Focus on CV risk, T Trials follows 20-year rise in testosterone use
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During the past 2 decades, Endocrine Today has reported on the latest developments in testosterone therapy, including new formulations, debates over indications, and trials assessing risks and benefits for older men.
For its 20th year, the publication is taking a look back.
“The biggest development over the past 20 years has been the explosion of testosterone supplementation among our patients,” Ronald Tamler, MD, PhD, an Endocrine Today Editorial Board Member and director of digital health implementation at Mount Sinai Health System and professor of medicine at the Icahn School of Medicine at Mount Sinai, told Healio. “That was a development that started in 2000 with the introduction of AndroGel (AbbVie), the first widely prescribed branded transdermal testosterone formulation, and with its ensuing marketing.”
At the start of the century, very few men were prescribed testosterone. Testosterone sales totaled $150 million globally in 2000, with a rate of 10.3 monthly doses per 1,000 people in the U.S., according to a 2013 study published in The Medical Journal of Australia. By 2011, sales had increased to $1.8 billion, and the rate of monthly doses in the U.S. increased nearly 10-fold to 98.5 per 1,000 people.
However, testosterone use began to decline by 2013 over concerns about cardiovascular risk. Prescriptions decreased about 0.5% annually in the U.S. from 2013 to 2016, according to a study published in JAMA in 2018.
In response to a dearth of data about benefits and risks, the NIH sponsored a set of clinical trials — the T Trials — beginning in 2009. Results published in 2016 and 2017 in JAMA and The New England Journal of Medicine showed improvements in libido, bone strength and anemia associated with testosterone therapy for older men, but also increased noncalcified coronary artery plaque. However, the studies were too small to demonstrate clinical effects on fracture or CVD events.
“It was a well-designed study,” Adrian S. Dobs, MD, MHS, director of the Johns Hopkins Clinical Research Network and professor of medicine and oncology in the division of endocrinology, diabetes and metabolism at The Johns Hopkins University School of Medicine, told Healio. “Peter J. Snyder, MD, wanted to look at multiple outcomes for benefit and also safety. His outcome measures were bone, brain, quality of life, sexual function, depression and muscle function. It was a nice design where people would be randomized into getting testosterone or not getting testosterone, but they also weren’t looking at all of the outcomes in every patient. They classified people into looking at the cognitive changes, bone changes or muscle changes in each population.”
Also during this period, researchers began exploring the association of low testosterone levels with cardiometabolic disease. In a study published in 2004 in The Journal of Clinical Endocrinology & Metabolism, Paresh Dandona, MD, PhD, SUNY distinguished professor and chief of endocrinology in the department of medicine at the University of Buffalo, New York, and colleagues found one-third of men with type 2 diabetes had hypogonadotropic hypogonadism.
“Part of that discovery was that the defect was in the hypothalamus. ... The hypothalamic-pituitary axis was responsible,” Dandona, also an Endocrine Today Editorial Board Member, told Healio. “The correlation of the low testosterone was not with the severity or the duration of diabetes, but with body fat, BMI. ... The higher the BMI, the lower the testosterone. That led to a few years later, the big study from our center, showing that obesity itself was responsible for 25% of the patients being hypogonadal.”
Dandona said that work adds potentially 19 million to the number of U.S. men with undiagnosed hypogonadism.
Rise, controversy surrounding testosterone prescribing
AndroGel, the first transdermal topical testosterone gel approved in the U.S., paved the way for a slew of new testosterone formulations to treat male hypogonadism, including oral testosterone, patches and sprays.
The new products led to expanded marketing, increasing patient requests for testosterone and an increase in prescriptions from both primary care providers and specialists.
As testosterone use approached its peak in 2013, concerns began to arise that too many men were being diagnosed with hypogonadism, according to Tamler. The Endocrine Society published a guideline in 2010 to better assist providers with diagnosing hypogonadism and prescribing testosterone. The guideline, last updated in 2018, recommended diagnosing men with hypogonadism only if they have signs and symptoms consistent with testosterone deficiency and consistently low serum testosterone levels. The Endocrine Society also recommended using accurate assays and confirming a hypogonadism diagnosis through repeat measurement of morning fasting total testosterone concentrations, something that many providers were not previously doing, according to Tamler.
“Instead of doing a workup to determine the origin of the male hypogonadism and to confirm the diagnosis, which required a second lab test in the morning, we were seeing that many providers were just starting testosterone in patients,” Tamler said. “Once patients are on testosterone, it’s very hard to get them off. It becomes a medication that they take for many, many years.”
In addition, some researchers identified increased risk for adverse CV outcomes associated with testosterone use. In one study published in JAMA in 2013, increased risks for myocardial infarction, ischemic stroke and all-cause mortality were observed in a cohort of men using testosterone in the Veterans Affairs health care system compared with men not using testosterone.
The findings on CV safety led the FDA to issue a drug safety communication stating that testosterone products are approved only for men with low testosterone levels caused by certain medical conditions and that the benefit and safety of the medications have not been established for the treatment of low testosterone levels due to aging.
Since then, the findings on CV risk with testosterone use have varied — some studies found an increased risk and others found none. A meta-analysis published in The Lancet Health Longevity concluded there is no evidence that testosterone increases short-term or medium-term CV risk, but researchers noted a paucity of data for long-term risk.
Tamler said the debate on CV health with testosterone use in older men remains open.
“There have been some studies that raised questions about the CV safety of testosterone, and there are other studies that rebuke those,” Tamler said. “This is only for older men — over age 65 or 70 years. If you are aged 30 years, testosterone is safe for CV health.”
Mixed findings emerge from T Trials
As testosterone use increased, more researchers began to ask how much it could benefit older men. In 2003, a committee from the National Academy of Medicine concluded that clinical research was insufficient and recommended the development of a coordinated set of trials on testosterone for men aged 65 years or older with low testosterone and symptoms possibly attributable to the condition.
These trials, named the Testosterone Trials, or the T Trials, completed enrollment of 788 older men in 2013 and continued follow-up visits through June 2015. Participants were randomly assigned to 5 g daily of AndroGel 1% or placebo for 12 months. The initial dose was adjusted based on serum testosterone levels at 1, 2, 3, 6 and 9 months. Results were published in seven articles examining the effects of testosterone compared with placebo on sexual function, physical function, vitality, cognitive function, anemia, bone health and CV health.
The overall results of the T Trials were mixed. There were some benefits, particularly with sexual function, as men randomly assigned to testosterone had increased sexual function and libido at all follow-up visits compared with placebo. The percentage of men with 1 g/dL of hemoglobin was significantly higher in the testosterone cohort compared with placebo at 12 months (54% vs. 15%), and among men with anemia of known cause, 60% of those using testosterone had their condition corrected vs. 14.8% of those in the placebo group. In the physical function trial, testosterone was associated with an increase in the percentage of participants whose distance walked increased by more than 50 m in a 6-minute walking test, though the improvement was minor.
In the bone trial, the testosterone group had significantly greater volumetric bone mineral density and bone strength at the spine and hip compared with placebo. However, the study was not long enough to analyze whether testosterone was associated with a reduced risk for fractures.
Due to the short duration, the trials were unable to answer whether testosterone reduced the risk for prostate adverse events. Dobs noted that, in years past, there was a concern that testosterone could increase the risk for prostate cancer, though that concern has dwindled among health care professionals in recent years.
“We knew that testosterone could increase prostate size slightly, and that made sense because hypogonadal men who had low testosterone all had small prostates,” Dobs said. “If you give them some testosterone, it can increase prostatic size. There was probably some increase in prostate size in truly hypogonadal men, but everyone has accepted the fact that it does not cause prostate cancer.”
There were also some unanswered questions regarding CV health. In the CV trial, men using testosterone had an increase in coronary artery plaque volume. Although testosterone use was not associated with an increase in adverse CV events, the researchers noted the sample size and length of the trial made it unable to draw definitive conclusions.
“Maybe in the future, we could identify patients who might be at risk for certain complications or patients that might benefit from it,” Dobs said. “We talk a lot about increased hematocrit with testosterone and increased blood pressure with testosterone. There is a growing appreciation about potential risk factors, but a risk factor with a true concern is CVD. It’s just pointing to the fact that we must be monitoring hematocrits a lot better because that could lead to the development of heart disease.”
Testosterone and cardiometabolic disease
Much of the debate surrounding testosterone over the past 20 years focused on sexual function, bone health and CV health, but researchers have also examined whether testosterone could treat cardiometabolic diseases. A study published in the European Journal of Endocrinology in 2006 found that men treated with intramuscular testosterone 200 mg every 2 weeks had a 0.37% reduction in HbA1c and less insulin resistance at 3 months.
More recent research has also found testosterone could help men with obesity lose weight and induce diabetes remission. In findings from a randomized controlled trial published in The Lancet Diabetes & Endocrinology in 2021, a cohort of men with type 2 diabetes using testosterone had a larger decrease in glucose levels at 2 years compared with men assigned placebo. In another study published in 2022, a cohort of 34 adolescent boys had a mean BMI reduction of 28.7% 5 years after undergoing bariatric surgery. In addition to weight loss, total testosterone more than doubled in the cohort at 2 years from 6.7 nmol/L at baseline to 17.6 nmol/L.
“It’s a remarkable growth area,” Dandona said. “We need to propagate the fact that every diabetic and every obese patient needs to have testosterone concentrations measured, because if you measure testosterone concentrations [in people with diabetes and obesity], you will find them to be low. If you treat, you will reverse the syndrome.”
Despite the findings, Dandona said, many physicians hesitate to prescribe testosterone therapy for men and adolescent boys with diabetes or obesity due to the concerns with CV risk.
“I am disappointed with the rate at which this has been taken up because the whole syndrome starts in childhood,” Dandona said. “These children, if they’re not treated appropriately, will remain sexually impotent and infertile. That’s the group I’m beginning to focus on right now.”
Dobs agreed that the research on testosterone’s effect on diabetes and obesity is fascinating. However, she added that prescribing testosterone to treat diabetes and obesity is not fully accepted in practice and more questions need to be answered in future studies.
“There’s a question of do you treat the underlying comorbidity, such as obesity, or do you treat the testosterone, or should they be done at the same time?” Dobs said. “How long should you let a man stay hypogonadal? If somebody truly has low testosterone levels and is truly symptomatic, even though it may be due to a comorbidity such as diabetes or obesity, what is the role of treating those men while they are getting better for their comorbidity?”
References:
- Baillargeon J, et al. JAMA. 2018;doi:10.1001/jama.2018.7999.
- Bhasin S, et al. J Clin Endocrinol Metab. 2018;doi:10.1210/jc.2018-00229.
- Dhindsa S, et al. J Clin Endocrinol Metab. 2004;doi:10.1210/jc.2004-0804.
- Dhindsa S, et al. Eur J Endocrinol. 2022;doi:10.1530/EJE-21-0545.
- Handelsman DJ. Med J Aust. 2013;doi:10.5694/mja13.10111.
- Hudson J, et al. Lancet Healthy Longev. 2022;doi:10.1016/S2666-7568(22)00096-4.
- Kapoor J, et al. Eur J Endocrinol. 2006;doi:10.1530/eje.1.02166.
- Snyder PJ, et al. Endocr Rev. 2018;doi:10.1210/er.2017-00234.
- Vigen R, et al. JAMA. 2013;doi:10.1001/jama.2013.280386.
- Wittert G, et al. Lancet Diabetes Endocrinol. 2021;doi:10.1016/S2213-8587(20)30367-3.
For more information:
Paresh Dandona, MD, PhD, can be reached at dandona.diabetes@gmail.com.
Adrian S. Dobs, MD, MHS, can be reached at adobs@jhmi.edu.
Ronald Tamler, MD, PhD, can be reached at ronald.tamler@mssm.edu.
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