Testosterone and Cardiovascular Risk: Meta-Analysis of Interventional Studies

BACKGROUND: The relationship between testosterone (T) and cardiovascular (CV) risk in men is conflicting. AIM: To verify whether T therapy (TTh) represents a possible risk factor for CV morbidity and mortality. METHODS: We conducted a random effect meta-analysis considering all available data from pharmaco-epidemiological studies as well as randomized placebo-controlled trials (RCTs). OUTCOMES: CV mortality and morbidity were investigated. RESULTS: After screening, 15 pharmaco-epidemiological and 93 RCT studies were considered. The analysis of pharmaco-epidemiological studies documented that TTh reduces overall mortality and CV morbidity. Conversely, in RCTs, TTh had no clear effect, either beneficial or detrimental, on the incidence of CV events. However, a protective role of TTh on CV morbidity was observed when studies enrolling obese (body mass index >30 kg/m2) patients were scrutinized (Mantel-Haenszel odds ratio 0.51 [95% CI 0.27-0.96]; P = .04), although this association disappeared when only high-quality RCTs were considered (Mantel-Haenszel odds ratio 0.64 [95% CI 0.22-1.88]; P = .42). Finally, an increased risk of CV diseases was observed in RCTs when T preparations were prescribed at dosages above those normally recommended, or when frail men were considered. CLINICAL IMPLICATIONS: Pharmaco-epidemiological studies showed that TTh might reduce CV risk, but this effect was not confirmed when RCTs were considered. STRENGTHS & LIMITATIONS: Meta-analysis of pharmaco-epidemiological studies indicates that TTh reduces overall mortality and CV morbidity. In addition, even in RCTs, a protective role of TTh on CV morbidity was envisaged when studies enrolling obese (body mass index >30 kg/m2) patients were considered. Pharmaco-epidemiological studies should be considered with caution due to the lack of completeness of follow-up and of the management of missing data. In addition, properly powered placebo-controlled RCTs with a primary CV end point, in men with late-onset hypo-gonadism, are not yet available. Finally, the duration of all studies evaluated in the present meta-analysis is relatively short, reaching a maximum of 3 years. CONCLUSIONS: Data from RCTs suggest that treatment with T is not effective in reducing CV risk, however, when TTh is correctly applied, it is not associated with an increase in CV risk and it may have a beneficial effect in some sub-populations