Changes in Glucose Metabolism and Glycemic Status With Once-Weekly Subcutaneous Semaglutide 2.4 mg Among Participants With Prediabetes in the STEP Program.

OBJECTIVE: This analysis of 3,375 adults with overweight/obesity across the Semaglutide Treatment Effect in People with obesity (STEP) 1, 3, and 4 trials evaluated whether more participants with prediabetes had normoglycemia after 68 weeks' treatment with once-weekly semaglutide 2.4 mg plus lifestyle intervention versus placebo and assessed changes in glucose metabolism in participants with prediabetes. RESEARCH DESIGN AND METHODS: STEP 1, 3, and 4 were phase 3, 68-week, randomized, placebo-controlled, multinational trials; STEP 4 had a 20-week semaglutide run-in and 48-week randomized period. Analyses included changes (week 0-68; before the washout period) in glycemic status (prespecified: STEP 1 and 3; post hoc: STEP 4), and in HbA1c, fasting plasma glucose (FPG), and HOMA insulin resistance (HOMA-IR) among participants with prediabetes (post hoc). RESULTS: Significantly more participants with baseline (week 0) prediabetes (n = 1,536) had normoglycemia at week 68 with semaglutide versus placebo (STEP 1, 84.1% vs. 47.8%; STEP 3, 89.5% vs. 55.0%; STEP 4, 89.8% vs. 70.4%; all P < 0.0001). Fewer participants with baseline normoglycemia had prediabetes at week 68 with semaglutide versus placebo (STEP 1, 2.9% vs. 10.9%; STEP 3, 3.2% vs. 5.8%; STEP 4, 1.1% vs. 5.0%). Semaglutide resulted in greater improvements in HbA1c, FPG, and HOMA-IR than placebo among participants with baseline prediabetes (all P < 0.01). CONCLUSIONS: STEP 1, 3, and 4 collectively provide a robust assessment of the effects of semaglutide on glucose metabolism and prediabetes in a large cohort of adults with overweight/obesity while on treatment. Among participants with baseline prediabetes, 68 weeks' treatment with semaglutide versus placebo led to significant improvements in glucose metabolism and a higher likelihood of normoglycemia.

Bajos niveles de colesterol de HDL y alto riesgo de enfermedad autoinmune. Dos estudios poblacionales de cohorte con 117.341 individuos incluidos. / Low HDL cholesterol and high risk of autoimmune disease. Two population-based cohort studies including 117, 341 individuals

Antecedentes. HDL es cuantitativamente la lipoproteína más importante en la mayoría de las especies y la evidencia mecanicista sugiere que HDL tendría un papel en la función inmunológica normal. Probamos la hipótesis que sugiere que las concentraciones plasmáticas de HDL están asociadas con el riesgo de enfermedades autoinmunes. Métodos. Se incluyeron 107.954 y 9.387 individuos con mediciones basales de colesterol-HDL provenientes de 2 estudios de la población general: el Estudio de la Población General de Copenhague y el Estudio del Corazón de Copenhague. Los pacientes fueron seguidos mediante el Registro Nacional Danés de pacientes desde el inicio del período 2003-2015 o 1991-1994 hasta 2017, tiempo durante el cual 4.078 y 1.101 individuos desarrollaron enfermedad autoinmune en los 2 estudios respectivamente. Resultados. En el Estudio de la Población General de Copenhague, en comparación a los individuos con colesterol de HDL =2,0 mmol/L (77 mg/dL), los índices de riesgo para cualquier enfermedad autoinmune, ajustados de manera multifactorial fueron 1,06 (IC 95%, 0,94-1,19) para individuos con colesterol-HDL entre 1,5 y 1,99 mmol/L (58 a 77 mg/dL), 1,18 (IC 95%, 1,04-1,35) para individuos con colesterol-HDL entre 1,0 y 1,49 mmol/L (39 a 58 mg/dL) y 1,84 (IC 95%, 1,52- 2,22) para individuos con colesterol-HDL <1,0 mmol/L (39 mg/dL) (p<0,001 para tendencia). Estos resultados fueron similares cuando: se excluyeron los eventos dentro de los 5 años del inicio del estudio, tanto en mujeres como hombres por separado, eventos en el inicio del estudio, independientemente de la inflamación de bajo grado o concentraciones de triglicéridos, para diferentes niveles de apolipoproteína A1 y para definiciones de punto final más restrictivas. Finalmente, el Estudio del Corazón de Copenhague proporcionó una confirmación independiente. Conclusiones: Los bajos niveles de colesterol-HDL se asocian con un alto riesgo de enfermedad autoinmune en individuos de la población general. Nuestros hallazgos observacionales no pueden determinar la causalidad.

Background. HDL is quantitatively the most important lipoprotein in most species and mechanistic evidence points toward a role for HDL in normal immune function. We tested the hypothesis that concentrations of HDL cholesterol are associated with risk of autoimmune disease. Methods. From 2 studies of the general population-the Copenhagen General Population Study and the Copenhagen City Heart study-we included 107,954 and 9,387 individuals with baseline measurements of HDL cholesterol. These were followed with the national Danish Patient Registry from baseline in 2003-2015 or 1991-1994 through 2017, during which time 4078 and 1101 individuals developed autoimmune disease in the 2 studies. Results. In the Copenhagen General Population Study, compared to individuals with HDL cholesterol =2.0 mmol/L (77 mg/dL), the multifactorially adjusted hazard ratios for any autoimmune disease were 1.06 (95% CI, 0.94-1.19) for individuals with HDL cholesterol of 1.5-1.99 mmol/L (58-77 mg/dL), 1.18 (95% CI, 1.04-1.35) for individuals with HDL cholesterol of 1.0-1.49 mmol/L (39-58 mg/dL), and 1.84 (95% CI, 1.52-2.22) for individuals with HDL cholesterol <1.0 mmol/L (39 mg/dL) (p for trend <0.001). These results were similar when excluding events within 5 years of baseline, in women and men separately, for events at baseline, irrespective of low-grade inflammation or triglyceride concentrations, for the apolipoprotein A1 part of HDL, and for more restrictive end point definitions. Finally, the Copenhagen City Heart Study provided independent confirmation. Conclusions. Low HDL cholesterol level is associated with high risk of autoimmune disease in individuals from the general population. Our observational findings cannot determine causality.