepatitis in a large middle-aged US cohort. J Hepatol. Aug 2021;75(2):284-291. Return to content
  • Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options. JHEP Rep. Oct 2019;1(4):312-328. Return to content
  • Yim JY, Kim J, Kim D, Ahmed A. Serum testosterone and non-alcoholic fatty liver disease in men and women in the US. Liver international : official journal of the International Association for the Study of the Liver. Nov 2018;38(11):2051-2059. Return to content
  • Jaruvongvanich V, Sanguankeo A, Riangwiwat T, Upala S. Testosterone, Sex Hormone-Binding Globulin and Nonalcoholic Fatty Liver Disease: a Systematic Review and Meta-Analysis. Annals of hepatology. May-Jun 2017;16(3):382-394. Return to content
  • Gyawali P, Martin SA, Heilbronn LK, et al. The role of sex hormone-binding globulin (SHBG), testosterone, and other sex steroids, on the development of type 2 diabetes in a cohort of communitydwelling middle-aged to elderly men. Acta Diabetol. Aug 2018;55(8):861-872. Return to content
  • Buysschaert M, Medina JL, Bergman M, Shah A, Lonier J. Prediabetes and associated disorders. Endocrine. Mar 2015;48(2):371-93. Return to content
  • Yassin AA, Alwani M, Talib R, et al. Long-term testosterone therapy improves liver parameters and steatosis in hypogonadal men: a prospective controlled registry study. The aging male : the official journal of the International Society for the Study of the Aging Male. Dec 2020;23(5):1553-1563. Return to content
  • Hoyos CM, Yee BJ, Phillips CL, Machan EA, Grunstein RR, Liu PY. Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial. Eur J Endocrinol. Oct 2012;167(4):531-41. Return to content
  • Huang G, Bhasin S, Tang ER, et al. Effect of testosterone administration on liver fat in older men with mobility limitation: results from a randomized controlled trial. J Gerontol A Biol Sci Med Sci. Aug 2013;68(8):954-9. Return to content
  • Dhindsa S, Ghanim H, Batra M, et al. Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes. Diabetes Care. Jan 2016;39(1):82-91. Return to content
  • Magnussen LV, Andersen PE, Diaz A, et al. MR spectroscopy of hepatic fat and adiponectin and leptin levels during testosterone therapy in type 2 diabetes: a randomized, double-blinded, placebo-controlled trial. Eur J Endocrinol. Aug 2017;177(2):157-168. Return to content
  • Gianatti EJ, Dupuis P, Hoermann R, Zajac JD, Grossmann M. Effect of testosterone treatment on constitutional and sexual symptoms in men with type 2 diabetes in a randomized, placebo-controlled clinical trial. J Clin Endocrinol Metab. Oct 2014;99(10):3821-8. Return to content
  • Zhang X, Huang K, Saad F, Haider KS, Haider A, Xu X. Testosterone Therapy Reduces Cardiovascular Risk Among Hypogonadal Men: A Prospective Cohort Study in Germany. Androgens: Clinical Research and Therapeutics. 2021/09/01 2021;2(1):64-72. Return to content
  • Saad F, Doros G, Haider KS, Haider A. Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study. Int J Obes (Lond). Jun 2020;44(6):1264-1278. Return to content
  • Saad F, Caliber M, Doros G, Haider KS, Haider A. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. The aging male : the official journal of the International Society for the Study of the Aging Male. Feb 20 2020;23(1):81-92. Return to content
  • Haider KS, Haider A, Saad F, et al. Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study. Diabetes, obesity & metabolism. Nov 2020;22(11):2055-2068. Return to content
  • Yassin A, Haider A, Haider KS, et al. Testosterone Therapy in Men With Hypogonadism Prevents Progression From Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study. Diabetes Care. Jun 2019;6(42):1104-1111. Return to content
  • Saad F, Doros G, Haider KS, Haider A. Hypogonadal men with moderate-to-severe lower urinary tract symptoms have a more severe cardiometabolic risk profile and benefit more from testosterone therapy than men with mild lower urinary tract symptoms. Investig Clin Urol. Nov 2018;59(6):399-409. Return to content