Remission of type 2 diabetes during long-term treatment with testosterone undecanoate injections
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
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.
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).
Figure 2: Improvement in lipid profile during long-term testosterone therapy.11
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.
Figure 4: Adverse events in testosterone treated men compared with untreated men.11
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.