Effects of a Novel Oral Testosterone Undecanoate on Ambulatory Blood Pressure in Hypogonadal Men

Background: 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. Methods: 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. Results: 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). Conclusion: 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. ClinicalTrials.gov identifier: NCT 03868059.

Important Food Sources of Fructose-Containing Sugars and Blood Pressure: A Systematic Review and Meta-Analysis of Controlled Trials

Objectives Overconsumption of fructose-containing sugars may increase blood pressure. Whether this effect is mediated by the food matrix is unclear. We conducted a systematic review and meta-analysis of controlled feeding trials of the effect of food sources of fructose-containing sugars at different levels of energy control on blood pressure (NCT02716870). Methods We searched MEDLINE, Embase and the Cochrane Library through January, 2020 for controlled trials ≥7d. Trial designs were prespecified based on energy control: substitution (energy matched replacement of sugars in the diet); addition (excess energy from sugars added to diets); subtraction (energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced in the diet) trials. Outcomes were systolic blood pressure (SBP) and diastolic blood pressure (DBP). Independent reviewers extracted data and assessed risk of bias. Certainty of evidence was assessed by GRADE. Results We included 76 trials (121 trial comparisons, N = 4 302) assessing 9 food sources (sugar-sweetened beverages [SSBs], sweetened dairy alternatives, 100% fruit juice, fruit, dried fruit, sweets, added nutritive sweetener, sweetened cereal grains/bars, and mixed sources) across the 4 levels of energy control. Total fructose-containing sugars decreased SBP (mean difference, −2.76 mmHg [95% CI, −4.36, −1.16], P = 0.001) and DBP (−1.26 mmHg [−2.29, −0.23], P = 0.016) in addition trials and the removal of these sugars decreased SBP (−1.79 mmHg [−3.36, −0.21], P = 0.026) in subtraction trials. There was evidence of interaction by food source with fruit decreasing and sweets and mixed sources increasing SBP and DBP in addition trials and the removal of SSBs decreased SBP in subtraction trials. The certainty of evidence was generally moderate to low for all food source-outcome relationships, except for the decreasing-effect of fruit on DBP in addition trials (high). Conclusions Food source and energy control appear to mediate the effect of fructose-containing sugars on blood pressure. The evidence provides a good indication that fruit decreases while excess calories from SSBs, sweets and mixed sources increase blood pressure. More high-quality trials of different food sources are needed to improve our estimates. Funding Sources Diabetes Canada.

078 Chronic sleep and circadian disruption differentially affects blood pressure, renal sodium retention, and aldosterone secretion

Introduction Chronic sleep restriction (CSR) and recurrent circadian disruption (RCD; e.g., rotating shiftwork) can increase an individual’s risk of cardiovascular and kidney disease. However, no study has assessed whether CSR and RCD together increase blood pressure (BP) and alter renal function (RF). We tested the hypotheses that the combination of CSR and RCD would increase blood pressure, renal sodium retention, and aldosterone secretion in individuals living for 3 weeks on an imposed non-24-h sleep-wake (SW) schedule (induces RCD) and controlled diet with or without CSR. Methods Seventeen (9M) healthy participants (aged 26.1±4.5y [mean±SD]) were scheduled to twenty-four 20-h Forced Desynchrony days and were randomized to either Control (1:2 sleep:wake, 6.67h sleep:13.33h wake; n=8) or CSR (1:3.3 sleep:wake, 4.67h sleep: 5.33h wake; n=9) SW conditions during a 32-day inpatient protocol. BP was measured following ~80–90 min in constant seated posture after scheduled waketime. All urine voids were collected, combined and sampled in 3-6h blocks throughout the study. Samples were assayed for sodium, potassium and aldosterone and analyzed as both excretion rates and total secretion (both per 20h). Data were assigned circadian phase using fitted core body temperature and analyzed using mixed-effects models with circadian phase, aligned/misaligned sleep, or time awake (with associated scheduled activity, sleep/wake, and feeding behaviors) and their interactions as fixed effects. Results There was a significant interaction between aligned/misaligned sleep and condition for resting BP (p=0.02), such that systolic BP was ~6% higher following circadian-misaligned sleep in CSR compared to Control (p=0.04). Renal sodium and potassium followed a robust circadian pattern (p&lt;0.0001), with limited influence of time awake. In contrast, the timing of aldosterone excretion was affected by time awake (p&lt;0.05). Total daily renal sodium secretion decreased from beginning to end of the protocol (p=0.03), with no change in sodium consumption and aldosterone secretion (p=0.95). Conclusion Under conditions similar to rotating shiftwork, systolic BP increased and sodium, potassium, and aldosterone were differentially influenced by circadian phase and scheduled behaviors. Additionally, renal sodium secretion decreased despite minimal changes in aldosterone secretion, suggesting increased renal aldosterone sensitivity. These findings may provide insight into mechanisms contributing to poor cardiovascular and renal health observed in shiftwork. Support (if any):

The need for accessibility to chloride to solubilize insoluble salts may underlie some cases of hypertension

Hypertension is the greatest risk factor for stroke. It is the most common comorbidity of COVID-19, and may be partly caused by the widespread distribution of insoluble and stiff calcium salts such as calcium oxalate. As an intrinsic defensive mechanism, tissues in hypertensive individuals increase blood pressure to pump NaCl to inaccessible parts of the body, and chloride, as a strong anion can solubilize insoluble and rigid salts which are stressful to cells.

BLOOD PRESSURE INCREASES INDUCED BY IATROGENESIS, OVER THE COUNTER SUBSTANCES, AND HERBALS PRODUCTS

A number of both prescription and over the counter drugs, herbal supplements, and miscellaneous substances can increase blood pressure in subjects by degrees that vary substantially within drug classes and individual patients; such increases often remain within the normal range but may cause overt hypertension (BP>140/90) mmHg and even precipitate hypertensive crises. Blood pressure increases are often potentiated by co-existing cardiovascular conditions, age, renal disease, diabetes, obesity, and interactions with other concomitant medications. The need to scrutinize for drugs or other substances that may be contributing to elevated blood pressures or impairing responses to anti-hypertensive medications is critically important, particularly in the evaluation of resistant and refractory hypertension. Anti-hypertensive effects of diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers may be blunted. The drugs most commonly associated with blood pressure elevations are non-steroidal anti-inflammatory agents, sympathomimetic amines, estrogen-containing oral contraceptives, certain antidepressants, angiogenesis inhibitors, and ephedra. Although most drug-induced blood pressure increases do not, in fact, lead to overt hypertension, systolic and diastolic blood pressure elevations of as little as 2 mmHg lead to significant increases in the risk of cardiovascular events. When a medication with the potential to increase blood pressure is added to a patient’s therapeutic regimen, it is most important to monitor for possible changes in blood pressure even within the normal range. An initial diagnosis of hypertension should not be made until a thorough examination of all over the counter products and herbal substances that a patient may be consuming.