Concerns about link between testosterone therapy, CV risk prompt 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 cardiovascular 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 Endocrine Today.

“The epidemiologic data indicate that hypogonadism or low testosterone is associated with increased CV risk,” Ronald Swerdloff, MD, professor of medicine, endocrinology, metabolism and nutrition at the David Geffen School of Medicine at UCLA and chief of the division of endocrinology at Harbor UCLA Medical Center, told Endocrine Today. “This would suggest that [testosterone] treatment might reverse this process; however, there have been a number of reports suggesting that the opposite might be true. Most of the people who have reviewed these data realize that the studies are not designed appropriately to resolve the issue.”

Photo by Jill Rollet

This concern has 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 myocardial infarction and stroke.

Endocrine 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.

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 testosterone-replacement products without recent testing of their testosterone levels.

“The use of testosterone in America has gone completely off the charts,” 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?”

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 FDA said that approval was really for people who have classical hypogonadism ... not just aging, or maybe a better word would be ‘functional,’” Endocrine Today Editorial Board member Glenn R. Cunningham, MD, said in an interview.

However, many patients receiving a prescription for TRT do not have classical hypogonadism.

“One of the major causes of functional low testosterone or hypogonadism is obesity ... the other is aging, and the two are often related in the same individual. [The FDA] wanted a labeling change ... to reflect the position that we don’t know if TRT will increase CV risk — that’s really what they’re addressing,” Cunningham said.

The FDA noted in the Drug Safety Communication that the agency has become aware that testosterone is being used extensively to relieve symptoms in men who have low testosterone for no apparent reason other than aging.”

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 Endocrine Today, Adrian Sandra Dobs, MD, professor of medicine and director of the Johns Hopkins Clinical Research Network, said 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, 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 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 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 last 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 last 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 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 for 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 younger than 65 years with no history of CVD. The researchers analyzed data on 55,593 men receiving an initial prescription for testosterone therapy and 167,279 men receiving a prescription for a phosphodiesterase type 5 inhibitor (Viagra [sildenafil, Pfizer] or Cialis [tadalafil, Lilly]).

A call for more research

For Swerdloff, “the data that are presently available weigh on both sides of the issue, but simply are not adequate to the resolve the question of whether or not TRT increases, decreases or has no effect on cardiovascular risk.”

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.

“It’s agreed by most people in the field that a long-term prospective properly controlled and powered study will be necessary to answer the question,” Swerdloff said.

The FDA is encouraging the pharmaceutical companies that market testosterone products to conduct such a study. Cunningham, who is serving as a consultant to the consortium trial in the effort, said the hope is for a study protocol to be developed and approved by the FDA sometime this summer. The randomized, placebo-controlled study would involve more than 5,000 men treated up to 5 years.

Several other barriers to resolving the question will remain, 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, AACE released a position statement published in Endocrine Practice in response to this issue. In the statement — of which Cunningham is an author — 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 testosterone therapy 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 testosterone therapy 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 have a thorough diagnostic workup.

Discussion with patients

Experts interviewed by Endocrine Today said they include the potential for CV events in their discussions with patients.

Swerdloff said the FDA has specifically advised physicians prescribing testosterone to discuss the available data, particularly with patients at increased CV risk.

“This is a very difficult thing because the average physician probably has not carefully reviewed all the data, and the best thing that I could say is that we simply do not know the answer to the question,” Swerdloff said.

“Any time you are prescribing medication, particularly for a non-life-threatening disease, you need to discuss it with the patient so they understand the potential benefits and risks,” Cunningham said. “The underlying issue here ... is that if you are going to treat a patient with testosterone, you really need to be sure that the person has symptoms consistent with testosterone deficiency and also low-testosterone levels.”

Dobs also recommended that treatment 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, Dobs emphasized the importance of continued monitoring during treatment. “Men [using testosterone therapy] should be monitored carefully to make sure they are improving. For example, low BMD 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. 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

Swerdloff points to the assessment of benefits of TRT in relation to mood and sexual and physical function described by Peter J. Snyder, MD, and colleagues in results of the T Trials published in The New England Journal of Medicine in February.

“In terms of balancing that against risk, the problem is that CVD is often slow in its development, and the impact of the treatment at a later time really is necessary to know whether the risk exists. If it exists, is it large enough to discourage treatment of individuals?” he asked.

“At the present time, we should use good clinical judgement, carefully select patients who will likely benefit from treatment and advise the patients of those areas that we have continued uncertainty.” – by Suzanne Bryla Reist with additional reporting by Jill Rollet

• 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.
• Snyder PJ, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1506119.
• Vigen R, et al. JAMA. 2013;doi:10.1001/jama.2013.280386.

• For more information:
• Glenn R. Cunningham, MD, can be reached at email: glennc@bcm.edu.
• 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.
• Steven E. Nissen, MD, can be reached at Cleveland Clinic Main Campus, Mail Code J2-3, 9500 Euclid Ave., Cleveland, OH 44195.
• Ronald Swerdloff, MD, can be reached at 1124 W. Carson St. RB-1, Torrance, CA 90502; email: swerdloff@labiomed.org.

Disclosures: Dobs, Nissen and Swerdloff report no relevant financial disclosures. Cunningham reports serving as a consultant to AbbVie, Apricus, Besins, Clarus Therapeutics, Endo Pharma, Ferring, Lilly, Pfizer and Repros Therapeutics and receiving research support from Ardana and Unimed.

Should testosterone-replacement therapy be prescribed for men with low testosterone due to aging?

A conservative approach regarding unproven therapies, such as testosterone-replacement therapy, that may increase cardiovascular risk is most prudent.

This issue demands a definitive answer since it impacts a large, growing segment of the population. 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 TRT is lacking.

I do not recommend TRT in men with one or more risk factors for CVD. I warn all men of the potential risk of TRT 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 these men that definitive clinical trial data regarding the safety and benefit of TRT are lacking.

I am 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.

Although the hypothesis is that low testosterone levels convey an increased CV risk, randomized clinical trial data supporting TRT 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.

Paul L. Douglass, MD, practices clinical and interventional cardiology at Metropolitan Atlanta Cardiology Consultants. He is chief of the division of cardiology and director of cardiovascular services at Atlanta Medical Center, chairman of the hospital board and clinical assistant professor of cardiology at Morehouse School of Medicine in Atlanta. Disclosure: Douglass reports no relevant financial disclosures.

There is no age beyond which one can be reasonably certain that a testosterone concentration is subnormal due to “aging.”

The FDA recommended last year that TRT “should not be used to relieve symptoms in men who have low testosterone for no reasons other than aging.” Testosterone concentrations decline at a rate of 1% to 2% per year. This decline is continuous across the life span of men beyond the age of 30 years, partly due to the rising prevalence of obesity, type 2 diabetes or chronic illnesses. These comorbidities are associated with subnormal testosterone concentrations at all ages, including adolescence. In many instances, determining the relative contribution of aging or illnesses to low testosterone concentrations is not possible.

Furthermore, a subnormal testosterone concentration in a patient with pituitary adenoma carries the same risk of adverse consequences of hypogonadism as in a patient without adenoma (or any other lesion in pituitary, hypothalamus or testis). One would not expect a different response to testosterone replacement in two patients with similar baseline testosterone concentrations but one with pituitary adenoma and one without. Also, FDA did not specifically mention type 2 diabetes and obesity as causes of hypogonadism. Both are common and carry a risk for hypogonadism of approximately 33% and 25%, respectively, according to the criteria of the Endocrine Society. Both are associated with heightened CV risk.

There has been a perception that testosterone is a “lifestyle hormone” [however] many published studies show an inverse relationship of testosterone concentrations with fat mass, metabolic syndrome, fractures, CVD and mortality. Testosterone replacement increases insulin sensitivity and lean mass, decreases fat mass and inflammation, and increases bone mineral density.

There is another perception that results of testosterone replacement on symptomatic benefits are not clear cut. This seems to be based on selective reading of the literature since many studies have documented the benefits of testosterone replacement in hypogonadal men at all ages.

Paresh Dandona, MD, PhD, is an Endocrine Today Editorial Board member and chief of endocrinology, diabetes and metabolism in the department of medicine in the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo. Disclosure: Dandona reports receiving research support, honorarium and/or grants from Abbott Laboratories, Allergan, Bristol-Myers Squibb, Conjuchem, the CDC, the Citrus Industry of Florida, Dannipon Pharmaceuticals, Eli Lilly, GlaxoSmithKline, Merck, the Millard Fillmore Foundation, Mitsubishi, the NIH, Novartis, Novo Nordisk, the Oishei Foundation, Proctor & Gamble Pharmaceuticals, Quigley Pharma, Sankyo Pharmaceuticals North America, Sanofi, Solvay Pharmaceuticals, Takeda Pharmaceuticals, ToleRx, Transition Therapeutics and the William G. McGowan Charitable Fund.