Low ’T’ Not Necessarily Troublesome for the Heart

The latest data on testosterone levels and cardiovascular (CV) risk offer both good news and just-okay news: Men with lower total testosterone concentrations were not at increased risk for myocardial infarction (MI), stroke, heart failure (HF), or major adverse CV events (MACE), although some other testosterone-based markers were linked with higher risks for some CV events.

In a cohort study of participants in the U.K. Biobank, lower total testosterone concentration (quintile 1 versus quintile 5) was not associated with incident MI (fully adjusted hazard ratio 0.89, (95% CI 0.80 to 1.00), according to Bu B. Yeap, PhD, of the University of Western Australia in Crawley, and co-authors. In quintile 1, the median testosterone concentration was 7.75 nmol/L and 223 ng/dL versus 16/73 nmol/L and 482 ng/dL for quintile 5.

The study authors also reported the following in the Annals of Internal Medicine with regard to a lack of association between lower total testostrone concentrations and:

• Hemorrhagic stroke: HR 0.94 (95% CI 0.70 to 1.26).
• Ischemic stroke (IS): HR 0.95 (95% CI 0.82 to 1.10).
• HF: HR 1.15 (95% CI 0.91 to 1.45).
• MACE: HR 0.92 (95%CI 0.84 to 1.00).

However, Yeap and co-authors reported that “[c]alculated free testosterone may be associated with risk for MACE,” and that men “with lower SHBG [sex hormone-binding globulin] concentrations have higher risk for MI but lower risk for IS and HF.” SHBG “is the major binding protein for circulating testosterone, yet few studies have assessed whether SHBG concentrations might be associated with incident CVD events, independent of testosterone,” they explained.

As for lower total testosterone, the authors suggested that it “may be a marker for various sociodemographic, lifestyle, and medical factors that are associated with risk for CVD events, rather than an independent risk factor for these outcomes.”

But the study had several limitations, most notably its observational design; thus, “causality cannot be determined.” Also, “serum total testosterone, SHBG, and other covariates were measured only once at baseline,” according to the authors, and the U.K. Biobank population “has a predominantly Anglo-Celtic ethnic background,” so the results may not apply to other racial/ethnic groups. Some previous studies have reported differences among ethnic groups for age-related drops in testosterone levels.

Still, the results in 210,700 men followed for 9 years—of whom 4.2% had an incident CV event—were in line with previous data, such as a 2014 study of men in the Cardiovascular Health Study, a 2016 study in men ages 17 to 97 (also by Yeap and colleagues), 2019 research specifically on SHBG levels and incident CV events, and the 2020 MrOS Prospective Study.

The current findings may help some clinicians and their patients sort out the mixed messaging regarding testosterone therapy. In 2015, the FDA supported testosterone therapy, but only for men with documented low endogenous testosterone levels caused by primary or secondary hypogonadism, explained Eliseo Guallar, MD, DrPH, of Johns Hopkins University, and Di Zhao, PhD, of Johns Hopkins University Bloomberg School of Public Health, both in Baltimore in an editorial accompanying the study.

They noted that the agency warned about possible therapy-related CV adverse events and that, a few years later, an Endocrine Society clinical practice guideline recommended against starting testosterone therapy for men with chronic conditions, including uncontrolled HF, MI, or stroke within the past six months.

The results from Yeap’s group “provide some warning against the use of testosterone therapy for the prevention of CVD in men,” Guallar and Zhao wrote, adding that the CV safety profile of the therapy remains “uncertain, and careful evaluation of the individual cardiovascular risk profile is needed before initiation of testosterone therapy for any patient.”

From the U.K. Biobank, Yeap and co-authors analyzed data from community-dwelling men, age 40 to 69 years (about 95% White; <4% South Asian). The age group was on the younger side, so “our findings cannot be extrapolated to older men, nor can we address whether higher testosterone concentrations might be protective in men aged 70 years or older,” they pointed out.

Assay tests were done for testosterone and SHBG, and free testosterone was calculated. Cox proportional hazard regression was done for the outcomes of incident MI, strokes, HF, and MACE. All were adjusted for sociodemographic, lifestyle, and medical factors.

They reported that men with lower calculated free testosterone values had a lower incidence of MACE (HR 0.90, 95% CI 0.84 to 0.97). Also, lower SHBG concentrations were linked with:

• Higher incidence of MI: HR 1.23 (95% CI 1.09 to 1.38).
• Lower incidence of IS: HR 0.79 (95% CI 0.67 to 0.94).
• Lower incidence of HF: HR 0.69 (95% CI 0.54 to 0.89).

However, lower SHBG concentrations were not tied to hemorrhagic stroke (HR 0.81, 95% CI 0.57 to 1.14) or MACE (HR 1.01, 95% CI 0.92 to 1.11), the authors stated.

Finally, Yeap’s group calculated the cumulative five-year incidences of all the CV events in the study for U.K. Biobank male participants with total testosterone, SHBG, cFT (free testosterone calculated using the Vermeulen formula), or FTZ (free testosterone calculated using empirical equation) values at the medians of quintile 1 and quintile 5, and reported that “the change in absolute risk attributable to this difference in total testosterone concentrations was small, being 0.14% or less across outcomes. Findings were similar with cFT and FTZ. A slightly larger difference of 0.19% was seen for risk for MI related to the difference in SHBG concentrations.”

Whether the results will mean anything to the $15 million-plus global testosterone supplementation market remains to be seen, although there’s less doubt about the impact of direct-to-consumer (DTC) marketing of such products.

A 2017 JAMA study of DTC advertising, testosterone testing, and initiation in the U.S. (2009 to 2013) found that the former was associated with substantial overall increases in testosterone testing and initiation, and that DTC adverts was tied to “more initiation of testosterone without recent serum testing, contrary to treatment guidelines,” according to J. Bradley Layton, PhD, of the University of North Carolina at Chapel Hill, and co-authors. A separate 2017 European Urology Focus study also found similar results, and added that “[t]here is a high prevalence of misinformation [on testosterone supplementation] on Internet advertising.”

In a 2020 Andrology review, Arcangelo Barbonetti, MD, PhD, of the University of L’Aquila, in L’Aquila, Italy, and co-authors advised that in pateints with late-onset hypogonadism (LOH) “[c]linicians must consider the unique characteristics of each patient and make the necessary adjustments in the management of LOH in order to provide the safest and most beneficial results” of testosterone therapy, and emphasized that the therapy “should not be started in case of a severe chronic heart failure myocardial infarction or stroke within the last 6 months, or thrombophilia. In case of decision to treat, hypogonadal men with chronic heart failure should be followed carefully with clinical assessment and T [testosterone] and haematocrit measurements on a regular basis.”

1. Men with lower total testosterone concentrations were not at increased risk for myocardial infarction (MI), stroke, heart failure (HF), or major adverse CV events (MACE).

2. Calculated free testosterone may be tied to a risk for MACE, while men with lower sex hormone-binding globulin concentrations had higher risk for MI but lower risk for ischemic stroke and HF.

Shalmali Pal, Contributing Writer, BreakingMED™

Cat ID: 358

Topic ID: 74,358,730,358,914,109,187,192,925