Testosterone Tx Gives Weak Signal for Cardiovascular Risk

There is no compelling evidence that testosterone therapy increases or decreases cardiovascular risk, according to a new position statement from the American Academy of Clinical Endocrinologists (AACE).

The statement was issued in response to recent publications that have raised concern that testosterone replacement therapy (TRT) increases cardiovascular risks in men and media reports about the dangers of testosterone therapy.

The detailed document noted that “randomized controlled trials have not been powered to evaluate the effect of testosterone replacement in men on cardiovascular events or mortality.” Retrospective studies have raised concern that testosterone therapy increases cardiovascular risk, but those studies have major flaws. A more recent retrospective cohort study that used enrollment and claims data or Medicare beneficiaries showed no effect of TRT on myocardial infarctions.

The AACE statement challenges several aspects of a recent FDA safety announcement that suggests “health-care professionals should make patients aware of the possible increased cardiovascular risk when deciding whether to start or continue a patient on testosterone therapy.” The FDA released a new warning and updated labeling on TRT to reflect the possible increased risk of heart attacks and strokes associated with testosterone use.

The committee that wrote the AACE report, led by Neil Goodman, MD, of the University of Miami Miller School of Medicine, “concurs in the FDA conclusion that the signal for cardiovascular risk is weak and that we need definitive studies.”

The FDA also recommended that TRT be used only for men who have disorders of the testicles, pituitary gland, or brain that cause hypogonadism and not to relieve the symptoms of low testosterone that result from aging.

However, the committee thinks this is not a clear recommendation. “It is our opinion that any patient being considered for TRT must undergo a thorough diagnostic work-up,” they stated. “The decision to replace testosterone should be guided by the signs/symptoms and testosterone concentrations rather than the underlying cause.”

The committee agrees with the FDA that the risk/benefit ratio of TRT is not well established in aging-associated hypogonadism.

Other key points in the position statement:

• Epidemiological studies strongly support the association of low testosterone concentrations and hypogonadism with cardiovascular events and all-cause mortality, especially in older men. However, low testosterone could be a marker of illness and not a causal factor.

• TRT favorably changes many cardiovascular risk factors. It decreases fat mass, increases muscle mass, decreases insulin resistance, and can reverse metabolic syndrome in some men.

In addition, the committee recommends that symptomatic men who have unequivocally low total and/or free testosterone levels that are assayed on at least 2 samples drawn before 10 a.m. should be considered for TRT.

The committee also advises practicing clinicians to use extra caution in symptomatic older patients with demonstrably low testosterone levels before embarking on replacement therapy and “to avoid treatment of the frail elderly until better outcome data are available.”

“Large-scale prospective randomized controlled trials on testosterone therapy, focusing on cardiovascular benefits and risks, are clearly needed,” according to the statement.