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Effects of Oral Testosterone Undecanoate (Kyzatrex) Versus Testosterone Gel (Androgel) on Long-Term (to 12 Months) Blood Pressure Levels (2022)
William B. White, * James S. Bernstein, Abraham Morgentaler, and Om Dhingra
Abstract
Purpose: Oral and injectable testosterone replacement therapies have been reported to increase blood pressure (BP) in hypogonadal men. Less is known about the effects of topical testosterone formulations on BP.
Materials and Methods: We studied the effects of a new oral testosterone undecanoate (TU) (Kyzatrex) and a topical testosterone gel (Androgel) on BP and heart rate, in a 2:1 randomized trial of men with hypogonadism. Digital BPs and clinical assessments were obtained at baseline and at 90, 180, and 365 days.
Results: There were 314 men randomized (mean age 49.7 years, 82% white, and 35% with treated hypertension). The mean changes from baseline in systolic BP were 2.2 mmHg (95% confidence interval [CI] 0.6–3.7) on the oral TU and 3.1 mmHg (95% CI 1.0–5.1) on the topical testosterone at 90 days. Similar findings were seen after 180 and 365 days. Heart rates increased by 4.3 and 2.7 beats/min at 90 days on oral and topical testosterone, respectively. For those men with treated hypertension, changes in systolic BP in the oral TU group were higher compared with those without hypertension, whereas those on topical testosterone had similar increases in systolic BP regardless of hypertension status. Outlier analyses for systolic BP at 90 days demonstrated a higher proportion of subjects with increases of 5 and 10 mmHg postbaseline on topical testosterone gel versus this oral TU.
Conclusions: These data demonstrate that the overall effects of the oral TU on BP were comparable with topical testosterone. In men without hypertension, the oral TU induced smaller changes in BP compared with topical testosterone.
Clinical Trial Registration (Home - ClinicalTrials.gov): NCT04467697
Introduction
The most common testosterone therapies for male hypogonadism (also known as testosterone deficiency) include injections, transdermal gels, and now oral formulations.1 Testosterone itself has limited oral bioavailability. Long-chain fatty acid esterification of testosterone to create testosterone undecanoate (TU) allows for absorption through the intestinal lymphatic system and bypasses first-pass metabolism in the liver.2 Testosterone is then liberated from TU by endogenous nonspecific esterases.2
Oral formulations of TU have been developed to provide average serum testosterone levels in the eugonadal range (typically 300–1000 ng/dL or 10.4– 34.7 nmol/L) and avoid peak concentrations above 1500 ng/dL. Some observational studies and meta-analyses have demonstrated no change or small reductions in blood pressure (BP) over time.3,4 However, randomized clinical trials focused on BP as a primary endpoint have demonstrated that testosterone formulations have increased BP,5-8 but the mechanism of these increases has not been entirely elucidated. Previously there has also only been one clinical trial evaluating the effects of an oral TU versus a topical gel on BP.5 Hence, we compared the effects of a new oral TU therapy (Kyzatrex) versus the testosterone gel (Androgel) in a long-term randomized trial that assessed BP along with standard clinical and laboratory parameters.
Results
*Subject disposition and baseline characteristics
*BP and heart rate
*BP changes in subgroups with treated hypertension
Conclusions
The new oral TU, Kyzatrex, induced small increases in BP within 90 days of the administration that did not increase further over the remainder of the 1-year study period. These changes were similar to those observed with a topical testosterone formulation. There were also small clinically unimportant increases in heart rate (<5 beats/min) in both treatment groups. Study participants with a history of hypertension taking antihypertensive therapy had larger increases in BP after chronic oral TU therapy than those without hypertension. In the oral TU group and in contrast to the topical testosterone gel group, hypogonadal men who were not receiving antihypertensive medication had negligible changes in BP.
William B. White, * James S. Bernstein, Abraham Morgentaler, and Om Dhingra
Abstract
Purpose: Oral and injectable testosterone replacement therapies have been reported to increase blood pressure (BP) in hypogonadal men. Less is known about the effects of topical testosterone formulations on BP.
Materials and Methods: We studied the effects of a new oral testosterone undecanoate (TU) (Kyzatrex) and a topical testosterone gel (Androgel) on BP and heart rate, in a 2:1 randomized trial of men with hypogonadism. Digital BPs and clinical assessments were obtained at baseline and at 90, 180, and 365 days.
Results: There were 314 men randomized (mean age 49.7 years, 82% white, and 35% with treated hypertension). The mean changes from baseline in systolic BP were 2.2 mmHg (95% confidence interval [CI] 0.6–3.7) on the oral TU and 3.1 mmHg (95% CI 1.0–5.1) on the topical testosterone at 90 days. Similar findings were seen after 180 and 365 days. Heart rates increased by 4.3 and 2.7 beats/min at 90 days on oral and topical testosterone, respectively. For those men with treated hypertension, changes in systolic BP in the oral TU group were higher compared with those without hypertension, whereas those on topical testosterone had similar increases in systolic BP regardless of hypertension status. Outlier analyses for systolic BP at 90 days demonstrated a higher proportion of subjects with increases of 5 and 10 mmHg postbaseline on topical testosterone gel versus this oral TU.
Conclusions: These data demonstrate that the overall effects of the oral TU on BP were comparable with topical testosterone. In men without hypertension, the oral TU induced smaller changes in BP compared with topical testosterone.
Clinical Trial Registration (Home - ClinicalTrials.gov): NCT04467697
Introduction
The most common testosterone therapies for male hypogonadism (also known as testosterone deficiency) include injections, transdermal gels, and now oral formulations.1 Testosterone itself has limited oral bioavailability. Long-chain fatty acid esterification of testosterone to create testosterone undecanoate (TU) allows for absorption through the intestinal lymphatic system and bypasses first-pass metabolism in the liver.2 Testosterone is then liberated from TU by endogenous nonspecific esterases.2
Oral formulations of TU have been developed to provide average serum testosterone levels in the eugonadal range (typically 300–1000 ng/dL or 10.4– 34.7 nmol/L) and avoid peak concentrations above 1500 ng/dL. Some observational studies and meta-analyses have demonstrated no change or small reductions in blood pressure (BP) over time.3,4 However, randomized clinical trials focused on BP as a primary endpoint have demonstrated that testosterone formulations have increased BP,5-8 but the mechanism of these increases has not been entirely elucidated. Previously there has also only been one clinical trial evaluating the effects of an oral TU versus a topical gel on BP.5 Hence, we compared the effects of a new oral TU therapy (Kyzatrex) versus the testosterone gel (Androgel) in a long-term randomized trial that assessed BP along with standard clinical and laboratory parameters.
Results
*Subject disposition and baseline characteristics
*BP and heart rate
*BP changes in subgroups with treated hypertension
Conclusions
The new oral TU, Kyzatrex, induced small increases in BP within 90 days of the administration that did not increase further over the remainder of the 1-year study period. These changes were similar to those observed with a topical testosterone formulation. There were also small clinically unimportant increases in heart rate (<5 beats/min) in both treatment groups. Study participants with a history of hypertension taking antihypertensive therapy had larger increases in BP after chronic oral TU therapy than those without hypertension. In the oral TU group and in contrast to the topical testosterone gel group, hypogonadal men who were not receiving antihypertensive medication had negligible changes in BP.
