Without Lifestyle Interventions, Glycemic Benefits of Testosterone Therapy Wane After 2 Years

Some of the metabolic benefits of testosterone replacement therapy in men with metabolic syndrome appeared to recede after 2 years without ongoing lifestyle management, new data showed.

Results from a 2-year extension, the RunOn study, of the randomized, double-blind, placebo-controlled Testosterone for the Prevention of Type 2 Diabetes (T4DM) trial were presented at ENDO 2026: The Endocrine Society Annual Meeting by Gary A. Wittert, MBBch, MD.

The original T4DM study included 1007 men aged 50-74 who were either newly diagnosed with type 2 diabetes (T2D) or at high risk of developing it. Adding testosterone therapy to a structured lifestyle intervention reduced the likelihood of T2D at 2 years by 41% (21.1% vs 12.4%; P < .001).

In the RunOn study, 121 participants from the original T2DM trials chose to continue blinded treatment for an additional 2 years, but without the formal lifestyle program. The analysis showed that most glycemic benefits occurred during the initial 2 years, although several metabolic parameters remained more favorable among testosterone-treated men than placebo-treated men through year 4. The proportion with T2D decreased slightly in the placebo group and increased in the testosterone group, Wittert reported.

“My take on this is that for a durable beneficial effect of testosterone, ongoing adherence to a healthy lifestyle program is required,” Wittert told Medscape Medical News.

“Clinicians should not simply be writing a prescription for testosterone but should look more carefully at men’s overall health-related behaviors, sleep, metabolic physical and psychological health, and waist circumference.”

Importance of Lifestyle

In the original T4DM trial, men with impaired glucose tolerance (2-hour glucose 7.8-11.0 mmol/L on oral glucose tolerance test [OGTT]), waist circumference ≥ 95 cm, and low serum testosterone (≤ 14 nmol/L) received intramuscular testosterone undecanoate 1000 mg or placebo at baseline, 6 weeks, and 12 weeks, along with participation in a community-based lifestyle program.

Findings from the original trial included greater reductions in 2-hour OGTT glucose levels with testosterone (mean difference, -0.75 mmol/L; P < .001) and lower fasting plasma glucose (mean difference, -0.17 mmol/L; P = .004).

Testosterone therapy was also associated with greater reductions in waist circumference and total abdominal fat, along with increases in muscle mass and grip strength. However, no significant effects were seen on A1c, blood pressure, or lipid levels.

Sexual function improved across all domains with testosterone therapy, although no significant benefits were observed for overall quality of life or mood. Testosterone also had no significant effect on lower urinary tract symptoms or prostate-specific antigen levels.

“Importantly, the benefits were not explained by the baseline testosterone concentration,” Wittert noted.

Glycemic Gains Greatest First 2 Years

Of the 121 analyzed for the RunOn study, 65 continued testosterone treatment and 59 continued placebo without the lifestyle program. Participants who chose to enter the extension study were less likely to have T2D at the end of the 2-year trial (6% vs 16%) and more likely to have prediabetes (94% vs 84%).

A significant treatment-by-time interaction was observed for both weight and waist circumference. Compared with those receiving placebo, men receiving testosterone weighed 2.3 kg less at 2 years and 2.6 kg less at 4 years. Waist circumference was 1.0 cm lower at year 2 and 1.6 cm lower at year 4 (P < .001 for all).

Testosterone therapy was associated with a mean 1.0 mmol/L lower OGTT glucose level over 4 years (P = .004), with no significant treatment-by-time interaction (P = .360).

“Most of the treatment effect occurred during the first 2 years and then was relatively stable over the subsequent 2 years,” Wittert noted.

Fasting plasma glucose rose over time in both groups (P < .001), although it remained modestly lower among testosterone-treated participants throughout 4-year follow-up (P = .026), again without a significant treatment-by-time interaction (P = .650).

By year 4, T2D was present in 9% of men receiving testosterone and 11% of those receiving placebo (P = .050).

Compared with placebo, sexual desire remained significantly improved with testosterone at year 4 (P < .001), but no significant differences were observed for erectile dysfunction or other domains of the International Index of Erectile Function questionnaire (P > .380).

Hemoglobin and hematocrit increased progressively over the 4 years, although no participant reached the threshold for withdrawal from the trial. No serious cardiovascular, prostate-related, or other major adverse events were reported, and testosterone had no effect on lower urinary tract or voiding symptoms.

Wittert acknowledged several limitations, including the small sample size and the fact that men entering the RunOn study appeared more adherent than those who did not continue in the extension study.

Reassuring Results

Asked to comment, session moderator Channa Jayasena, MD, PhD, professor of reproductive endocrinology and andrology at Imperial College London, London, England, noted the potential for section bias.

“T4DM was a very large study, and this is only about a tenth of those men,” Jayasena told Medscape Medical News. “It’s a small extension study, and there is potential for selection bias. You wonder whether the people who chose not to take part would have behaved the same way.”

Nonetheless, Jayasena said, “The reassuring thing is that when you select men for testosterone treatment, the benefits that were already observed appear to be maintained.”

Asked how adding a GLP1 receptor agonist might influence outcomes, Wittert emphasized that medical interventions should complement, rather than replace, lifestyle measures.

“The same applies,” he said. “It will be most effective when combined with elimination of processed foods, sugared drinks, and alcohol, and a diet consisting of high-quality protein from real food, adequate vegetables, salad items, legumes, and some fruit, along with at least 30-40 minutes of aerobic exercise each day.”

Resistance exercise using lighter weights and frequent repetitions at least three times a week should also be included, he added.

“Those are all interventions that increase blood testosterone concentrations and improve every aspect of health, transcending the benefits of weight loss alone,” Wittert said. “For men who are truly hypogonadal and require testosterone treatment, they will benefit maximally under these circumstances.”

Wittert reported consulting, speaking, and/or having advisory relationships with Lilly, Novo Nordisk, and Opella. Jayasena reported having no relevant disclosures. 

https://www.medscape.com/viewarticle/without-lifestyle-interventions-glycemic-benefits-2026a1000kzv