Jury Still Out on Cardiovascular Safety of Testosterone

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Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as heart attack or stroke, experts say the jury has still not been tried. A more definitive answer for the cardiovascular safety of testosterone therapy will come from the AbbVie-sponsored TRAVERSE dedicated cardiovascular outcomes trial, which will have up to 5 years of follow-up, with results expected later this year. The current meta-analysis by Jemma Hudson of the University of Aberdeen, UK, and colleagues was published online June 8 in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by lead author Channa Y. Jayasena, MD, PhD. In 2014, the United States Food and Drug Administration (FDA) imposed a label on testosterone products warning of possible increased cardiovascular risks and reserving treatment only for symptomatic hypogonadism. In contrast, the European Medicines Agency has concluded that when hypogonadism is correctly diagnosed and managed, there is currently no clear and consistent evidence that testosterone therapy leads to an increased cardiovascular risk. To address this uncertainty, Hudson and colleagues formed a global collaboration to obtain individual patient cardiovascular outcome data from randomized controlled trials of testosterone therapy for men with hypogonadism. They pooled data from 35 trials published from 1992 to August 27, 2018, including 17 trials (3431 patients) for which the researchers obtained patient-level data. Individual trials lasted 3 to 12 months, except for one 3-year trial. During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to receive testosterone treatment compared to placebo (odds ratio [OR], 1.07; P = 0.62), nor were there significantly increased risks of death, stroke, or different types of cardiovascular outcomes, although these numbers were small. This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide reassurance on the short- and medium-term safety of testosterone to treat male hypogonadism,” they conclude. However, they also acknowledge that “long-term data are needed to fully assess the safety of testosterone.” Erin D. Michos, MD, co-author of an accompanying editorial, told Medscape Medical News, “This study doesn’t tell me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a small number [for blood testosterone] with less severe symptoms. It really depends on each person, their symptoms and their cardiovascular risk.” “The trial is not definitive” Michos is not the only person to be skeptical. With Steven Nissen, MD, researcher for the trial TRAVERSE, she agrees that this new evidence is not yet conclusive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials. Nissen, a cardiologist at the Cleveland Clinic, Ohio , added that the individual trials were heterogeneous, with “very few actual cardiovascular events”, so the meta-analysis “is not definitive”, he said in an interview. “which pooled many smaller studies reassuring that there’s no sign of harm, it’s really inconclusive because the follow-up was really short – an average of just 9.5 months – and you really need a larger study with follow-up longer to be more conclusive,” Michos noted. “We should have more data soon” from TRAVERSE, said Michos, of the Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, who is not involved in this study. Meanwhile, “I don’t think [this analysis] changes current recommendations,” she said. “We must continue to exercise caution, as directed by the FDA label, and only use testosterone therapy selectively in people with true symptoms of hypogonadism”, and to be cautious about its use, especially in men with high cardiovascular risk due to family history or known personal heart disease. On the other hand, the meta-analysis didn’t show harm, she noted, “so we don’t necessarily need to take patients off treatment if they’re already taking it. But I wouldn’t start starting new patients right away unless they had a strong indication.” and the excessive cardiovascular events seen in the TOM trial, write Michos and fellow columnist Matthew J. Budoff, MD , from UCLA, in their editorial Previous data inconclusiveTestosterone levels decline gradually in men with age, at about 2% per year, Michos and Budoff write.In addition, obese or diabetic men have low levels of testosterone, Michos noted.Low blood levels of testosterone have been associated with insulin resistance, inflammation, dyslipidemia and atherosclerosis.Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and increase energy levels, mood, and muscle strength.But it is well known that testosterone increases hematocrit, which has the potential to increase reduce the risk of venous thromboembolism. Two large observational studies reported increased risks of heart attack, stroke and death in men taking testosterone, compared to nonusers, but the study designs were widely criticized, say Hudson and his co-authors in their article. A placebo-controlled trial was terminated prematurely by its Data and Safety Monitoring Board following an increase in cardiovascular events in men aged 65 and over who received 6 months of testosterone. Other controlled trials did not observe these effects, but none were sufficiently powerful. Meta-analysis results Hudson and colleagues performed a meta-analysis of 35 trials in 5601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who were randomized to receive a testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes. The men had an average age of 65 years, had an average body mass index of 30 kg/m2 and most (88%) were Caucasian. A quarter had angina pectoris, 8% had a history of myocardial infarction and 27% suffered from diabetes. Cardiovascular and cerebrovascular outcomes were not primary outcomes. During an average follow-up of 9.5 months, in the 13 trials providing this information, the rate of cardiovascular events was similar in men who received testosterone (120/1601, 7.5%) compared to to those who received a placebo (110/1519, 7.2%). In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1621, 0.4%) than during placebo treatment (12/1537, 0.8%), but these figures were too low to establish whether testosterone reduced the risk of mortality. . The most common cardiovascular events were arrhythmia, followed by coronary artery disease, heart failure, and myocardial infarction. Patient age, baseline testosterone, smoking status, or diabetic status were not associated with cardiovascular risk. The only adverse effects detected were edema and a modest drop in HDL cholesterol. “Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” lead author of the meta-analysis Jayasena said in an email to Medscape Medical News. However, Jayasena added, “Mass testosterone screening has no benefit in asymptomatic men.” “Older men can still benefit from testosterone, but only if they have the clinical characteristics [of hypogonadism] and low testosterone levels,” he concluded. The current study is supported by the National Institute of Health Research’s Health Technology Assessment Program. The TRAVERSE trial is sponsored by AbbVie. Jayasena said he received research grants from LogixX Pharma. relevant financial relationships. Disclosures for other authors are listed in the article. Michos said he received support from the Amato Fund for Women’s Heart Health at Johns Hopkins School of Medicine and served on the medical advisory boards of Novartis, Esperion, Amarin and AstraZeneca outside of the submitted work. Budoff said he received a grant from General Electric. Lancet Healthy Longev. 2022;3:E381-E393, E368-E369. Full Text, Editorial ENDO 2022. To be presented June 13, 2022. Abstract OR-25. For more diabetes and endocrinology news, follow us on Twitter and Facebook.

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