Daily Endocrinology Research Analysis
Analyzed 64 papers and selected 3 impactful papers.
Summary
A phase 3 randomized-withdrawal trial showed that the selective glucocorticoid receptor modulator relacorilant better maintained hypertension control in Cushing’s syndrome than placebo, with a favorable safety profile. A Nature Metabolism study revealed that free fatty acids drive uncoupled respiration via ATP/ADP carriers in white adipocytes, contributing to thermogenesis independently of UCP1 in specific settings. A large multicenter RCT found that protocolized hyponatremia correction increased normonatremia rates but did not reduce 30-day mortality or rehospitalization.
Research Themes
- Cushing’s syndrome therapeutics and selective GR modulation
- Adipocyte thermogenesis and metabolic energy expenditure mechanisms
- Inpatient electrolyte management and outcomes in hyponatremia
Selected Articles
1. Efficacy and safety of relacorilant for the treatment of patients with Cushing's syndrome (GRACE): a multicentre, phase 3, double-blind, placebo-controlled, randomised-withdrawal study.
In a phase 3 randomized-withdrawal trial, relacorilant better maintained hypertension control than placebo among Cushing’s syndrome patients who initially responded in an open-label run-in. Safety was favorable, with no adrenal insufficiency, hypokalemia, or QT prolongation observed.
Impact: This is the first phase 3 randomized-withdrawal evidence that a selective GR modulator can sustain clinical benefit in endogenous hypercortisolism with a clean safety profile. It advances therapeutic options beyond steroidogenesis inhibitors and non-selective antagonists.
Clinical Implications: Relacorilant may be considered to maintain blood pressure control and mitigate hypercortisolism sequelae with favorable tolerability. Longer-term data and head-to-head comparisons with existing therapies will clarify placement in treatment algorithms.
Key Findings
- During randomized withdrawal, more placebo-treated patients lost hypertension control versus relacorilant (proportion difference 34%; OR 0.17 [95% CI 0.04–0.77]; p=0.022).
- 62 responders were randomized after 22 weeks’ open-label relacorilant; 95 completed the open-label phase.
- No cases of adrenal insufficiency, endometrial hypertrophy-related bleeding, drug-induced hypokalemia, or QT prolongation were observed.
Methodological Strengths
- Multicenter, double-blind, placebo-controlled randomized-withdrawal design with prespecified primary endpoint
- Rigorous masking and intention-to-treat analysis for the primary outcome
Limitations
- Relatively small randomized-withdrawal sample (n=62) and short randomized phase (12 weeks)
- Primary endpoint focused on hypertension response; broader metabolic and hard outcomes were secondary or not assessed long term
Future Directions: Head-to-head trials versus mifepristone or steroidogenesis inhibitors, longer-term outcome studies (glycemic control, cardiovascular events), and biomarker-guided patient selection are warranted.
BACKGROUND: Relacorilant is a selective glucocorticoid receptor modulator designed to reduce excess cortisol activity by competing with cortisol for glucocorticoid receptor binding, mitigating the clinical manifestations of endogenous hypercortisolism (Cushing's syndrome). The aim of this study was to assess the efficacy and safety of relacorilant in adults with endogenous hypercortisolism. METHODS: This multicentre, phase 3, double-blind, placebo-controlled, randomised-withdrawal study enrolled adults with endogenous hypercortisolism and hypertension, hyperglycaemia, or both and was conducted at 77 study centres across 11 countries. Key inclusion criteria included being aged 18-80 years with at least two clinical signs or symptoms of hypercortisolism. In the open-label phase, patients received oral, once-daily relacorilant (escalation from 100 mg up to 400 mg) for 22 weeks. Patients who met response criteria were randomly assigned (1:1) by the interactive web response system to continue relacorilant 400 mg (or highest tolerated dose) or placebo for 12 weeks in the randomised-withdrawal phase. Participants and investigators were masked to treatment assignment. The primary outcome was the proportion of patients who lost hypertension response during the randomised-withdrawal phase compared between relacorilant and placebo at week 12. As per protocol, this outcome was assessed in all participants who received at least one dose of study drug in the study period (intention-to-treat population). Missing randomised-withdrawal week 12 values were considered a loss of response. Safety was assessed in all enrolled patients who received at least one dose of study drug in that period. This study is registered with ClinicalTrials.gov, NCT03697109. FINDINGS: Between Oct 16, 2018, and April 15, 2024, 404 patients were screened, 152 were enrolled, and 95 completed the open-label relacorilant phase. 62 patients met response criteria and were randomly assigned to relacorilant (30 total participants [21 met hypertension response criteria]) or placebo (32 total participants [22 met hypertension response criteria]). In the 30 participants in the relacorilant group, the mean age was 46·6 years (SD 11·0), 22 (73%) were female, and eight (27%) were male. In the 32 participants in the placebo group, the mean age was 48·8 years (SD 14·4), 26 (81%) were female, and six (19%) were male. During the randomised-withdrawal phase, significantly more patients with baseline hypertension who were randomly assigned to placebo lost hypertension control compared with those who continued relacorilant (proportion difference 34%; odds ratio 0·17 [95% CI 0·04-0·77]; p=0·022). In the randomised-withdrawal phase safety population, the most common adverse events in the 30 participants given relacorilant and the 32 participants given placebo were back pain (5 [17%] vs 6 [19%]), acne (3 [10%] vs 0), arthralgia (3 [10%] vs 3 [9%]), bursitis (3 [10%] vs 0), headache (3 [10%] vs 4 [13%]), and insomnia (0 vs 4 [13%]). There were no cases of excessive glucocorticoid receptor antagonism, adrenal insufficiency, vaginal bleeding associated with endometrial hypertrophy, drug-induced hypokalaemia, or drug-induced QT interval prolongation. INTERPRETATION: Patients treated with relacorilant were more likely to maintain hypertension control compared with patients treated with placebo. The findings support consideration of relacorilant as a therapeutic option to reduce the harmful and debilitating effects of endogenous hypercortisolism. FUNDING: Corcept Therapeutics.
2. Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.
This mechanistic study shows that free fatty acids induce uncoupled respiration through ATP/ADP carriers in white adipocytes, independent of fatty acyl-CoAs or beta-oxidation. In obese thermoneutral-adapted mice, this UCP1-independent pathway contributed to thermogenesis and cold tolerance, implicating a potential anti-obesity target.
Impact: It identifies a previously underappreciated UCP1-independent thermogenic mechanism in white adipocytes with in vivo relevance under thermoneutral obesity. This reshapes concepts of adipose bioenergetics and opens drug discovery avenues.
Clinical Implications: While preclinical, targeting ATP/ADP carrier–mediated uncoupling in white adipocytes may augment whole-body energy expenditure and support obesity therapies, especially in settings where brown adipose tissue activity is limited.
Key Findings
- Free fatty acids, not fatty acyl-CoAs or beta-oxidation, drive uncoupled respiration via ATP/ADP carriers in white adipocytes.
- In obese thermoneutral-adapted mice, white adipocyte uncoupling contributes to thermogenesis and cold tolerance independent of brown adipose tissue or muscle.
- Re-esterification suppresses respiration in lipolytic adipocytes; STAT3 promotes respiration by inhibiting re-esterification via GPAT3.
Methodological Strengths
- Convergent mechanistic evidence across cellular assays and in vivo mouse models
- Physiological validation under thermoneutral and obese conditions demonstrating functional thermogenic relevance
Limitations
- Preclinical study; translational applicability to human adipose biology remains to be established
- Molecular specificity of ATP/ADP carrier interactions with fatty acids in human tissues requires further definition
Future Directions: Define druggable nodes regulating ATP/ADP carrier–mediated uncoupling, validate in human adipocytes/tissues, and test metabolic efficacy and safety in translational models.
Energy stored in adipocytes as triglycerides is mobilized via lipolysis, releasing fatty acids and glycerol into the circulation. Re-esterification of fatty acids that remain within the adipose tissue is the primary driver of adipocyte ATP consumption. Paradoxically, re-esterification suppresses respiration in lipolytic adipocytes. We previously found that STAT3 drives respiration by inhibiting re-esterification via GPAT3. Here we show that free fatty acids drive uncoupled respiration in complex with the ATP/ADP carriers. The impacts of lipolysis and re-esterification on uncoupled respiration correspond with fatty acids, not fatty acyl-CoAs or beta-oxidation. Under standard housing conditions, brown adipocyte uncoupling via uncoupling protein 1 is the dominant thermogenic pathway. However, in obese thermoneutral-adapted mice, uncoupled respiration in white adipocytes contributes to thermogenesis and cold tolerance, independent of brown adipose tissue or muscle activity. Our results suggest that uncoupled respiration in white adipocytes contributes to whole-body energy expenditure and could be a promising target for obesity treatment.
3. A Randomized Trial of Targeted Hyponatremia Correction in Hospitalized Patients.
In a multicenter RCT of 2173 hospitalized patients with chronic hyponatremia, a targeted correction strategy achieved higher normonatremia rates than routine care but did not reduce 30-day mortality or rehospitalization. Overcorrection was uncommon and no osmotic demyelination occurred.
Impact: This large negative RCT clarifies that protocolized sodium correction alone does not improve short-term hard outcomes, informing de-implementation of resource-intensive strategies and guiding future trials toward patient-centered endpoints.
Clinical Implications: Hyponatremia correction should prioritize safety and individualized goals; improving sodium values does not necessarily translate into short-term survival or readmission benefits. Focus on underlying etiology and longer-term, functional outcomes is warranted.
Key Findings
- Targeted correction increased normonatremia achievement (60.4% vs 46.2%) compared with routine care.
- No significant difference in 30-day composite of death or rehospitalization (20.5% vs 21.8%; absolute difference -1.3 percentage points; P=0.45).
- Overcorrection was infrequent (2.3% vs 1.4%) and no osmotic demyelination syndrome occurred.
Methodological Strengths
- Large, multicenter randomized controlled design with robust sample size (n=2173)
- Pre-registered (ClinicalTrials.gov NCT03557957) with clearly defined primary composite endpoint
Limitations
- Open-label pragmatic design with heterogeneous hyponatremia etiologies may dilute treatment effects
- Short 30-day follow-up may miss longer-term benefits or harms
Future Directions: Evaluate tailored correction strategies by etiology and severity, extend follow-up to functional and quality-of-life outcomes, and assess integration with comprehensive care bundles.
BACKGROUND: Chronic hyponatremia is associated with adverse outcomes, including falls, neurocognitive disorders, and mortality, but whether hyponatremia itself increases morbidity and mortality, or is simply an indicator of underlying disease severity, remains unclear. We aimed to evaluate the effects of targeted hyponatremia correction versus routine care on mortality and rehospitalization rates. METHODS: We conducted a randomized, controlled, parallel-group, multicenter trial across nine European centers. Hospitalized participants with plasma sodium lower than 130 mmol/l were assigned to undergo either a multifaceted targeted correction of hyponatremia (intervention) or routine care for hyponatremia (control). The primary outcome was the combined risk of death or rehospitalization within 30 days of trial inclusion. RESULTS: A total of 2173 patients were randomly assigned to intervention (n=1079) or control (n=1094). The median age was 73 years (interquartile range, 63 to 81) and 48% were male. The median baseline sodium levels were 127 mmol/l (interquartile range, 124 to 128) in both groups. The mean (± standard deviation) maximum absolute change in sodium levels during the treatment period was 10.0 mmol/l (±5.6) in the intervention group, compared with 8.7 mmol/l (±5.6) in the control group, resulting in normal sodium levels (defined as 135-145 mmol/l) in 641 (60.4%) and 492 (46.2%) patients in the intervention and control groups, respectively. Within 30 days after inclusion, the primary outcome occurred in 20.5% (218 of 1065 patients) in the intervention group and 21.8% (234 of 1073 patients) in the control group (estimated absolute difference, -1.3 percentage points; 95% confidence interval, -4.9 to 2.2; P=0.45). Death occurred in 86 (8.0%) patients and rehospitalization in 141 (13.2%) patients in the intervention group compared with 88 (8.0%) patients and 151 (14.1%) patients in the control group. Overcorrection occurred in 25 (2.3%) patients in the intervention group and 16 (1.4%) patients in the control group; no cases of osmotic demyelination syndrome were observed. CONCLUSIONS: In hospitalized patients with chronic hyponatremia, a targeted correction intervention resulted in higher normonatremia rates but did not reduce a composite outcome of 30-day mortality and rehospitalization. (Funded by the Swiss National Science Foundation [grant number, 33 IC30_192979]; ClinicalTrials.gov number, NCT03557957.).