What is known about testosterone, obesity and type 2 diabetes
Testosterone levels decline with increasing degree of obesity, commonly assessed by surrogate obesity markers such as waist circumference, waist-to-height ratio and BMI. Up to 80% of obese men have hypogonadism.9,10 Consequently, the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) recommend that men with obesity (waist circumference ≥102 cm or BMI ≥30) and/or diabetes should be assessed for hypogonadism, and in case of low testosterone and symptoms of androgen deficiency be offered testosterone therapy.11
Hypogonadism is also common in men with type 2 diabetes, regardless of body weight.2 Nevertheless, men with type 2 diabetes who also have obesity are particularly prone to also have hypogonadism. This prompted the American Diabetes Association (ADA) to add the clinical guideline recommendation that testosterone levels should be measured in men with type 2 diabetes who have symptoms of hypogonadism such as erectile dysfunction, loss of libido, fatigue and depressed mood.12
What this case study adds
This case presents a 57-year-old man who was referred to a urologist due to benign prostatic hyperplasia and erectile dysfunction. He had type 2 diabetes, overweight (BMI 28.4 kg/m2), abdominal obesity (waist circumference 102 cm), hypertension, dyslipidemia and a history of myocardial infarction.
At the time of referral, the patient was taking several medications; metformin 1000 mg twice daily), simvastatin 40 mg once daily, acetylsalicylic acid 100 mg once daily, and ramipril 5 mg twice daily.
Despite medications, diabetes, lipid and blood pressure control was insufficient: HbA1c 7.2%, fasting blood glucose 6.6 mmol/L, insulin resistance (HOMA-IR: 8.5), dyslipidemia (total cholesterol 7.4 mmol/L; LDL 4.9 mmol/L; HDL 0.9 mmol/L; LDL/HDL ratio 5.4; triglycerides 3.0 mmol/L) and hypertension (176/118).
The patient’s blood test showed a low total testosterone level of 11.1 nmol/L, which is below the commonly used diagnostic threshold of 12 nmol/L as defined by the European Association of Urology (EAU).13 His symptoms were assessed with the Aging Males’ Symptom (AMS) questionnaire; with a total AMS score of 65, the patient had severe symptoms. Low testosterone levels combined with symptoms constitute the diagnosis of hypogonadism. Therefore, testosterone therapy was started with intramuscular injections of testosterone undecanoate at 3-month intervals after an initial 6-week interval. In this report we present testosterone treatment data for a follow-up period of 11 years and 9 months. Prior to each injection, the patient underwent medical examination, which included laboratory testing of testosterone levels (representing trough values) and metabolic risk factors.
After the first injection, the patient’s testosterone level raised to 15 nmol/L and at 36 months to 20 nmol/L, and thereafter remained at 15-20 nmol/L throughout the observation time. During the first 4 years of testosterone therapy, the patient progressively lost weight (–10 kg), resulting in a BMI of 25 kg/m2, with an accompanying reduction in waist circumference by 8 cm. The weight loss was maintained throughout the entire follow-up period.
Glycemic control and lipid profile improved progressively during the testosterone undecanoate treatment period. HbA1c dropped to 6.5% at month 21 and 5.7% at month 36 and stayed below 5.7% for the rest of the treatment period. Fasting blood glucose decreased to 6.0 mmol/L after 3 months, to 5.7 mmol/L after 12 months, and stayed below 5.7 mmol/L for the rest of the treatment period. Insulin resistance improved, with HOMA-IR dropping to 3.9 at month 24. Blood pressure and serum lipid levels had markedly improved by month 30 (137/84 mmHg, LDL/HDL ratio < 3, triglycerides ⩽ 2.5 mmol/L).
As a result of the improvement in glycemic control, metformin was reduced from 1000 mg twice daily to once daily at month 10 and discontinued at month 30 (2.5 years after start of testosterone therapy). Glycemic control continued to improve with continued testosterone undecanoate treatment despite discontinuation of metformin (figure).
Figure: Large improvement in glycemic control during long-term treatment with testosterone undecanoate injections (Nebido®).8
As a result of improvement in blood pressure and lipid profile, ramipril 5 mg could be reduced from twice to once daily at month 25, and simvastatin medication was reduced from 40 mg once daily to 20 mg once daily at month 38. At the beginning of year 6, both ramipril and simvastatin were stopped completely upon decision by the patient’s family physician.
The patient’s lower urinary tract symptoms (LUTS) also significantly improved: residual bladder volume of originally 55 mL dropped to 10 mL (despite an increase of prostate volume from 28 to 34 mL due to benign BPH), and the International Prostate Symptom Score (IPSS) decreased from 8 (moderate symptoms) to 2 (mild symptoms). The patient’s AMS score of 65 (severe symptoms) at the time of referral dropped to below 20 (no symptoms) after 1 year of testosterone therapy and remained constant below 20 during the following years of testosterone therapy.
Despite free diabetes education opportunities to patients with type 2 diabetes, most patients fail to achieve a therapeutic weight loss, as was the case for the patient presented here. During the first 4 years of testosterone therapy, this patient achieved healthy weight, which reduced BMI from 28.4 to 25 kg/m2, and no longer met the diagnostic threshold for abdominal obesity. Remarkably, this waist and weight loss was maintained throughout the entire 11-year period of treatment with testosterone undecanoate. Large sustained weight loss, around 10%, with long-term testosterone undecanoate treatment for up to 8 years has been documented in several “real-life” registry studies.14-18
The reductions in obesity parameters explain, at least partly, the improvement in cardiometabolic and LUTS parameters, which returned to normal range. Considering the patient’s history of a myocardial infarction, the reduction of cardiometabolic risk factors is particularly clinically relevant. Support for this comes from a long-term “real-life” registry study which found that men who had been treated with testosterone undecanoate for up to 10 years had a marked reduction in mortality, compared to untreated men.19 There were 2 deaths in the testosterone treated group, none of which was related to cardiovascular events. In contrast, there were 21 deaths in the untreated group, 19 of which were related to cardiovascular events.19
In community settings, remission of type 2 diabetes without bariatric surgery is very rare.20 For example, in an integrated healthcare delivery system the incidence of diabetes remission was analysed among 122,781 adults with type 2 diabetes.20 Remission was defined as the absence of ongoing drug therapy, and three forms of type 2 diabetes remission were distinguished:
- Partial diabetes remission: at least 1 year of prediabetic hyperglycemia (HbA1c 5.7-6.4% [39-46 mmol/mol]).
- Complete diabetes remission: at least 1 year of normoglycemia (HbA1c <5.7% [<39 mmol/mol]).
- Prolonged diabetes remission: complete remission for at least 5 years.
It was found that the 7-year cumulative incidence of partial, complete, or prolonged remission was 1.47%, 0.14%, and 0.007%, respectively.20
In the present case-report, the patient went into diabetes remission at month 30 (2.5 years), when metformin was discontinued. Remarkably, glycemic control continued to improve with continued testosterone undecanoate treatment despite discontinuation of metformin. At the final visit, 11 years and 9 months (141 months) after having started treatment with testosterone undecanoate, the patient’s HbA1c was 5.5%. Hence, the remission period was 111 (141 – 30) months, or 9.25 years, indicating prolonged remission.
We previously reported remission of type 2 diabetes in a man with obesity who was treated with testosterone undecanoate for 10 years.7 For more information, see https://hcp.nebido.com/hcp/testosterone-news-resources/research-news/remission-of-type-2-diabetes-in-a-hypogonadal-man-after-long-term-testosterone-therapy
His BMI dropped from 37.1 to 29.6, with a weight loss of 24 kg (20.2%) and reduction in waist circumference of 12 cm.7 Metformin was discontinued in year 10. This contrasts with the patient reported here, who achieved remission after 2.5 years of testosterone therapy. It is to be expected that it will take longer time for a patient with obesity and more severe glycemic status to achieve diabetes remission with testosterone therapy than a patient with overweight and less severe glycemic status. Nevertheless, these two case reports demonstrate that long-term treatment with testosterone undecanoate injections in men with type 2 diabetes can result in diabetes remission, regardless of baseline degree of obesity. The key for achievement of diabetes remission is testosterone treatment duration and adherence.
The present case report is highly remarkable, showing that long-term treatment with testosterone undecanoate injections for 11 years results in prolonged complete remission of type 2 diabetes.There was a progressive normalization of HbA1c and normal glucose regulation was achieved by month 36 onward, now documented for 11 years. Furthermore, there were improvements in all components of the metabolic syndrome. The large amount of weight loss that was maintained during the entire course of testosterone therapy for 11 years likely explains, in large part, the complete remission. 21 Since the weight loss was maintained for such a long period of time, it is expected that the remission will persist with ongoing testosterone therapy.
The symptomatic relief, assessed with the AMS questionnaire, during the first year of testosterone therapy was expected. What is notable is that not only did the score drop during the first year of treatment but it remained low during the following 10 years despite the patient’s aging. At the final visit the patient was 68 years old, without suffering from hypogonadism symptoms and free from type 2 diabetes. These vitally important patient benefits were accompanied by a large reduction in healthcare costs.
The patients in the present 8 and previous 7 case report are continued on treatment with testosterone undecanoate injections and followed for more data collection. A new study published in Diabetes Care showed that treating men with hypogonadism and prediabetes with testosterone undecanoate injections for up to 8 years completely prevented progression to overt type 2 diabetes and also restored normoglycemia (HbA1c <5.7%) in almost all patients. In contrast, among untreated patients, 40.2% progressed to type 2 diabetes (HbA1c >6.5%).15
A larger “real-life” registry study of men with hypogonadism and type 2 diabetes receiving long-term treatment with testosterone undecanoate injections is underway. An abstract from this study has been published, reporting that the average time to discontinuation of diabetes medications, and hence remission of diabetes, is 6.2 years after start of treatment with testosterone undecanoate injections.22 We will report more details about this study once it has been published in its entirety.