William B. White

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 rate 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 proportions 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 a topical testosterone. In men without hypertension, the oral TU induced smaller changes in BP compared with topical testosterone. Clinical Trial Registration: ( https://www.clinicaltrials.gov/ ) : NCT04467697.

Intra-abdominal injury after blunt abdominal trauma is a leading cause of preventable deaths in children in the US.¹ However, early and accurate diagnosis of intra-abdominal injury in children is challenging. Current diagnostic strategies are suboptimal because of the trade-off between missed injury and resource overutilization, including children’s exposure to ionizing radiation from computed tomography (CT) scans.

Introduction: Worsening kidney function (WKF) is frequent among patients with type 2 diabetes (T2D) and a recent acute coronary syndrome (ACS) and is associated with a poor prognosis. An accurate prediction of WKF is clinically important. Aims: Using data from the Cardiovascular Outcomes Study of Alogliptin in Patients with Type 2 Diabetes and Acute Coronary Syndrome trial including patients with T2D and a recent ACS, and a large biomarker panel incorporating proteins measured both in blood and urine, we aim to determine those with best performance for WKF prediction. Methods: WKF was defined as a ≥40% estimated glomerular filtration rate (eGFR) drop from baseline, eGFR Results: 5,131 patients were included from whom 222 (4.3%) developed at least one WKF episode over a median follow-up of 18 months. Patients who developed WKF were more frequently women, had longer diabetes duration, a more frequent heart failure history, higher anemia prevalence, and impaired kidney function. In multivariable models including all variables (clinical and biomarkers) independently associated with WKF with a p value ≤0.0001, blood kidney injury molecule 1 (KIM-1) was (by far) the variable with strongest WKF association, followed by anemia. KIM-1 alone provided good discrimination for WKF prediction (area under the curve = 0.73). Patients in the high KIM-1-derived risk tertile had a 6.7-fold higher risk of any WKF than patients classified as low risk. In time-updated Cox models, the occurrence of WKF was independently associated with a higher risk of death: adjusted hazard ratio = 4.93 (3.06–7.96), p value Conclusion: Blood KIM-1 was the biomarker with the strongest association with WKF. The occurrence of WKF was independently associated with a higher risk of subsequent cardiovascular events and mortality.

Testosterone replacement therapies may increase blood pressure (BP) with chronic use but the mechanism is not clear. TLANDO™ is a new oral testosterone undecanoate (TU) under development for the treatment of male hypogonadism. We studied the effects of the TU at 225 mg twice daily on ambulatory BP (ABP) and heart rate, in 138 men with hypogonadism (mean age, 54 years, 79% white, 48% with hypertension). Ambulatory BP and heart rate and hematologic assessments were obtained at baseline and following 4-months of therapy. Changes from baseline in ambulatory 24-hour, awake, and sleep systolic BP (SBP) of 3.8 (P < 0.001), 5.2 (P < 0.001), and 4.3 mmHg (P = 0.004) were observed post-treatment, respectively. Lesser changes in the diastolic BP (DBP) were observed (1.2 (P = 0.009), 1.7 (P = 0.004), and 1.7 mmHg (P = 0.011) for 24-hour, awake, and sleep, respectively). Hematocrit and hemoglobin were increased by 3.2% and 0.9 g/dL (P < 0.001), respectively. In those men in the top quartile of changes in hematocrit (range of 6% to 14%), the largest increases in ambulatory SBP (mean, 8.3 mmHg) were observed, whereas the changes in ambulatory SBP in the lower 3 quartiles were smaller (mean, 1.9, 3.3, and 2.1 mmHg in 1st, 2nd and 3 rd quartiles, respectively). These data demonstrate that small increases in ABP occurred following 4 months of the oral TU. For those men whose hematocrit rose by >6%, BP increases were of greater clinical relevance. Hence, hematocrit may aid in predicting the development of BP increases on testosterone therapy. NCT 03868059.

Testosterone replacement therapies have been shown to increase blood pressure (BP) in hypogonadal men. We studied the effects of a new formulation of testosterone undecanoate (Kyzatrex™) on ambulatory blood pressure (ABP) and heart rate, in 155 men with hypogonadism (mean age, 50.5 years, 76.8% white, 36.1% on antihypertensive therapy). The ABP, heart rate and clinical assessments were obtained at baseline and following 120 and 180 days of therapy. Mean changes from baseline in 24‐h ambulatory systolic BP of 1.7 mmHg (95% CI, 0.3, 3.1) at day 120 and 1.8 mmHg (95% CI, 0.3, 3.2) at day 180 were observed post‐treatment. For those men on antihypertensive drug therapy, increases in mean 24‐h systolic BP were greater than those not taking antihypertensive drugs (3.4 vs 0.7 mmHg at day 120 and 3.1 vs 1.0 mmHg at day 180, respectively). Changes from baseline in 24‐h diastolic BP and heart rate at day 120 were smaller (<1 mmHg and <1 beat/min, respectively). There were no relationships observed between testosterone concentration or hemoglobin levels with ABP. Multivariable analyses showed that baseline ambulatory BP and antihypertensive therapy were significantly correlated with BP changes. These data demonstrate small increases in ambulatory BP following 120 days on this oral testosterone undecanoate with no further changes at 180 days. Changes in ambulatory BP were minimal in patients not taking antihypertensive therapy.

Context A novel formulation of oral testosterone (T) undecanoate (TU) was evaluated in a phase 3 clinical trial. Objective Determine efficacy, short-term safety, and alignment of new oral TU formulation with current US approval standards for T replacement therapy. Design Randomized, active-controlled, open-label study. Setting and Patients Academic and private clinical practice sites; enrolled patients were clinically hypogonadal men 18 to 65 years old. Methods Patients were randomized 3:1 to oral TU, as prescribed (JATENZO^®; n = 166) or a topical T product once daily (Axiron^®; n = 56) for 3 to 4 months. Dose titration was based on average T levels (C_avg) calculated from serial pharmacokinetic (PK) samples. T was assayed by liquid chromatography–mass spectrometry/mass spectrometry. Patients had 2 dose adjustment opportunities prior to final PK visit. Safety was assessed by standard clinical measures, including ambulatory blood pressure (BP). Results 87% of patients in both groups achieved mean T C_avg in the eugonadal range. Sodium fluoride-ethylenediamine tetra-acetate plasma T C_avg (mean ± standard deviation) for the oral TU group was 403 ± 128 ng/dL (~14 ± 4 nmol/L); serum T equivalent, ~489 ± 155 ng/dL (17 ± 5 nmol/L); and topical T, 391 ± 140 ng/dL (~14 ± 5 nmol/L). Modeling/simulation of T PK data demonstrated that dose titration based on a single blood sample 4 to 6 h after oral TU dose yielded efficacy (93%) equivalent to C_avg-based titration (87%). Safety profiles were similar in both groups, but oral TU was associated with a mean increase in systolic BP of 3 to 5 mm Hg. Conclusion A new oral TU formulation effectively restored T to mid-eugonadal levels in hypogonadal patients.

Background: Spironolactone (SPIRO) reduces BP in patients (pts) with resistant hypertension (RHTN); however, its use in pts with advanced chronic kidney disease (CKD) is often limited by hyperkalemia (HK). In AMBER, patiromer (PAT) enabled more persistent use of SPIRO in pts with RHTN and CKD. As SPIRO is recommended in RHTN and DM increases HK risk, we report results in prespecified subgroups with type 1 or 2 DM (DM⁺) and without (DM^-). Methods: Randomized, double-blind, placebo (PBO)-controlled trial in adults with RHTN and eGFR 25 to ≤45 mL/min/1.73 m². Pts were assigned (1:1) to PBO or PAT, and SPIRO 25 mg QD, with dose titrations permitted after 1 wk for PAT and 3 wks for SPIRO. Primary endpoint: between-group difference at Wk 12 in % of pts on SPIRO. Results: 295 pts were randomized, 145 (49%) DM⁺ and 150 (51%) DM^-. Baseline mean (SD) serum K⁺ (mEq/L) was 4.76 (0.34) in DM⁺ and 4.67 (0.39) in DM^-. Significantly more pts treated with PAT than with PBO remained on SPIRO at Wk 12 in both subgroups (Figure). LS Mean (SE) cumulative SPIRO dose was higher with PAT than PBO, by 438.7 (177.7) mg in DM⁺ and 317.8 (175.0) mg in DM^-. Adverse events of hyperkalemia or blood K⁺ increased occurred in 7 (PBO) and 8 (PAT) DM⁺ patients and 7 (PBO) and 1 (PAT) DM^- patients. Conclusions: PAT enabled more pts with advanced CKD and RHTN to continue treatment with SPIRO, regardless of DM status. Disclosure R. Agarwal: Other Relationship; Self; AbbVie Inc., Akebia Therapeutics, Amgen, AstraZeneca, Bayer Inc., Bird Rock Bio, Boehringer Ingelheim Pharmaceuticals, Inc., Celgene, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline plc., Ironwood Pharmaceuticals, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, OPKO Health, Inc., Reata, Relypsa, Inc.,Sandoz, Sanofi, Takeda Pharmaceutical Company Limited, ZS Pharma. P. Rossignol: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Idorsia, Novartis France, Novo Nordisk Inc., Relypsa, Inc., Servier, Vifor Pharma Group. Stock/Shareholder; Self; CardioRenal: cofounder. S. Arthur: Employee; Self; Relypsa, Inc. A. Conrad: Employee; Self; Relypsa, Inc. Stock/Shareholder; Self; Vifor Pharma Group. W.B. White: Consultant; Self; Relypsa, Inc. B. Williams: Consultant; Self; Novartis AG, Relypsa, Inc., Vascular Dynamics Inc. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Novartis AG, Pfizer Inc., Servier. Funding Relypsa, Inc.