Daily Endocrinology Research Analysis
Three impactful endocrinology studies stood out today: a large RCT showed weekly semaglutide increases walking capacity in patients with peripheral artery disease and type 2 diabetes; a longitudinal study revealed that bariatric surgery can impair the accuracy of the dexamethasone suppression test; and a nationwide matched cohort confirmed persistently elevated mortality in Cushing’s syndrome with reduction after remission.
Summary
Three impactful endocrinology studies stood out today: a large RCT showed weekly semaglutide increases walking capacity in patients with peripheral artery disease and type 2 diabetes; a longitudinal study revealed that bariatric surgery can impair the accuracy of the dexamethasone suppression test; and a nationwide matched cohort confirmed persistently elevated mortality in Cushing’s syndrome with reduction after remission.
Research Themes
- GLP-1 receptor agonists improving functional capacity in vascular complications of diabetes
- Diagnostic accuracy after bariatric surgery: endocrine dynamic testing pitfalls
- Long-term outcomes in Cushing’s syndrome and the effect of biochemical remission
Selected Articles
1. Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): a phase 3b, double-blind, randomised, placebo-controlled trial.
In 792 patients with symptomatic PAD and T2D, weekly semaglutide 1.0 mg for 52 weeks significantly increased maximum walking distance versus placebo (treatment ratio 1.13; p=0.0004). Safety was acceptable with low rates of serious treatment-related adverse events and no treatment-related deaths.
Impact: This high-quality RCT demonstrates functional benefits of GLP-1RA therapy in PAD with T2D, a domain with few effective options to improve walking capacity.
Clinical Implications: Consider semaglutide to improve functional capacity in patients with PAD and T2D alongside guideline-directed therapies and supervised exercise; monitor GI adverse events.
Key Findings
- Semaglutide increased maximum walking distance at 52 weeks vs placebo (estimated treatment ratio 1.13; 95% CI 1.06–1.21; p=0.0004).
- Median ratio to baseline MWD: 1.21 with semaglutide vs 1.08 with placebo.
- Serious treatment-related adverse events were infrequent (1–2%) with no treatment-related deaths.
Methodological Strengths
- Phase 3b, double-blind, randomised, placebo-controlled, multicentre trial across 20 countries
- Prespecified functional endpoint (constant-load treadmill maximum walking distance) with adequate sample size (n=792)
Limitations
- Population restricted to T2D with Fontaine IIa PAD (ability to walk >200 m), limiting generalizability to more severe PAD or non-diabetic PAD
- Mechanisms of benefit and effects in non-diabetic PAD were not addressed
Future Directions: Assess mechanisms (e.g., endothelial function, inflammation, microvascular perfusion) and efficacy/safety in PAD without diabetes; compare with other GLP-1RA and SGLT2i for functional endpoints.
BACKGROUND: Peripheral artery disease is a highly morbid type of atherosclerotic vascular disease involving the legs and is estimated to affect over 230 million individuals globally. Few therapies improve functional capacity and health-related quality of life in people with lower limb peripheral artery disease. We aimed to evaluate whether semaglutide improves function as measured by walking ability as well as symptoms, quality of life, and outcomes in people with peripheral artery disease and type 2 diabetes. METHODS: STRIDE was a double-blind, randomised, placebo-controlled trial done at 112 outpatient clinical trial sites in 20 countries in North America, Asia, and Europe. Participants were aged 18 years and older, with type 2 diabetes and peripheral artery disease with intermittent claudication (Fontaine stage IIa, able to walk >200 m) and an ankle-brachial index of less than or equal to 0·90 or toe-brachial index of less than or equal to 0·70. Participants were randomly assigned (1:1) using an interactive web response system to receive subcutaneous semaglutide 1·0 mg once per week for 52 weeks or placebo. The primary endpoint was the ratio to baseline of the maximum walking distance at week 52 measured on a constant load treadmill in the full analysis set. Safety was evaluated in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT04560998 and is now completed. FINDINGS: From Oct 1, 2020, to July 12, 2024, 1363 patients were screened for eligibility, of whom 792 were randomly assigned to semaglutide (n=396) or placebo (n=396). 195 (25%) participants were female and 597 (75%) were male. Median age was 68·0 years (IQR 61·0-73·0). The estimated median ratio to baseline in maximum walking distance at week 52 was significantly greater in the semaglutide group than the placebo group (1·21 [IQR 0·95-1·55] vs 1·08 [0·86-1·36]; estimated treatment ratio 1·13 [95% CI 1·06-1·21]; p=0·0004). Six serious adverse events in five (1%) participants in the semaglutide group and nine serious adverse events in six (2%) participants in the placebo group were possibly or probably treatment related, with the most frequent being serious gastrointestinal events (two events reports by two [1%] in the semaglutide group and five events reported by three [1%] in the placebo group). There were no treatment-related deaths. INTERPRETATION: Semaglutide increased walking distance in patients with symptomatic peripheral artery disease and type 2 diabetes. Research implications include the need for future studies to further elucidate mechanisms of benefit and to assess the efficacy and safety in patients with peripheral artery disease who do not have type 2 diabetes. FUNDING: Novo Nordisk.
2. Impaired accuracy of the dexamethasone suppression test after bariatric surgery: implications for post-surgical cortisol interpretation.
Intraindividual comparisons before and 2 years after bariatric surgery showed higher post-DST cortisol and substantially lower plasma dexamethasone concentrations post-surgery, yielding potential false-positive DST results. Measuring dexamethasone levels can improve DST interpretation in post-bariatric patients.
Impact: Identifies a clinically relevant diagnostic pitfall after bariatric surgery that may lead to overdiagnosis of hypercortisolism and unnecessary workup.
Clinical Implications: In post-bariatric patients undergoing Cushing’s screening, co-measure plasma dexamethasone and consider alternative tests (late-night salivary cortisol, 24h urinary free cortisol). Avoid labeling DST >1.8 µg/dL as positive without confirming adequate dexamethasone exposure.
Key Findings
- Post-bariatric patients had higher post-DST cortisol than pre-surgery (0.9 vs 0.7 µg/dL; p<0.01).
- Four post-bariatric subjects exceeded the 1.8 µg/dL cut-off without autonomous cortisol secretion, indicating false positives.
- Plasma dexamethasone levels were significantly lower post-surgery (1.9 ng/dL) vs non-operated severe obesity (3.7 ng/dL) and healthy controls (4.0 ng/mL), p<0.01.
Methodological Strengths
- Prospective longitudinal intraindividual design (pre vs 2 years post-bariatric surgery)
- Comparator groups (non-operated severe obesity and healthy controls) and multivariable analyses identifying predictors of dexamethasone levels
Limitations
- Modest sample size and single-center cohorts limit external validity
- Potential variability in bariatric procedures and absorption not fully parsed
Future Directions: Validate findings in larger, diverse cohorts and define dexamethasone concentration thresholds ensuring DST interpretability across bariatric procedures.
IMPORTANCE: The impact of bariatric surgery (BS) on the performance of the 1 mg dexamethasone suppression test (DST) is not well established. OBJECTIVE: (1) To evaluate the intraindividual results of the DST in a group of patients before and 2 years after BS, and (2) to assess plasma dexamethasone levels and other factors influencing the reliability of the DST. METHODS: We conducted a prospective longitudinal study, including 38 subjects evaluating DST before and 2 years after BS. We also compared DST results, plasma dexamethasone levels, and related factors across 3 groups: individuals of the previous cohort 2 years post-BS (n = 21), patients with severe obesity without BS (pwO; n = 10), and healthy controls (n = 7). RESULTS: Post-BS patients had higher cortisol levels after DST compared with prior (0.9 vs 0.7 µg/dL; P < .01). Four individuals post-BS had cortisol levels >1.8 µg/dL in the absence of autonomous cortisol secretion. Plasma dexamethasone levels were significantly lower in post-BS patients (1.9 ng/dL) compared with non-operated pwO (3.7 ng/dL) and healthy controls (4.0 ng/mL), P < .01. Multivariate analysis identified BS (β = -1.258, P = .01) and sex hormone-binding globulin levels (β = -.013, P = .04) as significant independent predictors of plasma dexamethasone concentrations. CONCLUSION: Post-BS subjects showed higher post-DST cortisol levels and reached lower plasma dexamethasone concentration compared with non-operated individuals, which may lead to false-positive results. These findings highlight the need to consider dexamethasone measurements to enhance DST interpretation in post-BS patients. Further studies are necessary to validate these findings in broader populations. The underlying mechanisms need to be explored.
3. Mortality in Cushing's syndrome: declining over 2 decades but remaining higher than the general population.
In a 609-patient national CS cohort matched to 3018 controls and followed for a median of 16 years, all-cause mortality was significantly higher in CS (HR 1.44). Both Cushing disease and adrenal CS were associated with increased mortality; achieving remission within 2 years was linked to lower mortality.
Impact: Provides robust, population-matched evidence on contemporary mortality in CS and quantifies the survival benefit of early remission.
Clinical Implications: Prioritize rapid control and remission of hypercortisolism (surgical cure or effective medical therapy) and address modifiable risk factors (malignancy surveillance, cardiovascular risk) to improve long-term survival.
Key Findings
- All-cause mortality was higher in CS vs matched controls (HR 1.44; 95% CI 1.19–1.75).
- Both Cushing disease (HR 1.73; 95% CI 1.27–2.36) and adrenal CS (HR 1.31; 95% CI 1.00–1.81) had increased mortality risk.
- Failure to achieve remission within 2 years was associated with higher mortality vs remission (HR 1.44; 95% CI 1.00–2.17).
- Independent mortality risk factors included older age, male sex, and prior malignancy.
Methodological Strengths
- Large national cohort with 1:5 matching on age, sex, socioeconomic status, and BMI
- Long median follow-up (16 years) enabling robust mortality estimates
Limitations
- Retrospective design may leave residual confounding
- Potential misclassification of remission timing and cause-specific mortality in administrative data
Future Directions: Define drivers of residual excess mortality post-remission (e.g., cardiovascular, thromboembolic, infection) and evaluate strategies to mitigate risks.
OBJECTIVE: Patients with endogenous Cushing's syndrome (CS) have elevated mortality, particularly during active disease. A recent meta-analysis reported reduced mortality rates after 2000 in adrenal CS and Cushing disease (CD), though many studies lacked population-matched controls. METHODS: Nationwide retrospective study (2000-2023) in Israel using the Clalit Health Services database to assess all-cause mortality in patients with endogenous CS matched 1:5 with controls by age, sex, socioeconomic-status, and body mass index (BMI). Primary outcome was all-cause mortality. Secondary outcomes included cause-specific mortality, impact of hypercortisolism remission, disease source, and mortality risk factors. RESULTS: The cohort included 609 cases with CS (mean age 48.1 ± 17.2 years; 65.0% women) and 3018 matched controls (47.9 ± 17.2 years; 65.4% women). Over a median follow-up of 16 years, 133 cases (21.8%) and 472 controls (15.6%) died (HR = 1.44, 95% CI, 1.19-1.75). Both patients with CD (HR = 1.73, 95% CI, 1.27-2.36) and adrenal CS (HR = 1.31, 95% CI, 1.00-1.81) had increased mortality risk. Patients without remission within 2 years had a higher mortality risk than those achieving remission (HR = 1.44, 95% CI, 1.00-2.17). Mortality was similar for CD and adrenal CS (HR = .83, 95% CI, .56-1.24). Older age, male gender, and prior malignancy were independent risk factors for mortality. CONCLUSION: This is the largest national cohort study on mortality risk in CS over the past 2 decades, showing a significantly higher risk compared to matched controls in a homogeneous database. While etiology had no impact, remission significantly affected mortality, highlighting the importance of disease control for long-term survival.