Effects of growth hormone on cardiovascular risk factors and atherosclerosis

Hypopituitary patients with growth hormone (GH) deficiency (GHD) have increasedmorbidity and mortality from cardiovascular disease (CVD). GH treatment has both beneficialand potentially negative cardiovascular effects. The mechanism for the dyslipidemia observedin these patients is not completely understood and animal experiments indicate that GH isimportant for dietary effects on serum cholesterol. The aim was to investigate effects of GHon diet-induced changes in serum cholesterol and on other cardiovascular risk factors andatherosclerosis.Effects of GH on cholesterol metabolism were evaluated in a cross-over study of sixGHD patients during a high-fat and high-cholesterol 17-day diet with and without GHtreatment. GH attenuated the increase in cholesterol biosynthesis induced by the high-fat diet,probably due to maintained LDL receptor activity. In contrast to animal studies, GH did notinfluence serum LDL cholesterol levels during fat feeding in humans.Effects of GH on cardiovascular risk factors in relation to atherosclerosis were studiedin 34 cardiovascularly healthy hypopituitary patients with GHD, in an open prospective 3-year trial. Results were compared with two healthy control groups matched for age, sex andsmoking. Hypopituitary patients with GHD had higher waist-to-hip ratio, resting heart rate,fasting insulin levels, interleukin-6 (IL-6) concentrations and tissue plasminogen activatorantigen levels together with lipid disturbances including higher serum triglycerides, lowerHDL cholesterol and smaller LDL particles than both the BMI-matched and the non-obesecontrol group. Patients had higher intima-media thickness (IMT) of the carotid bulb (IMTCAB)than non-obese controls at baseline. Female patients had a more pronouncedcardiovascular risk profile compared to their BMI-matched controls. IMT of the commoncarotid artery (CCA) correlated to serum IL-6 levels at baseline in the patient group.Independent risk factors for high IMT-CAB were age and pituitary disease in the total cohort.The waist circumference and CRP levels decreased but insulin resistance increased inpatients after GH treatment. The IMT-CAB increased during three years in both controlgroups, but was unchanged in GH-treated patients. The IMT-CCA was unchanged in all threegroups. The change in IMT-CCA was independently correlated to the change in serum tumournecrosis factor-á in the patient group, but none of the measured variables correlatedindependently to the change in IMT-CAB.In conclusion, we found that GH attenuated the increased cholesterol synthesis inducedby fat feeding, but GH did not influence the increase in serum LDL cholesterol during diet.Pituitary-deficient GHD patients without manifest CVD demonstrated several cardiovascularrisk factors compared to controls independent of their BMI and female patients were at higherrisk. Despite this high risk pattern, GH treatment in GHD patients reduced the rate ofprogression of atherosclerosis in the CAB. The atherosclerosis progression rate in CCA wassimilar in patients to that observed in healthy BMI-matched as well as non-obese controls

Premature mortality in patients with Addison's disease: a population-based study.

BACKGROUND: The survival rate of patients with primary adrenal insufficiency (Addison's disease) undergoing currently accepted replacement therapy is not known, although well-informed patients are considered to have a normal survival rate. In this study, we evaluated the mortality of patients with Addison's disease in Sweden. METHODS: A population-based, retrospective, observational study was performed, using the National Swedish Hospital and Cause of Death Registers, covering the period from 1987-2001. After a diagnosis of Addison's disease, each patient was followed until the end of follow-up or death. Mortality was compared with that of the Swedish background population. FINDINGS: We identified 1675 patients (995 women and 680 men) diagnosed with primary adrenal insufficiency. The average follow-up from initial diagnosis was 6.5 yr. Five hundred seven patients died during the study period compared with an expected 199. The risk ratio for all-cause mortality was 2.19 (confidence interval 1.91-2.51) for men and 2.86 (confidence interval 2.54-3.20) for women. The excess mortality in both men and women was attributed to cardiovascular, malignant, and infectious diseases. Concomitant diabetes mellitus was observed in 12% of the patients, but only contributed to the increased mortality to a minor extent. INTERPRETATION: Compared with the background population, we observed that the risk ratio for death was more than 2-fold higher in patients with Addison's disease. Cardiovascular, malignant, and infectious diseases were responsible for the higher mortality rate

Visceral Fat and Novel Biomarkers of Cardiovascular Disease in Patients With Addison\u27s Disease: A Case-Control Study

Context: Patients with Addison\u27s disease (AD) have increased cardiovascular mortality. Objective: To study visceral fat and conventional and exploratory cardiovascular risk factors in patients with AD. Subjects: Patients (n = 76; n = 51 women) with AD and 76 healthy control subjects were matched for sex, age, body mass index (BMI), and smoking habits. Main outcome measures: The primary outcome variable was visceral abdominal adipose tissue (VAT) measured using computed tomography. Secondary outcome variables were prevalence of metabolic syndrome (MetS) and 92 biomarkers of cardiovascular disease. Results: The mean 6 standard deviation age of all subjects was 53 6 14 years; mean BMI, 25 6 4 kg/ m2; and mean duration of AD, 17 6 12 years. The median (range) daily hydrocortisone dose was 30 mg (10 to 50 mg). Median (interquartile range) 24-hour urinary free cortisol excretion was increased in patients vs controls [359 nmol (193 to 601 nmol) vs 175 nmol (140 to 244 nmol); P, 0.001]. VAT did not differ between groups. After correction for multiple testing, 17 of the 92 studied biomarkers differed significantly between patients and control subjects. Inflammatory, proinflammatory, and proatherogenic risk biomarkers were increased in patients [fold change (FC),.1] and vasodilatory protective marker was decreased (FC

Balcinrenone plus dapagliflozin in patients with heart failure and chronic kidney disease: Results from the phase 2b MIRACLE trial

Aims: Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study. Methods and results: From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m2 and urinary albumin‐to‐creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose–response relationship. There were possible dose‐dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non‐significant trends towards reduced N‐terminal pro‐B‐type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo. Conclusion: While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo

Ticagrelor in Patients with Stable Coronary Disease and Diabetes.

Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear. In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02). In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.)