Daily Endocrinology Research Analysis

IMPORTANCE: Major adverse cardiovascular events (MACEs) are primary causes of morbidity and mortality in adults with type 2 diabetes (T2D), yet few head-to-head randomized trials have compared the effects of glucose-lowering medications on MACEs, and most observational analyses are limited by inadequate bias adjustment methods. OBJECTIVE: To compare the effectiveness of sustained exposure to 4 classes of glucose-lowering medications (sulfonylureas, dipeptidyl peptidase-4 inhibitors [DPP4is], sodium-glucose cotransporter-2 inhibitors [SGLT2is], and glucagon-like peptide-1 receptor agonists [GLP-1RAs]) on MACEs in US adults with T2D using modern causal methods combined with machine learning. DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness study included adults with T2D who were members of 6 large US health care delivery systems and initiated treatment with 1 of 4 medication classes (sulfonylureas, DPP4is, SGLT2is, and GLP-1RAs) between January 1, 2014, and December 31, 2021. Data analysis was conducted from May 1 to December 31, 2024. EXPOSURE: New use of a sulfonylurea, DPP4i, SGLT2i, or GLP-1RA based on filled prescriptions. MAIN OUTCOMES AND MEASURES: The primary outcome was MACEs defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Analyses were conducted using targeted learning within a trial emulation framework. Heterogeneity of treatment effects was assessed for prespecified subgroups. RESULTS: This study included 296 676 adults. The cohort for emulating a 4-arm trial included a subset of 241 981 adults (mean [SD] age, 57.2 [12.9] years; 54.3% male) with T2D. In adjusted analyses, 2.5-year MACE risk was lowest in patients with sustained exposure to GLP-1RAs, followed by SGLT2is , sulfonylureas, and DPP4is. Comparing DPP4is with sulfonylureas and SGLT2is with GLP-1RAs, the 2.5-year cumulative risk difference was 1.9% (95% CI, 1.1%-2.7%) and 1.5% (1.1%-1.9%), respectively. Risk differences in patients with vs without atherosclerotic cardiovascular disease (ASCVD) were similar in direction but typically much smaller for patients without ASCVD. Evidence of a benefit of GLP-1RAs over SGLT2is was most pronounced in patients with baseline ASCVD or heart failure (HF), age 65 years or older, or low to moderate kidney impairment but was not found in patients younger than 50 years. CONCLUSIONS AND RELEVANCE: In this study, MACE risk varied significantly by medication class, with most protection achieved with sustained treatment with GLP-1RAs followed by SGLT2is, sulfonylureas, and DPP4is. The magnitude of benefit of GLP-1RAs over SGLT2is depended on baseline age, ASCVD, HF, and kidney impairment. These results, along with consideration of cost, availability, and collateral clinical benefits, may inform treatment decisions for adults with T2D.

OBJECTIVE: The association between autoimmune diseases and type 1 diabetes (T1D) is mostly based on studies among people with T1D at baseline. We assessed the risk of incident T1D among adolescents with other autoimmune diseases. RESEARCH DESIGN AND METHODS: Included were all Israeli adolescents without a history of dysglycemia, aged 16-19 years, undergoing medical evaluation before mandatory military service between January 1996 and December 2016. Data were linked with information on adult-onset T1D from the Israeli National Diabetes Registry. The cohort was dichotomized by the presence of any autoimmune disease. Cox proportional hazards modeling was applied. RESULTS: A total of 1,426,362 people were included, of whom 38,766 (2.7%) had a history of autoimmunity at study entry (10,333 with autoimmune thyroid disease [AITD] and 9,603 with celiac disease). Over 15,810,751 person-years of follow-up, there were 37 and 740 incident cases of T1D among people with and without autoimmunity, respectively, and a crude incident rate of 9.6 and 4.8 case/105 person-years, respectively. In a multivariable model adjusted for sex, birth year, and sociodemographic variables the hazard ratio (HR) for incident T1D among people with autoimmunity was 2.19 (95% CI 1.57-3.04) versus those without. Results persisted when islet-autoantibody data were used as mandatory criteria for T1D case definition (HR 2.22, 95% CI 1.13-4.35). The HRs among people with AITD and celiac disease were 3.99 (2.5-6.4) and 2.82 (1.46-5.45), respectively. CONCLUSIONS: Autoimmune diseases in late adolescence were associated with an increased risk of T1D in adulthood in both sexes, especially among those with AITD and celiac disease.

DESIGN: Morning cortisol predicts the outcome of the short synacthen test (SST). There is a paucity of studies examining this in a dedicated cohort of children and adults weaning off glucocorticoids and using a modern immunoassay. This study aimed to identify early morning serum cortisol (EMC) cut-offs which predict the SST outcome in children and adults during glucocorticoid weaning. METHODS: A retrospective cohort study of pediatric and adult patients on long-term glucocorticoids with suspected glucocorticoid-induced adrenal insufficiency (GIAI) undergoing an SST. Our main outcomes were cut offs with 95% and 99% sensitivity and specificity for EMC analysed on modern immunoassays, determined via receiver operating characteristic (ROC) curve analysis. A pass on SST was defined as 30-min cortisol of ≥430 nmol/L (15.6 µg/dL). RESULTS: 151 and 372 SSTs were included in the pediatric and adult cohorts, respectively, of which 32% and 37% were passed. ROC curve analysis demonstrated that EMC performed well in both cohorts with area under curve (AUC) of 0.79 (95% CI, 0.71, 0.87) and 0.88 (95% CI, 0.84, 0.91), respectively. EMC cut offs to predict a pass on SST were 278 (10.1 µg/dL) and 290 nmol/L (10.5 µg/dL) at 95% sensitivity, and 316 (11.5 µg/dL) and 349 nmol/L (12.7 µg/dL) at 99% sensitivity, respectively. Further analysis in adults showed that using a 95% cut off in clinical practice was effective as 48/51 patients with EMC between 290 and 349 nmol/L (10.5-12.7 µg/dL), were weaned off without adverse events. CONCLUSION: Morning serum cortisol can predict the SST outcome in children and adults weaning from glucocorticoids. An EMC > 290 nmol/L in adults predicts a patient can stop glucocorticoid therapy and will recover adrenal function.