The clinical management of hypogonadism in aging males has shifted toward a multimodal strategy centered on metabolic stabilization and vascular protection. This review evaluates the impact of testosterone replacement therapy on metabolic homeostasis, vascular resilience, and cardiovascular safety, incorporating evidence available through 2026. Data from landmark clinical trials, including the Testosterone for Diabetes Mellitus (T4DM) and the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response (TRAVERSE) studies, indicate that testosterone replacement therapy improves glycemic control and reduces visceral adiposity. Reductions in glycated hemoglobin typically range from 0.6% to 1.2%, accompanied by a decrease in insulin resistance as measured by the HOMA-IR index. Testosterone replacement therapy enhances vascular resilience by improving flow-mediated dilation and promoting nitric oxide bioavailability. These changes contribute to systemic reductions in systolic blood pressure. The TRAVERSE trial provides evidence that testosterone replacement therapy is non-inferior to placebo regarding major adverse cardiovascular events in high-risk populations, which addresses historical safety concerns. However, the results emphasize the necessity of rigorous clinical monitoring, particularly concerning hematocrit levels and prostate-specific antigen to mitigate risks of erythrocytosis. Monitored testosterone replacement therapy is an effective modality for disrupting the cycle of obesity and insulin resistance while reinforcing the cardiovascular system in hypogonadal men. A precision medicine approach to dosing and delivery systems is essential for optimizing long-term health outcomes.
Karczewska et al. (2026) studied this question.