Testosterone Therapy Halts Prediabetes in Men with Hypogonadism

Testosterone replacement halted the progression to diabetes in 90% of men who had hypogonadism, achieving improvement risk factor measures including body weight and lipids, in men who had a diagnosis of prediabetes prior to treatment.

With W. Timothy Garvey, MD, and Sangeeta Kashyap, MD

Long-term testosterone therapy proved effective in preventing the progression of prediabetes to type 2 diabetes in men with hypogonadism, based on findings published in Diabetes Care. In addition, testosterone therapy improved the patients’ glycemia, lipid profiles, and overall quality of life, according to the researchers.

In men with type 2 diabetes and impaired glucose tolerance, the incidence of hypogonadism is between 20% and 64%. How often do you consider this condition in your patients?

Identifying hypogonadism is essential to avoid risk of diabetes and heart disease in men.

Testosterone Treatment Highly Beneficial in Hypogonadism

For this study, 229 men were treated with testosterone and 87 received only a placebo,. In the treated group, 90% of these men achieved normal glucose regulation as calculated by a hemoglobin A1c (HbA1c) of less than 5.7% while 40.2% in the untreated group progressed to type 2 diabetes (T2D)."These men not only had low T but symptoms of hypogonadism," Dr. Garvey stated.

"The study resulted in really dramatic data," said co-author, W. Timothy Garvey, MD, the Butterworth Professor of Nutrition Sciences and director of the UAB Diabetes Research Center at the University of Alabama at Birmingham.

"We've known for quite a while that testosterone replacement in hypogonadal men with diabetes may help in diabetes control," Dr. Garvey said. It has also been known that men with hypogonadism were at increased risk of developing insulin resistance, and eventually T2D.

"And yet, this study really addressed a cohort known for being at high risk for diabetes," he said, and the findings were so dramatic as to surprise us, he said, "it was really quite remarkable, in my opinion."

In the paper, Dr. Garvey and his research team stated: "Our study showed for the first time that long-term testosterone therapy (TTh) completely prevented progression of prediabetes to overt T2D in men with hypogonadism and prediabetes." The treated group also experienced significant improvements in their serum cholesterol levels as well as the Aging Males' Symptoms (AMS) scale.

Long-term Robust Trial of Men with Hypogonadism, Prediabetes

The researchers followed the 316 men enrolled in the clinical trial for eight years. Patients were pooled from two ongoing urological registries.  

At baseline, both the treated group and the control group had similar measures for body mass index (BMI) and serum glucose levels (HbA1c). One difference was noted--the mean age of the treated group was somewhat younger—58.2 years old as compared to the control group whose mean age was 66.4 years old.1

The average BMI was 30.7 kg/m2 in the treated group, and 29.8 in the untreated. Both groups' average A1c was 5.9% kg/m2. All patients had total testosterone levels of < 12.1 nmol/L combined and presented with symptoms of hypogonadism.1

Impact of Testosterone Therapy on Diabetes Progression

In effect, treatment with testosterone hormone replacement normalized total testosterone levels after the first injection in the cohort of men with hypogonadism and prediabetes, said Dr. Garvey. Trough levels were measured before the next injection, falling between 461-519 ng/dL (16-18 nmol/L) throughout the entire follow up period.1

In comparison, among men in the control group, testosterone levels remained in the 260-317 ng/dL (9-11 nmol/L) range for the duration of the study. As a frame of reference, the Endocrine Society guidelines consider a low T level at 263 ng/dL and below.2

By the end of the study,1 the HbA1c levels had declined by 0.39 (P < 0.0001) in the treatment group as compared to the control group, in which the men experienced an increase in HbA1c of 0.63 in (P < 0.0001). Fasting blood glucose decreased in the treated group (-0.4 mmol/L) and increased in the untreated men of 0.80 (P < 0.0005; an estimated adjusted difference between groups). After eight years, the men receiving testosterone replacement achieved a weight loss on average of 8.8 kg with the untreated men gaining an average of 9.1 kg.1

At the last follow-up, all participants in the treated group had an HbA1c below 6.5% and 90% of men had reached normal glucose regulation with an HbA1c below 5.7%.  Only one of the 87 untreated control subjects had an HbA1c below 5.7%, and 40.2% of controls had progressed to frank T2D with an HbA1c of more than 6.5%.Retention was very good; only two men in the treated group dropped out after relocating.

Testosterone replacement therapy also resulted in a reduction of total cholesterol, LDL and triglyceride levels and an increase in HDL levels. Total cholesterol decreased by 1.3 mmol/L in the treated group and increased by 0.8 mmol/L in the controls (P < 0.0001). The LDL decreased by 0.9 mmol/L in the treated group; increased 0.5 mmol/L in the untreated men (P < 0.0001). Triglycerides decreased 0.5 mmol/L in the treatment group, yet rose 0.5 mmol/L in the control group (P < 0.0001). 4

Also of note: mortality was 16.1% in the untreated group and 7.4% in the treated. Six men had a nonfatal myocardial infarction, with all but one coming from the non-treated cohort, and one patient in the control group experienced a nonfatal stroke.1  Dr. Garvey et al stated that the findings were consistent with previous research on the metabolic benefits of TTh in those with hypogonadism and diabetes.4

“Exactly why the testosterone halted the progression of the prediabetes remains uncertain,” Dr. Garvey told EndocrineWeb. Certainly, weight loss may be one contributing factor, Another factor may be the increase in lean muscle mass as a result of TTh treatment. "If patients have an increase in lean muscle mass, they will be able to handle a higher glucose load better," he said.

Testosterone Therapy Endorsed to Prevent Diabetes Progression 

"This data are encouraging for patients with both prediabetes and hypogonadism, suggesting that their metabolic abnormalities may be attributed to their hypogonadal state," said Sangeeta Kashyap, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine, in reviewing the findings for EndocrineWeb.   

"The effects of testosterone replacement therapy on the prevention of diabetes in those at increased risk for this chronic disease as in this trial are impressive, particularly in that no subjects on testosterone treatment developed diabetes as opposed to the experience of those in the non-treatment control group," Dr. Kashyap said.

Of most interest to clinicians, she said, is the added benefit of not only treating symptomatic hypogonadism but also preventing the progression of prediabetes to T2D, and arresting the complications such as hyperlipidemia. "These effects may be due to the favorable impact of testosterone on body composition and weight loss, insulin sensitivity, and greater quality of life," she said, agreeing with the conclusions shared by Dr. Garvey.

The data, Dr. Kashyap added, ''will encourage physicians to evaluate their male patients for hypogonadism when a diagnosed of prediabetes and metabolic syndrome are noted."

More Attentiveness Needed to Identify at Risk Men 

Will the findings change practice? "I believe so," Dr. Garvey said. At the very least, these results are compelling enough that physicians will want to more aware of the need to screen patients who are in this subset with prediabetes and hypogonadism. "We need to put this a little higher on our radar," Dr. Garvey told EndocrineWeb. “This may prove challenging since patients are not always forthcoming about discussing symptoms of hypogonadism.”

“Therefore, if you have a patient with prediabetes or appears at high risk of diabetes, you should ask about symptoms that may suggest screening for hypogonadism," he said. In his practice, he simply asks, for instance: "Have you had a decreased interest in sexual activity?"

You might also consider asking them to complete the Androgen Deficiency in Aging Male questionnaire (ADAM). A testosterone level of 8 nmol/L and a  positive ADAM score may be considered a sound screening for hypogonadism.

Neither Dr. Garvey nor Dr. Kashyap had any relevant financial conflicts. Other co-authors on the paper received travel grant and speakers' honoraria from Bayer AG, one researcher is a fulltime Bayer AG employee. Bayer AG, which makes testosterone undecanoate (Nebido), contributed funding to support the study.

Continue Reading:
Higher Risk for Cardiovascular Events Found With Testosterone Injections Versus Gels
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