Remission of type 2 diabetes during long-term treatment with testosterone undecanoate injections

July 2020

STUDY: 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

Men with type 2 diabetes have lower testosterone levels1 and higher prevalence of hypogonadism than men without type 2 diabetes. Up to 81% of men with type 2 diabetes have hypogonadism.2-7 Testosterone therapy in men with type 2 diabetes and hypogonadism reduces insulin resistance (HOMA-IR) and improves glycemic control.8,9 Confirmation of the beneficial effect of testosterone therapy on glycemic control comes from a real-world evidence study which showed that testosterone therapy with testosterone undecanoate injections for up to 8 years in men with hypogonadism and prediabetes prevented progression to overt type 2 diabetes and restored normal glucose regulation (HbA1c <5.7%).10 For more information about this study, see Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes Here we summarise results from another real-world evidence study, which examined whether long-term treatment with testosterone undecanoate injections can result in remission of type 2 diabetes in men with hypogonadism and established type 2 diabetes.11

KEY POINTS

  • Treatment with testosterone undecanoate injections for 8 years in men with hypogonadism and type 2 diabetes resulted in a significant progressive and sustained reduction in fasting glucose, HbA1c and fasting insulin. In contrast, men with hypogonadism and type 2 diabetes who did not get treatment with testosterone undecanoate injections experienced progressive increases in fasting glucose, HbA1c and fasting insulin over time.
  • Men receiving treatment with testosterone undecanoate injections also had a significant weight loss (-19.3%), reduced waist size (-13.3 cm) and improved lipid profile. All parameters worsened over time in men who did not get treatment with testosterone undecanoate injections.
  • 34% of men receiving testosterone therapy achieved remission of type 2 diabetes, 47% achieved normal glucose regulation and 83% reached the HbA1c target of 6.5%. In contrast, no remission or reduction in glucose or HbA1c levels was seen in untreated men.
  • Mortality rate was 7% in testosterone treated men and 29% in untreated men.
  • There was no myocardial infarction or stroke in testosterone treated men. Among untreated men, incidence of myocardial infarction and stroke was 31% and 25%, respectively.

What is known about

Hypogonadism contributes to development of insulin resistance and elevated blood glucose levels,12 and is a strong risk factor for type 2 diabetes.13 Accordingly, it has been suggested that low testosterone levels may be a reversible risk factor for type 2 diabetes.14,15 For instance, a 2006 meta-analysis showed that men with testosterone levels >15.6 nmol/L (450 ng/dL) have a 42% reduced risk of developing type 2 diabetes compared to men with testosterone levels ≤15.6 nmol/L.14 It is notable that >15.6 nmol/L (450 ng/dL) is higher than the thresholds recommended by clinical guidelines for making the diagnosis of hypogonadism. Another meta-analysis of 13 prospective population studies with 16,709 men showed that higher total and free testosterone levels significantly reduced the risk of type 2 diabetes by 38% and 23%, respectively.13 For more information, see Hypogonadism markedly increases risk of type 2 diabetes and death.

If low testosterone is a reversible risk factor for type 2 diabetes, then it would be expected that long-term testosterone therapy in men with type 2 diabetes and hypogonadism would reduce the severity of type 2 diabetes and possibly also result in remission of type 2 diabetes. The present study aimed to investigate this.

What this study adds

356 men with type 2 diabetes and hypogonadism (total testosterone ≤12.1 nmol/L (350 ng/dL) combined with symptoms) were included in the study.16 All patients received standard diabetes treatment. 178 men additionally received testosterone therapy with testosterone undecanoate injections 1000 mg every 12 weeks (following an initial 6-week interval) for 11 years. The remaining 178 men opted against testosterone therapy and served as control group.

In men who had been treated with testosterone undecanoate injections there were significant progressive and sustained reductions in fasting glucose, HbA1c and fasting insulin throughout the entire treatment period. In contrast, the control group had significant progressive elevations in fasting glucose, HbA1c and fasting insulin. Testosterone treated men who had been on insulin at baseline had a reduction in insulin dose requirement compared with the control group, suggesting improved β -cell function. In contrast, 20 patients in the control group were started on insulin treatment during the observation time, suggesting deteriorated β -cell function.

Remission of type 2 diabetes was defined as HbA1c <6.5% and discontinuation of all diabetes drugs, including metformin. Among testosterone treated men, 34.3% (61 out of 178 patients) achieved remission of their diabetes, of whom 22 had been on insulin at baseline. The average time to discontinuation of diabetes medications was 8.6 years. Average time in remission was 2.5 years. There were no relapses. 46.6% of patients achieved normal glucose regulation. 83.1% of testosterone treated men reached HbA1c target of 6.5%, 90% achieved HbA1c target of 7.0% (figure 1). In contrast, no remission of diabetes or reduction in glucose or HbA1c levels was observed in the control group.

Proportion of patients achieving remission of type 2 diabetes, normal glucose regulation (HbA1c <5.7% or 39 mmol/mol)

Figure 1: Proportion of patients achieving remission of type 2 diabetes, normal glucose regulation (HbA1c <5.7% or 39 mmol/mol), and HbA1c targets of 6.5% or 7.0% (47.5 or 53.0 mmol/mol).11

There were marked changes in the lipid profile throughout the observation period. In testosterone treated men, total cholesterol, LDL, non-HDL, remnant cholesterol and triglyceride levels significant decreased, while HDL increased (figure 2). In contrast, in the control group all parameters progressively worsened over time (figure 3).

Improvement in lipid profile during long-term testosterone therapy

Figure 2: Improvement in lipid profile during long-term testosterone therapy.11

Worsening lipid profile in men with hypogonadism who do not receive testosterone therapy

Figure 3: Worsening lipid profile in men with hypogonadism who do not receive testosterone therapy.11

Testosterone therapy resulted in a progressive and sustained reduction in body weight of -22.1 kg (-19.3%) and waist circumference of -13.3 cm. In contrast, the control group had an increase in body weight and waist circumference of +6.8 kg (+7.4%) and +7.1 cm, respectively.

Estimated glomerular filtration rate (eGFR) – calculated by the Modification of Diet in Renal Disease formula – markedly improved in testosterone treated men (+9.8 ml/min/1.73 m2) compared to the control group (-22.3 ml/min/1.73 m2). Inflammation (assessed by hsCRP) was significantly reduced in the testosterone group (-3.9 mg/L) and increased (+1.5 mg/L) in the control group.

Quality of life, assessed by AMS (Aging Males’ Symptom) questionnaire, and erectile function, assessed by IIEF-EF, improved significantly in the testosterone group and declined in the control group. In testosterone treated men, the improvement in quality of life was significant vs. previous year for the first 4 years, and the improvement in erectile function was significant vs. previous year for the first 5 years and year 11 vs. year 10. In the control group, quality of life and erectile function significantly worsened for each successive year vs. previous year for all 11 years.

There was a significantly higher number of adverse events in the control group than the testosterone group (figure 4). There were 13 (7.3%) deaths in the testosterone group and 52 (29.2%) deaths in the control group. There was not a single case of myocardial infarction or stroke among testosterone treated men, who also had significantly fewer diabetic complications and reduced incidence of prostate cancer and falls than the control group.

Adverse events in testosterone treated men compared with untreated men

Figure 4: Adverse events in testosterone treated men compared with untreated men.11

Commentary

The main finding in this real-world evidence study is that long-term testosterone therapy resulted in a significant progressive improvement in blood glucose, HbA1c, insulin and HOMA-IR, culminating in remission of type 2 diabetes in one third of men with type 2 diabetes and hypogonadism.11 Normal glucose regulation was achieved in 47%. Some of these patients were still on diabetes drugs; upcoming follow-up analyses will examine how many of these patients – who are prime candidates for discontinuation of diabetes drugs – will go into remission.

The Testosterone for Diabetes Mellitus (T4DM) study provides high-quality evidence that treatment with testosterone undecanoate injections for two years combined with lifestyle intervention in men with low testosterone levels significantly reduced prevalence of type 2 diabetes compared to lifestyle intervention alone.17 For more information, see Testosterone therapy for prevention and reversal of type 2 diabetes in men enrolled in a lifestyle program

In the present real-life evidence study, the progressive and significant worsening of insulin resistance, fasting glucose and HbA1c in men with hypogonadism and type 2 diabetes who did not receive treatment with testosterone undecanoate injections suggests that untreated hypogonadism can prevent successful treatment of men with type 2 diabetes.11 The rise in glucose and HbA1c was particularly steep after 6 years of follow-up, suggesting declining β-cell function or β-cell apoptosis. This underscores the importance of early treatment of hypogonadism in order to prevent future health consequences.

Another important finding in the present study is that men who had been treated with testosterone undecanoate injections had significantly lower incidence of death, myocardial infarction, stroke, prostate cancer, diabetic complications and falls than the control group (Figure 4).11 This is consistent with previous studies showing reduced mortality in men with hypogonadism and type 2 diabetes who receive testosterone therapy,18,19 as well as reduced incidence of prostate cancer.20-24 A 14‐year follow‐up study of men with type 2 diabetes found that mortality in men with low testosterone levels was nearly twice as high compared to men with higher baseline testosterone levels.25

For more information, see:

Testosterone levels, testosterone therapy and all-cause mortality in men with type 2 diabetes

Hypogonadism and testosterone treatment following stroke in men with type 2 diabetes

Changes in testosterone levels within individuals and risk of prostate cancer in hypogonadal men

Is there a protective role of testosterone against high-grade prostate cancer?

Dispelling the myth of testosterone treatment and prostate cancer

Testosterone therapy in men with prostate cancer – new research

Incidence of prostate cancer after testosterone therapy for up to 17 years

In the present study, men receiving treatment with testosterone undecanoate injections had significantly increased glomerular filtration rate and significantly lower rate of nephropathy, compared to men in the control group.11 This suggests that long-term testosterone therapy may improve kidney function. Further evidence comes from another real-life evidence study showing that treatment with testosterone undecanoate injections for up to 12 years significantly reduces fatty liver index (FLI, calculated according to Mayo Clinic guidelines) (83.6 to 66.91), gamma-glutamyl transferase (39.31 to 28.95 U/L), bilirubin (1.64 to 1.21 mg/dL) and triglycerides (252.35 to 213 mg/dL).26 These data suggest that long-term testosterone therapy may improve hepatic steatosis and liver function in men with hypogonadism. It is likely that improvement in liver function may have contributed to reduction in heart disease mortality seen in men receiving long-term treatment with testosterone undecanoate injections.10,11,26-28

The present study provides further evidence for the clinical guideline recommendation that men with type 2 diabetes29 and/or obesity30 should have their testosterone level measured and, if diagnosed with hypogonadism, receive testosterone therapy. By improving insulin resistance31 and possibly also β -cell function,32 the underlying causes of type 2 diabetes,33-38 as well as sexual symptoms and health-related quality of life,10,11,17,26-28 testosterone therapy is a unique treatment.

The milestone Testosterone for Diabetes Mellitus (T4DM) study,17 combined with a number of real-life evidence studies10,11,26-28 and cost-effectiveness analyses,39 provide convincing evidence that long-term testosterone therapy may be of significant clinical and economic value for the rapidly growing population of men with hypogonadism and type 2 diabetes.

References

  • Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian journal of endocrinology and metabolism. Jul-Aug 2016;20(4):546-51. Return to content
  • Biswas M, Hampton D, Newcombe RG, Rees DA. Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. Clin Endocrinol (Oxf). May 2012;76(5):665-73. Return to content
  • Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. Jul 2006;60(7):762-9. Return to content
  • Rezvani MR, Saadatjou SA, Sorouri S, Hassanpour Fard M. Comparison of serum free testosterone, luteinizing hormone and follicle stimulating hormone levels in diabetics and non-diabetics men- a case-control study. J Res Health Sci. Dec 13 2012;12(2):98-100. Return to content
  • Hackett GI, Cole NS, Deshpande AA, Popple MD, Kennedy D, Wilkinson P. Biochemical hypogonadism in men with type 2 diabetes in primary care practice. The British Journal of Diabetes & Vascular Disease. 2009;9(5):226-231. Return to content
  • Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab. Nov 2004;89(11):5462-8. Return to content
  • Kapoor D, Aldred H, Clark S, Channer KS, Jones TH. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care. Apr 2007;30(4):911-7. Return to content
  • Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. Jun 2006;154(6):899-906. Return to content
  • 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. Apr 2011;34(4):828-37. 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
  • 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
  • Saad F. Testosterone Therapy and Glucose Homeostasis in Men with Testosterone Deficiency (Hypogonadism). Adv Exp Med Biol. 2017;1043:527-558. Return to content
  • Yao QM, Wang B, An XF, Zhang JA, Ding L. Testosterone level and risk of type 2 diabetes in men: a systematic review and meta-analysis. Endocr Connect. Jan 2018;7(1):220-231. Return to content
  • Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. Mar 15 2006;295(11):1288-99. 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;42(6):1104-1111. 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. Jun 19 2020; Return to content
  • Wittert G, Bracken K, Robledo KP, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. The lancet Diabetes & endocrinology. Jan 2021;9(1):32-45. Return to content
  • Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. Dec 2013;169(6):725-33. Return to content
  • Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long-term testosterone therapy in type 2 diabetes is associated with reduced mortality without improvement in conventional cardiovascular risk factors. BJU Int. Mar 2019;123(3):519-529. Return to content
  • Xu X, Zhang X, Zhong Y, et al. Dynamic Patterns of Testosterone Levels in Individuals and Risk of Prostate Cancer among Hypogonadal Men: A Longitudinal Study. J Urol. Feb 2018;199(2):465-473. Return to content
  • Debruyne FM, Behre HM, Roehrborn CG, et al. Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men. BJU Int. Feb 2017;119(2):216-224. Return to content
  • Ory J, Flannigan R, Lundeen C, Huang JG, Pommerville P, Goldenberg SL. Testosterone Therapy in Patients with Treated and Untreated Prostate Cancer: Impact on Oncologic Outcomes. J Urol. Oct 2016;196(4):1082-9. Return to content
  • Haider A, Zitzmann M, Doros G, Isbarn H, Hammerer P, Yassin A. Incidence of Prostate Cancer in Hypogonadal Men Receiving Testosterone Therapy: Observations from Five Year-median Follow-up of Three Registries. J Urol. Jun 26 2015;193(1):80-86. Return to content
  • Yassin A, Salman M, Talib RA, Yassin D-J. Is there a protective role of testosterone against high-grade prostate cancer? Incidence and severity of prostate cancer in 553 patients who underwent prostate biopsy: a prospective data register. The Aging Male. 2017/04/03 2017;20(2):125-133. Return to content
  • Malipatil NS, Yadegarfar G, Lunt M, et al. Male hypogonadism: 14-year prospective outcome in 550 men with type 2 diabetes. Endocrinology, Diabetes & Metabolism. 0(0):e00064. 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. Jan 13 2021:1-11. 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. Mar 2020;23(1):81-92. Return to content
  • American Diabetes Association. Summary of Revisions: Standards of Medical Care in Diabetes 2018. Diabetes Care. Jan 2018;41(Suppl 1):S4-S6. Return to content
  • Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Available at https://www.endocrinepractice.org/article/S1530-891X(20)44630-0/fulltext (accessed November 17, 2020) Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Jul 2016;22 Suppl 3:1-203. 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
  • Dimitriadis GK, Randeva HS, Aftab S, et al. Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy. Endocrine. Apr 2018;60(1):175-184. Return to content
  • Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. Sep 1999;104(6):787-94. Return to content
  • Chiasson JL, Rabasa-Lhoret R. Prevention of type 2 diabetes: insulin resistance and beta-cell function. Diabetes. Dec 2004;53 Suppl 3:S34-8. Return to content
  • Kasuga M. Insulin resistance and pancreatic beta cell failure. J Clin Invest. Jul 2006;116(7):1756-60. Return to content
  • Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. May 2006;29(5):1130-9. Return to content
  • Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia. Jan 2003;46(1):3-19. Return to content
  • Cerf ME. Beta cell dysfunction and insulin resistance. Frontiers in endocrinology. 2013;4:37. Return to content
  • Yeo S, Holl K, Peñaherrera N, Wissinger U, Anstee K, Wyn R. Burden of Male Hypogonadism and Major Comorbidities, and the Clinical, Economic, and Humanistic Benefits of Testosterone Therapy: A Narrative Review. ClinicoEconomics and outcomes research : CEOR. 2021;13:31-38. Return to content