Treatment of low T not risk free

Testosterone and Cardiovascular Risk

The Medical Letter on Drugs and Therapeutics • March 3, 2014 (Issue 1437) p. 17

Read our blog post on this topic (posted below)

Prompted by the recent publication of 2 retrospective studies, the FDA has announced that it is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products.1

The first study examined the records of 8709 men with low testosterone levels (<300 ng/dL) who underwent coronary angiography between 2005 and 2011; 1223 of these men started testosterone therapy after a median of 531 days following coronary angiography. Three years after coronary angiography, the Kaplan-Meier estimated cumulative percentages of men who died or had a myocardial infarction (MI) or ischemic stroke were 26% of those treated with testosterone and 20% of those who were not treated with the hormone, a hazard ratio of 1.29 (95% CI 1.04-1.58; P=0.02).2 The second study compared the rate of nonfatal MI during the 90 days after filling a prescription with the rate in the prior year in 56,000 men given a prescription for testosterone and in 167,000 given a phosphodiesterase type 5 inhibitor (sildenafil [Viagra] or tadalafil [Cialis]). In the testosterone group as a whole, the post / pre-prescription rate ratio was 1.36, but in men ≥65 years old it was 2.19 and in younger men with a history of heart disease it was 2.90. In men who received a prescription for sildenafil or tadalafil, the rate ratio was 1.08 for all ages, 1.15 for those ≥65 years old, and 1.40 for younger men with a history of heart disease.3 A recent meta-analysis of randomized, placebo-controlled trials of testosterone therapy also found an increased risk of cardiovascular-related events in men treated with the hormone (odds ratio [OR] 1.54; 95% CI 1.09-2.18); an analysis by funding source found that the risk was greater in trials not funded by the pharmaceutical industry (OR 2.06 vs. 0.89).4

 Testosterone Replacement Therapy

The next (March 3, 2014) issue of The Medical Letter will include a short article on the cardiovascular risks of testosterone replacement therapy. The impetus for this piece was a Drug Safety Communication from the FDA announcing that the agency was investigating the risk of stroke, heart attack, and death in men taking FDA-approved replacement products.

Testosterone is popular. A 2011 article in The Medical Letter mentioned 4 transdermal products (3 gels and a patch), one buccal tablet, and 2 injectable formulations. A 2013 editorial in The New England Journal of Medicine estimated that nearly $2 billion per year are spent on these products. Undoubtedly some of those dollars are spent on the FDA-approved indication, which is hypogonadism (defined by testosterone serum concentrations <300 ng/dL), but I suspect that many or most of them come from young men seeking to enhance their appearance or their athletic prowess and older men trying to regain the energy and sexual prowess of youth, without regard for their serum testosterone levels.

Testosterone actually can increase feelings of wellbeing, strength, physical performance, muscle mass, and libido. But is it safe? The main concern with prescribing the hormone has been whether it could promote the growth of prostate cancer. Androgen deprivation through surgical or medical castration is a standard treatment for the disease, but there is no convincing evidence that testosterone replacement therapy increases the risk of prostate cancer. A 2006 study published in the Journal of the American Medical Association described prostate biopsies obtained at baseline and after 6 months of testosterone replacement therapy in 40 elderly men with hypogonadism; no treatment-related change was observed in prostate histology.

Now we have a cardiovascular signal. Is it weak or is it strong? The next issue of The Medical Letter will shed some light on that question, but the large long-term controlled trial we need to really know the answers to all of our questions about testosterone replacement therapy is nowhere in sight.

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