Daily Endocrinology Research Analysis

BACKGROUND: Tirzepatide, a dual incretin agonist of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, has favorable effects on glycemic control and body weight. The effects on cardiovascular outcomes are uncertain. METHODS: We conducted an active-comparator-controlled, double-blind, noninferiority trial in which patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomly assigned in a 1:1 ratio to receive a weekly subcutaneous injection of tirzepatide (up to 15 mg) or dulaglutide (1.5 mg), an agent that has been shown to reduce the incidence of cardiovascular events. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke and was tested for noninferiority of tirzepatide to dulaglutide with a margin of 1.05 for the upper limit of the 95.3% confidence interval for the hazard ratio. An upper limit of less than 1.00 was considered to indicate superiority of tirzepatide to dulaglutide. RESULTS: A total of 13,299 patients underwent randomization; 134 were subsequently excluded because they did not meet inclusion criteria. The modified intention-to-treat population thus included 6586 patients in the tirzepatide group and 6579 in the dulaglutide group. The mean (±SD) age of the patients was 64.1±8.8 years, 29.0% were women, the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 32.6±5.5, the mean glycated hemoglobin level was 8.4±0.9%, and the mean duration of diabetes was 14.7±8.8 years. A primary end-point event occurred in 801 patients (12.2%) in the tirzepatide group and 862 (13.1%) in the dulaglutide group (hazard ratio, 0.92; 95.3% confidence interval, 0.83 to 1.01; P = 0.003 for noninferiority; P = 0.09 for superiority). The incidence of adverse events appeared to be similar in the two groups, although more gastrointestinal adverse events were observed in the tirzepatide group. CONCLUSIONS: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was noninferior to dulaglutide with respect to a composite of death from cardiovascular causes, myocardial infarction, or stroke. (Funded by Eli Lilly; SURPASS-CVOT ClinicalTrials.gov number, NCT04255433.).

CONTEXT: Whether over- or under-replacement with thyroid hormone is associated with incident heart failure remains unclear. OBJECTIVE: Elucidate the relationship between thyroid hormone over- and under-replacement and incident heart failure. DESIGN: Retrospective cohort study of 641,504 adults who initiated thyroid hormone treatment between 2004 and 2017. SETTING: Veterans Health Administration. PARTICIPANTS: Two cohorts of adults aged ≥18 years treated with thyroid hormone were separately studied: 638,323 adults with at least two outpatient thyroid stimulating hormone (TSH) measurements, and 338,249 adults with at least two outpatient free thyroxine (FT4) measurements, between thyroid hormone initiation and incident heart failure or study conclusion. EXPOSURE: Time-varying TSH and FT4. MAIN OUTCOME MEASURE: Incident heart failure. RESULTS: Overall, 564,152/641,504 (87.9%) patients were men. Median age was 66 years. Incident heart failure occurred in 81,286/641,504 (12.7%) patients. Following adjustment for age, sex, and cardiovascular risk factors (e.g., smoking, hypertension), under-replacement (e.g., TSH>20 mIU/L, adjusted odds ratio [AOR], 1.93, 95% confidence interval [CI], 1.84-2.02; FT4<0.7 ng/dL, AOR 1.08; 95% CI, 1.04-1.12) and over-replacement (e.g., TSH<0.1 mIU/L, AOR, 1.06; 95% CI, 1.01-1.12; FT4>1.9 ng/dL, AOR, 1.23; 95% CI, 1.14-1.32) were associated with increased incident heart failure compared to euthyroidism. Incident heart failure risk was cumulative over time with both thyroid hormone over- and under-replacement, but association was strongest with under-replacement (e.g., TSH>5.5 mIU/L associated with a 5.8-fold increase in incident heart failure over 5 years). CONCLUSIONS: Our findings suggest that thyroid hormone treatment intensity may be a modifiable risk factor for heart failure.

OBJECTIVE: Constitutional duplications of PRKACA (PRKACAdup) have been described in rare cases of bilateral nodular adrenocortical disease (BNAD). The aim here was to clarify the phenotype in case of PRKACAdup, through systematic screening in BNAD patients, and study the molecular mechanisms involved. METHODS: Between 2020 and 2024, 781 index cases (IC) with BNAD (693 bilateral macronodular hyperplasia and 88 primary pigmented nodular adrenocortical diseases (PPNAD)), were genotyped using next-generation sequencing with a panel targeting ARMC5, KDM1A, MEN1, PRKAR1A, PRKACA, or whole-genome sequencing (WGS). Chromatin conformation analyses were performed with Hi-C libraries generated from 3 tumors. RESULTS: PRKACAdup was identified in 8/781 IC and 8/12 screened relatives. WGS performed on 4 IC presenting with PPNAD revealed no other genetic alterations in genes associated with human pathology within the duplicated region, nor any other alterations related to adrenal pathology. All IC with PRKACAdup underwent adrenalectomy for ACTH-independent hypercortisolism, with pathology confirming PPNAD. Other manifestations of Carney Complex were observed, in 8 of the 16 patients with PRKACAdup, limited to lentiginosis and benign tumors of the gonads. Immunohistochemistry using PRKACA/PRKAR1A antibodies facilitated the differentiation of the responsible genetic alteration. PRKACAdup was found to generate topologically associated neo-domains, in tumor Hi-C maps, as compared to controls. CONCLUSION: PRKACAdup causes PPNAD but no other forms of BNAD, so these should be sought in the absence of a pathogenic PRKAR1A variants.