[OA] Testosterone Therapy: Has Overuse Undermined Use?
“Remember when you had more energy for 18 holes with your buddies?
More passion for the one you love?
More fun with your family and friends?”
So asked one of the many direct-to-consumer (DTC) television advertisements for testosterone replacement therapy that filled the airwaves in the USA until 2014—with the voiceover going on to suggest that “low T” might be the cause, “so don't blame it on ageing”. Other commercials abounded with similar claims and imagery—eg, cars and speedboats—designed to appeal to ageing men, suggesting the youthful vigour achievable with testosterone products.
Such advertising helped to turn testosterone gels into a highly profitable blockbuster, used by many middle-aged and older men with non-specific symptoms and normal or low-normal testosterone levels, despite a lack of evidence and unclear risk–benefit profile.
It was against this background that, in January, an advisory panel of the US Food and Drug Administration (FDA) voted against the approval of two oral formulations of testosterone (undecanoate capsules) for the treatment of hypogonadism in men. Although another oral formulation (methyltestosterone) is available, it is not widely used because of a risk of hepatotoxicity, meaning that undecanoate could have the potential to fill an important unmet need in some patients, such as those with Klinefelter's syndrome.
But while panel members wanted to see more safety data and raised questions about effects of the drugs seen in their pivotal trials—eg, on blood pressure and other biomarkers—the likelihood that, like existing products, the capsules could be widely used off-label in ageing patients without pathological hypogonadism weighed heavily on the decision-making process. Although the FDA is not bound by the votes, the agency often follows advisory panel recommendations.
The issue of the cardiovascular safety of testosterone therapy is of particular relevance in this context, although the evidence from both trials and observational studies is conflicting and inconclusive. Whereas in patients with pathological hypogonadism the benefits of testosterone treatment could be recognised to outweigh any potential cardiovascular risk, in the large population of healthier off-label users, the possibility of an increased risk of cardiovascular events is a major cause for concern.
Indeed, existing testosterone products are currently the subject of a class-action lawsuit from patients alleging that the companies promoted “low T” as a disease state associated with various non-specific symptoms in order to expand the market and sell testosterone as a lifestyle drug.
Meanwhile evidence from the placebo-controlled Testosterone Trials have suggested that testosterone treatment is not quite the panacea promised by the commercials. The trial programme—done in men aged 65 years and older with low testosterone and symptoms such as decreased libido or low vitality, but without evidence of pathological hypogonadism—had mixed results.
A small improvement in sexual function was reported, although this tended to decline in the latter part of the 12 month study; a small effect on mood was identified, but with no significant effects on vitality or physical function. A cardiovascular substudy showed a concerning increase in coronary artery non-calcified plaque volume, although the implications of this finding are unclear and equipoise remains on this crucial issue.
The FDA panel votes on oral testosterone undecanoate follow previous attempts by the agency to counter off-label use. In 2014, the FDA cautioned that testosterone is approved as replacement therapy only for men who have low testosterone concentrations due to disorders of the testicles, pituitary gland, or brain. Pharmaceutical firms were required to update their product labelling to clarify approved uses and warn about possible increased risk of heart attacks and strokes. Since then, manufacturers have also voluntarily discontinued DTC television adverts.
However, inappropriate and overuse of testosterone therapy remains widespread. The FDA panel recommendation raises questions about appropriate mechanisms for regulation of drugs with the potential for inappropriate use. It is unfortunate—if understandable, from the perspective of decision-makers—that such situations might undermine the chances of potentially useful drugs being made available to those patients with clear need and evidence of benefit.
One clear point that does emerge is the potential for harm when prescription drugs are marketed to the public at large. In 2015, the American Medical Association called for a ban on DTC advertising of drugs and medical products, citing the money spent as an important driver of increasing drug costs. The recent history of testosterone use provides an additional rationale in support of this position.
The Lancet D, amp, Endocrinology. Testosterone therapy: has overuse undermined use? The Lancet Diabetes & Endocrinology 2018;6:157. http://dx.doi.org/10.1016/S2213-8587(16)30062-6
“Remember when you had more energy for 18 holes with your buddies?
More passion for the one you love?
More fun with your family and friends?”
So asked one of the many direct-to-consumer (DTC) television advertisements for testosterone replacement therapy that filled the airwaves in the USA until 2014—with the voiceover going on to suggest that “low T” might be the cause, “so don't blame it on ageing”. Other commercials abounded with similar claims and imagery—eg, cars and speedboats—designed to appeal to ageing men, suggesting the youthful vigour achievable with testosterone products.
Such advertising helped to turn testosterone gels into a highly profitable blockbuster, used by many middle-aged and older men with non-specific symptoms and normal or low-normal testosterone levels, despite a lack of evidence and unclear risk–benefit profile.
It was against this background that, in January, an advisory panel of the US Food and Drug Administration (FDA) voted against the approval of two oral formulations of testosterone (undecanoate capsules) for the treatment of hypogonadism in men. Although another oral formulation (methyltestosterone) is available, it is not widely used because of a risk of hepatotoxicity, meaning that undecanoate could have the potential to fill an important unmet need in some patients, such as those with Klinefelter's syndrome.
But while panel members wanted to see more safety data and raised questions about effects of the drugs seen in their pivotal trials—eg, on blood pressure and other biomarkers—the likelihood that, like existing products, the capsules could be widely used off-label in ageing patients without pathological hypogonadism weighed heavily on the decision-making process. Although the FDA is not bound by the votes, the agency often follows advisory panel recommendations.
The issue of the cardiovascular safety of testosterone therapy is of particular relevance in this context, although the evidence from both trials and observational studies is conflicting and inconclusive. Whereas in patients with pathological hypogonadism the benefits of testosterone treatment could be recognised to outweigh any potential cardiovascular risk, in the large population of healthier off-label users, the possibility of an increased risk of cardiovascular events is a major cause for concern.
Indeed, existing testosterone products are currently the subject of a class-action lawsuit from patients alleging that the companies promoted “low T” as a disease state associated with various non-specific symptoms in order to expand the market and sell testosterone as a lifestyle drug.
Meanwhile evidence from the placebo-controlled Testosterone Trials have suggested that testosterone treatment is not quite the panacea promised by the commercials. The trial programme—done in men aged 65 years and older with low testosterone and symptoms such as decreased libido or low vitality, but without evidence of pathological hypogonadism—had mixed results.
A small improvement in sexual function was reported, although this tended to decline in the latter part of the 12 month study; a small effect on mood was identified, but with no significant effects on vitality or physical function. A cardiovascular substudy showed a concerning increase in coronary artery non-calcified plaque volume, although the implications of this finding are unclear and equipoise remains on this crucial issue.
The FDA panel votes on oral testosterone undecanoate follow previous attempts by the agency to counter off-label use. In 2014, the FDA cautioned that testosterone is approved as replacement therapy only for men who have low testosterone concentrations due to disorders of the testicles, pituitary gland, or brain. Pharmaceutical firms were required to update their product labelling to clarify approved uses and warn about possible increased risk of heart attacks and strokes. Since then, manufacturers have also voluntarily discontinued DTC television adverts.
However, inappropriate and overuse of testosterone therapy remains widespread. The FDA panel recommendation raises questions about appropriate mechanisms for regulation of drugs with the potential for inappropriate use. It is unfortunate—if understandable, from the perspective of decision-makers—that such situations might undermine the chances of potentially useful drugs being made available to those patients with clear need and evidence of benefit.
One clear point that does emerge is the potential for harm when prescription drugs are marketed to the public at large. In 2015, the American Medical Association called for a ban on DTC advertising of drugs and medical products, citing the money spent as an important driver of increasing drug costs. The recent history of testosterone use provides an additional rationale in support of this position.
The Lancet D, amp, Endocrinology. Testosterone therapy: has overuse undermined use? The Lancet Diabetes & Endocrinology 2018;6:157. http://dx.doi.org/10.1016/S2213-8587(16)30062-6
