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Concern about link between testosterone therapy, CV risk prompts discussion in medical community
The current research base yields conflicting information on the association between testosterone-replacement therapy and heart disease, with some studies showing evidence of increased risk for CV events and others demonstrating no link.
However, in light of the high volume of testosterone-replacement therapy (TRT) prescribed in the United States today, more research is needed to clarify the potential for CV risk in testosterone users, experts told Cardiology Today.
This issue has also caught the attention of the FDA. In March 2015, the agency issued a Drug Safety Communication cautioning that prescription testosterone products are approved only for men who have low testosterone levels caused by certain medical conditions and noting that the benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man’s symptoms seem related to low testosterone. The FDA further announced that it would require manufacturers of prescription testosterone products to change their labeling to more clearly indicate approved uses and also include a warning about possible increased risk for MI and stroke.
Cardiology Today interviewed experts in the field about the current use of TRT in the United States, available data, and the need for more evidence on the link between use and risk for CV events.
Current use
In the past 5 years, the use of TRT has increased from about 1.3 million patients in 2009 to 2.3 million patients in 2013 receiving a prescription for a testosterone product. Currently, approximately 70% of men who receive testosterone prescriptions through retail pharmacies are aged 40 to 64 years, according to information from the FDA.
Photo: Cleveland Clinic; reprinted with permission.
Other research, led by J. Bradley Layton, MD, from the University of North Carolina at Chapel Hill, and published in the Journal of Clinical Endocrinology & Metabolism in January 2014, indicate that the use of TRT in the United States has almost quadrupled from 2000 to 2011. Layton and colleagues also concluded that many men are using TRT without recent testing of their testosterone levels.
“The use of testosterone in America has gone completely off the charts,” Cardiology Today Editorial Board member Steven E. Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic, said in an interview. “Now we have a significant fraction of the male population — middle aged and older — who are prescribed testosterone. How can it make any public health sense to manipulate the hormones of millions of men without any good quality CV outcome trials?”
Cardiology Today Editorial Board member Paul L. Douglass, MD, said, “This issue demands a definitive answer since it impacts a large, growing segment of the population.”
“This story should not be about the use of testosterone therapy, it should be about the abuse of testosterone therapy,” Nissen said.
Appropriate indications debated
FDA-approved testosterone formulations include gel, solution, skin patch, intramuscular injection, pellets implanted under the skin and a buccal system applied to the upper gum or inner cheek.
According to the recent FDA statement, health care professionals should prescribe TRT only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests. Testosterone is FDA-approved as replacement therapy only for men who have low testosterone levels due to disorders of the testicles, pituitary gland or brain that cause hypogonadism. Examples of these disorders include failure of the testicles to produce testosterone because of genetic problems or damage from chemotherapy or infection.
“The benefits of testosterone-replacement therapy in appropriately indicated patients, i.e., those with so-called ‘classical hypogonadism’ due to well-characterized diseases of the testes, pituitary gland and the brain, are proven and exceed any potential risk. The FDA has approved testosterone-replacement therapy only for this indication,” Sanjay Kaul, MD, attending cardiologist at Cedars-Sinai Medical Center, said in an interview.
However, many patients receiving a prescription for TRT do not have classical hypogonadism. The FDA noted in the Drug Safety Communication that the agency has become aware that testosterone is being used extensively in attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging.
“There has been a nearly fourfold increase in the number of prescriptions for testosterone-replacement therapy in the last decade, mostly for ‘age-related hypogonadism,’ which represents an off-label use of testosterone-replacement therapy,” Kaul told Cardiology Today.
According to Douglass, “the declining level of serum testosterone in aging men associated with decreased libido, muscle mass, and mental acuity presents an opportunity for replacement therapy, however the scientific basis of support for replacement therapy is lacking. Douglass practices clinical and interventional cardiology at Metropolitan Atlanta Cardiology Consultants; is chief of the division of cardiology and director at the Cardiovascular Services at Atlanta Medical Center; past chairman of the hospital board; and clinical assistant professor of cardiology at Morehouse School of Medicine in Atlanta.
Nissen said he believes that falling testosterone levels are “a natural phenomenon that occurs with aging.
“It is not a disease, and it is being turned into a disease. And, now that we are beginning to get more research on this issue, it looks worrisome,” he said.
In an interview with Cardiology Today, Adrian Sandra Dobs, MD, professor of medicine and director of the Johns Hopkins Clinical Research Network, acknowledged that the “data linking testosterone therapy with heart disease is rather poor, but we do need to be careful about its use.
“Testosterone therapy should not be used indiscriminately. It should be used in indications in which there is a reason for low testosterone and there are reasonable data that the men will improve after prescribing testosterone,” she said.
Benefit vs. risk, conflicting evidence
Some studies have demonstrated that TRT is associated with little or no CV risk, while others have suggested significant risk. Further, there is a lack of evidence on the long-term effects of prolonged use of TRT. However, more research is beginning to emerge.
Most recently, at the American Heart Association Scientific Sessions in November 2015, J. Brent Muhlestein, MD, of Intermountain Medical Center Heart Institute in Salt Lake City, Utah, and colleagues reported data that demonstrate no increased risk for major CV events including MI or stroke when TRT was prescribed to generally healthy men aged older than 50 years to normalize testosterone levels. The study included 1,472 men aged 52 to 63 years with no prior history of CVD who were categorized based on whether they had or had not received at least 90 days of topical or injected testosterone. Follow-up was performed at 1 and 3 years at the Intermountain Medical Center Heart Institute.
“Our research examined the potential CV risks associated with generally healthy men who use testosterone supplements to normalize their levels and found no increase in those risk factors. In fact, testosterone therapy in this population was shown to reduce the risk of heart attack, stroke and death, when compared to those men who weren’t taking testosterone supplementation,” Muhlestein said in a press release.
In addition, two studies presented at the American College of Cardiology Annual Scientific Session in March 2015 failed to find a connection between TRT in men and CV events. The new studies include a meta-analysis of data from 29 studies involving more than 120,000 men and an observational study of more than 7,200 men from a Wisconsin health system.
An observational cohort study of data on 83,010 male veterans with documented low testosterone levels published in the European Heart Journal this year by Rishi Sharma, MD, from Kansas City VA Medical Center, and colleagues highlighted a significant reduction in MI, stroke and all-cause mortality with the use of TRT to normalize testosterone levels in men with no history of CVD (mean follow-up, 4.5 to 6.2 years).
In another placebo-controlled, double blind, parallel-group, randomized study by Shehzad Basaria, MD, of Brigham and Women’s Hospital, and colleagues published this year in JAMA, testosterone administration for 3 years did not significantly increase the rate of progression to subclinical atherosclerosis compared with placebo. The study enrolled 308 men aged 65 years and older. Basaria and colleagues noted, however, that this research was designed to evaluate atherosclerosis progression, not the CV safety of TRT.
Further research indicates adverse outcomes associated with use of TRT.
Nissen referenced the NIH’s Adverse Events Associated with Testosterone Administration trial, published by Basaria and colleagues in The New England Journal of Medicine in 2010. The trial included 209 men aged older than 65 years with mobility limitations and a total serum testosterone level of 100 ng/dL to 350 ng/dL or free serum testosterone level less than 50 pg/ml. The men were randomly assigned daily testosterone gel or placebo gel for 6 months. The study was halted early due to a high incidence of adverse CV events in the testosterone group compared with the placebo group.
In 2013, a retrospective national cohort study of 8,709 men with low testosterone in the VA health care system was published in JAMA.Rebecca Vigen, MD, from the University of Texas Southwestern Medical Center, Dallas, and colleagues reported that 1,223 of the men had a low serum testosterone level and began TRT following coronary angiography after a median of 531 days. Among these men, the risk of mortality, MI and stroke was found to be increased.
Research published in PLoS One in 2014 by William D. Finkle, PhD, of Consolidated Research Inc., Los Angeles, and colleagues suggested that the risk for acute MI in older men and in younger men with a history of CVD is increased within 90 days of receiving a TRT prescription. The risk for acute MI was not increased in men aged younger than 65 years with no history of CVD. The researchers analyzed data on 55,593 men receiving an initial prescription for TRT and 167,279 men receiving a prescription for a phosphodiesterase type 5 inhibitor (sildenafil [Viagra, Pfizer] or tadalafil [Cialis, Lilly]).
A call for more research
For Kaul, “the quality and quantity of data are insufficient to adjudicate the CV adverse effects of testosterone-replacement therapy. There is inconsistent evidence with some studies showing harm, while others observing benefits and a few reporting neutral effects.”
He noted that most evidence is derived from nonrandomized or observational studies, including retrospective studies and meta-analyses, which have substantial limitations that challenge the interpretability of the findings.
“Thus, there are no reliable data to either implicate or exonerate testosterone-replacement therapy with regard to CV risk,” he said.
The only “reliable and credible” way to determine the effects of testosterone therapy on CV outcomes is to conduct an adequately powered randomized controlled trial, according to Kaul. He said this would require a large sample size — perhaps 10,000 to 20,000 subjects, “which might be prohibitive for a single company.” As such, “the FDA is appropriately encouraging all companies to pool their resources to conduct a single trial,” he noted.
Several other barriers exist, however. For one, “I don’t think we even know what normal [testosterone] levels are,” Nissen said. “I hope the industry will be responsible and not promote these drugs in ways that are designed to get the wrong people to take them.”
Increased awareness
In September 2015, the American Association of Clinical Endocrinologists (AACE) released a position statement published in Endocrine Practice in response to this issue. In the statement, AACE cited the lack of evidence showing a link between increased risk for CV events and the use of TRT and acknowledged that the risk-benefit ratio of TRT is unclear. The association further noted that low testosterone may not be the causal factor of CV issues, but instead is often a marker of CVD.
AACE also called for large-scale studies to examine the link between TRT and CV risk. However, in the interim, the association recommended that clinical decisions regarding TRT should be guided by the signs and symptoms of individual patients, as well as confirmed by testosterone concentrations. AACE further recommended that all men considered for TRT should have a thorough diagnostic workup.
“Both the FDA and AACE statements acknowledge lack of conclusive data regarding CV risk associated with TRT. This is not dissimilar from previous statements by the Endocrine Society in 2014 or the Institute of Medicine report in 2002.
“The CV safety of testosterone products in older men remains an important public health concern. Given the widespread use of testosterone for age-related hypogonadism, and the lack of substantial evidence to support such use, the FDA was left with no choice but to require labeling changes. However, requiring label changes alone is not sufficient given the unknown effect of the label changes on prescribing patterns, hence the FDA recommendation for conducting a large, controlled clinical trial to adjudicate the CV effects of testosterone-replacement therapy, to guide accurate drug labeling and to inform clinical decision-making,” Kaul said.
Discussion with patients
Experts interviewed by Cardiology Today said they include the potential for CV events in their discussions with patients.
“Our first obligation toward our patients should be to inform them about lack of good quality evidence,” Kaul said, noting that he discusses the potential CV risks of testosterone therapy with his patients and discourages use if the patient has pre-existing CVD and their quality of life is not substantially impaired. He reminds patients that TRT is currently approved only for classical hypogonadism, informs them that the benefit-risk balance for off-label use has not been determined and shares with them the possibility of a weak signal for CV adverse events, especially in those with pre-existing heart disease.
Douglass too does not recommend testosterone therapy in men with one or more risk factors for CVD. “I warn all men of the potential risk of testosterone-replacement therapy and encourage lifestyle modifications, such as weight loss, exercise, good nutrition and moderate alcohol consumption, as a more appropriate strategy for dealing with the consequences of aging. I advise them that definitive clinical trial data regarding the safety and benefit of testosterone-replacement therapy is lacking,” he said.
Dobs recommended that treatment should not be based on a single sample. “In my practice, I make sure the men have a full evaluation, which means getting multiple samples on multiple days,” she said. Also, during treatment, Dobs emphasized the importance of continued monitoring. “Men [using testosterone therapy] should be monitored carefully to make sure they are improving. For example, a low bone mineral density and osteoporosis is one thing I would monitor to make sure there are improvements. If there was a problem with sexual function, that should be monitored to make sure there is an improvement. I think the decision to start and to continue therapy has to be in communication with the patient.”
Nissen said he does not treat aging men with testosterone products. When patients ask about TRT, “I tell them that the jury is out, but I am very worried about the safety of the products. If you want to look younger and feel younger, do it the old-fashioned way with exercise and fitness training,” he said.
Until more data are available
In discussing this issue, Douglass said he is “reminded of the misguided recommendations regarding estrogen-replacement therapy for women that we unknowingly made for decades prior to randomized clinical trials. Also, the growing debate regarding vitamin D replacement suffers from the same paucity of reliable data.”
In the meantime, professional society guidelines that emphasize evidence-based recommendations and clarify how to optimize the benefit-risk balance of TRT might be instructive, according to Kaul. “Any CME-based activity on this topic should be strictly faithful to the evidence and aligned with the guideline recommendations,” he added.
“Although the hypothesis is that low testosterone levels convey an increased CV risk, randomized clinical trial data supporting replacement therapy are absent. My hope is that we will produce reliable clinical outcomes data upon which we can base evidence-based therapy. Until then, I do not feel that these agents should be administered without appropriate indications. I believe that a conservative approach regarding unproven therapies that may increase CV risk is most prudent,” Douglass said. – by Suzanne Bryla Reist
- References:
- AACE position statement. Endocrine Practice. 2015;doi:abs/10.4158/EP14434.PS.
- Bair TM, et al. Cardiovascular Clinical Effects of Testosterone Supplementation Among Healthy Hypoandrogenic Men: Information From the Intermountain Healthcare Health Plans Database. Presented at: American Heart Association Scientific Sessions; Nov. 7-11, 2015; Orlando, Fla.
- Basaria S, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa1000485.
- Basaria S, et al. JAMA. 2015;314:570-581.
- Clinical Decisions: Testosterone-Replacement Therapy. N Engl J Med. 2014;doi:10.1056/NEJMc1de11406595.
- Finkle WD, et al. PLOS One. 2014;doi:10.1371/journal.pone.0085805.
- Jahangir A, et al. Effects of testosterone supplement therapy on cardiovascular outcomes in men with low testosterone. Presented at: American College of Cardiology Scientific Sessions; March 14-16, 2015; San Diego.
- Layton JB, et al. J Clin Endocrinol Metab. 2014;doi:10.1210/jc.2013-3570.
- Morales A, et al. CMAJ. 2015;doi:10.1503/cmaj.150033.
- Nguyen CP, et al. N Engl J Med. 2015;doi:10.1056/NEJMp1506632.
- Patel P, et al. Effect of testosterone therapy on adverse cardiovascular events among men: A meta-analysis. Presented at: American College of Cardiology Scientific Sessions; March 14-16, 2015; San Diego.
- Sharma R, et al. Eur Heart J. 2015;doi:10.1093/eurheartj/ehv346.
- Vigen R, et al. JAMA. 2013;doi:10.1001/jama.2013.280386.
- For more information:
- Adrian Sandra Dobs, MD, can be reached at The Johns Hopkins Hospital, 600 N. Wolfe St., Sheikh Zayed Tower, Suite 328, Baltimore, MD 21287; email: adobs@jhmi.edu.
- Paul L. Douglass, MD, can be reached at Metropolitan Atlanta Cardiology Consultants, 999 Peachtree St. NE #850, Atlanta, GA 30309; email: pldouglass@macc-heart.com.
- Sanjay Kaul, MD, can be reached at Cedars-Sinai Medical Center, 8700 Beverly Blvd., West Hollywood, CA 90048; email: sanjay.kaul@cshs.org.
- Steven E. Nissen, MD, can be reached at Cleveland Clinic Main Campus, Mail Code J2-3, 9500 Euclid Ave., Cleveland, OH 44195.
Disclosures: Dobs, Douglass and Nissen report no relevant financial disclosures. Kaul reports consulting for AbbVie, a sponsor of Androgel (August 2014).