Testosterone Prevents Progression to Diabetes in Hypogonadal Men

Liam Davenport

March 26, 2019

Normalizing testosterone levels through replacement therapy could prevent men with low testosterone levels, or hypogonadism, and prediabetes from progressing to type 2 diabetes, the results of a registry study suggest.

Aksam Yassin, MD, Institute for Urology and Andrology, Norderstedt, Germany, and colleagues looked at more than 300 men from two registries who had low testosterone levels, symptoms of hypogonadism, and raised HbA1c levels.

Of almost 90 men, 40% who opted out of testosterone therapy went on to develop type 2 diabetes over 8 years, but none of the more than 200 men who took testosterone replacement therapy progressed to diabetes, according to the results, published online March 12 in Diabetes Care.

Crucially, the vast majority of the treated men achieved normal glucose regulation, in addition to which they saw improvements in lipid levels and quality of life.

The team writes that "to our knowledge, this study is the first to show that testosterone therapy can completely prevent prediabetes progression to overt type 2 diabetes."

They add: "Interventions that aim to prevent prediabetes progression to diabetes ideally should restore normoglycemia rather than just maintain the prediabetes state.

"In this regard, it is particularly notable that 90% of men treated with testosterone achieved regression to normal glucose regulation."

"Dramatic" Results That Will Have "Impact"

Study author W. Timothy Garvey, MD, Department of Nutrition Sciences, University of Alabama at Birmingham, told Medscape Medical News that he was "surprised" by the "dramatic results," which he believes are "going to have a lot of impact."

He nevertheless cautioned that testosterone therapy should not be given to "any man with prediabetes who has low total testosterone," as testosterone levels are lower in men with insulin resistance because of the reduced production of sex hormone binding globulin.

The "important issue" is that the men in the study had symptoms of hypogonadism, and so had "true hypogonadism."

He added: "It's really the presence of symptoms that make the difference."

Overall, Garvey believes the results add "another reason" to treat men with hypogonadism "and get testosterone levels up to normal."

Approached for comment, Louis Philipson, MD, PhD, director of the Kovler Diabetes Center at the University of Chicago, Illinois, told Medscape Medical News that, despite a number of limitations, "it is a study that grabs one's attention."

He pointed out that it was a nonrandomized, unblinded study supported by a drug company and there were baseline differences between the treatment and control groups, yet "the editors clearly felt this was a study worth publishing because this is a win."

Philipson continued that the take home message is that "if men have symptoms of low testosterone, they should by all means discuss it with their doctor and, if it is low, testosterone replacement could have multiple benefits."

He also agreed with Garvey that treatment should be reserved for men who have proven hypogonadism.

"This is not about the general population," he said. "We don't want to run around giving people testosterone. Lord knows the world has enough testosterone."

"But in those men who are, by blood test, low it turns out they have a higher chance then of getting diabetes, but if you replace it those chances go down."

Testosterone-Treated Men Less Likely to Die or Have a Heart Attack

The researchers say that men with hypogonadism have an increased risk of developing insulin resistance and, subsequently, type 2 diabetes.

With long-term testosterone therapy also leading to sustained weight loss, the researchers examined whether treating men with hypogonadism and prediabetes would slow their progression to type 2 diabetes.

They pooled data from two ongoing urological registries on 316 men with prediabetes, defined as an HbA1c level between 5.7% and 6.7%, and total testosterone level ≤ 12.1 nmol/L, as well as symptoms of hypogonadism.

After a 6-week interval, 229 men were given parenteral testosterone undecanoate (TU) 1000 mg every 12 weeks. The 87 men who chose not to have testosterone therapy acted as controls.

Anthropometric and metabolic measures, including total testosterone, fasting glucose, and HbA1c levels, were assessed at least twice a year.

The group treated with testosterone were significantly younger than those who opted out of treatment, at a mean of 58.2 years versus 66.4 years (P < .0001).

Treated men were also significantly heavier than untreated men, at a mean of 96.5 kg versus 92.9 kg (P < .05), and had a significantly larger average waist circumferences, at 104.2 cm versus 101.1 cm (P < .005).

Men given testosterone therapy had also significantly lower high-density lipoprotein cholesterol (HDL-C), higher triglycerides, and worse scores on the Aging Males' Symptoms (AMS) quality of life scale (P < .0001 for all).

In addition, the testosterone group had lower mean testosterone levels at baseline than the untreated group, at an average of 8.2 nmol/L versus 9.6 nmol/L (P < .0001).

Over 8 years, contributing 1993 patient-years of follow-up, HbA1c levels decreased by an average of 0.39% in the testosterone group compared with a mean increase of 0.63% in the untreated group (P < .0001).

At the final assessment, all 229 patients in the testosterone group had an HbA1c < 6.5%, and 205 (90%) had achieved a normal glucose level, at a mean HbA1c < 5.7%.

In contrast, just one (1%) of the 87 patients in the untreated group had an HbA1c < 5.7% and 35 (40.2%) had progressed to type 2 diabetes, with an HbA1c > 6.5%.

The testosterone group also lost an average of 8.8% (9.2 kg) in body weight over the study period, compared with a mean gain of 9.1% (8.0 kg) in the untreated group (P < .0001).

In addition, the testosterone group had a reduced waist circumference of 6.8 cm versus an increase of 7.4 cm in the untreated group.

There was also reductions in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels and an increase in HDL-C levels in the treated group. AMS scores also improved.

After 8 years, there was also a significant difference in mortality between treated and untreated men, at 7.4% versus 16.1% (P < .05), and in rates of myocardial infarction, at 0.4% versus 5.7% (P < .005).

Discussing the findings, the team says that weight loss of 10% through diet and exercise interventions "is notoriously difficult to achieve, and even harder to maintain long term."

Multifactorial Risk Reduction in Hypogonadism With Prediabetes

Noting that their attrition rate, at only two men overall, was "extremely low," they say that "long-term testosterone therapy with TU injections is effective for achieving marked lasting weight loss and prevention of diabetes and feasible long term in real life."

Nevertheless, they suggest that the "main mechanism explaining how testosterone therapy prevents development of diabetes is likely improvement in insulin sensitivity," as indicated by the impact on HDL-C and triglyceride levels, among other parameters.

"In summary, given the observed improvements in glycemia, insulin resistance, body weight, and lipids, our study shows that testosterone therapy provides a multifactorial and comprehensive cardiovascular disease risk reduction in men with hypogonadism and prediabetes."

Philipson noted, however, "For anybody contemplating this kind of therapy, one has to balance the good with the bad, and testosterone we know can increase prostate size."

He added: "There's a small fear that testosterone replacement could, say, enhance prostate cancer, but in this study they were careful to give a low dose of testosterone."

"And also, of course, it has to be given by injection...so men either have to learn how to give it themselves at home or come into the doctor at some interval...anywhere from every 2 weeks to once a month."

The study was financially supported by Bayer AG. Yassin and Ahmad Haider received financial contributions for data entry, travel grants, and speakers honoraria from Bayer AG. Karim S. Haider received travel grants and speakers honoraria from Bayer AG. Gheorghe Doros received payment for statistical analyses from Bayer AG. Farid Saad is a full-time employee of Bayer AG.

Diabetes Care. March 12, 2019. Full text

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