Clinical efficacy and predictors of response to dulaglutide in type-2 diabetes.

Aim of this retrospective multicenter observational study was to evaluate the efficacy and safety of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) dulaglutide in a type-2 diabetic real-world population and to determine the factors predicting the response in terms of glycated haemoglobin (HbA1c) and other relevant clinical outcomes. Data for efficacy outcomes, adverse events and drug discontinuation were collected from records of patients with type-2 diabetes treated with once-a-week 1.5 mg of dulaglutide for 12 months in routine clinical practice. Initial analysis included 782 patients and 626 had complete follow-up at 6- and 12-months. There was a significant reduction of HbA1c at 6 months (-1 ± 0.8 %, p < 0.0001), which remained stable at 12-months follow-up (-1 ± 0.9 %, p < 0.0001). The percentage of subjects with HbA1c≤7.0 % increased significantly from 7.2 % at baseline to 52.7 % at 6 months to 55.8 % at 12 months. Predictors of the achievement of HbA1c≤7.0 % were low baseline HbA1c and short duration of diabetes. The reduction of HbA1c was associated with reductions of BMI, waist circumference, fasting plasma glucose and blood pressures. Neither sex nor age had significant effects on any clinical or laboratory outcome. The effects of dulaglutide on HbA1c, BMI and SBP tended to be greater in patients who shifted from dipeptidyl peptidase-IV inhibitors (-0.8 ± 0.8 %) than other GLP-1 RA, even if an improvement of HbA1c reduction (-0.5 %) was also seen in those shifting from other GLP-1 RA. This study confirms that addition of dulaglutide 1.5 mg once a week in real word settings has beneficial effects on both clinical and laboratory outcomes in patients with uncontrolled type-2 diabetes. Dulaglutide has a greater effect on HbA1c in patients with higher baseline values and helps achieve a target HbA1c≤7.0 %, more consistently in patients with lower baseline HbA1c and shorter diabetes duration.

Other aspects of bariatric surgery: liver steatosis, ferritin and cholesterol metabolism.

Bariatric surgery developed in the late 1970 to treat severe hyperlipidemias in overweight individuals, not necessarily obese. Several techniques have been developed, and the concept has come first of a surgery for morbid obesity, then of a cure for diabetes in morbid obesity. There are other aspects of bariatric surgery that deserve attention, beyond BMI and diabetes, such as hypertension, poor life expectancy, increased prevalence of cancer, congestive heart failure, social inadequacy. The aim of this presentation is to review some recent development in clinical research, in the fields of liver steatosis, ferritin metabolism, and cholesterol metabolism. Liver steatosis, also called fatty liver encompasses a graduation of diseases with different clinical relevance and prognosis. NAFLD correlates with atherosclerosis, insulin resistance and diabetes mellitus. There is now evidence that weight loss, obtained through diet or restrictive surgery, reduces the prevalence (and the severity) of NAFLD. An other issue is represented by serum ferritin concentrations, that are strongly associated with fibrosis, portal and lobular inflammation in NAFLD patients, especially in the presence of obesity. Body iron contributes to excess oxidative stress already at non iron overload concentrations. Moreover, serum ferritin is an important and independent predictor of the development of diabetes. Weight loss is accompanied by reduction of ferritin, more after restrictive than malabsorptive surgery. Metabolic changes are greater after malabsorptive or mixed surgery than after purely restrictive surgery, and this has been ascribed to a greater weight loss. Studies comparing the two kinds of surgery indicate that, for the same amount of weight loss, decrease of cholesterol is greater with the former than with the latter techniques, and this difference is mainly due to a greater reduction of intestinal absorption of cholesterol. In the choice of surgery for the single patient, among other aspects, malabsorptive surgery seems to be more indicated in subjects with hyperlipidemia, especially with high cholesterol levels.

La cirugía bariátrica se desarrolló a finales de la década de los 70 para tratar la hiperlipidemia severa en personas con sobrepeso, no necesariamente obesos. A lo largo de los años se han desarrollado varias técnicas quirúrgicas que han sido utilizadas en primer lugar en la obesidad mórbida y posteriormente en el tratamiento de la diabetes. Hay otros aspectos de la cirugía bariátrica que merecen atención más allá del IMC y la diabetes, como la hipertensión, la pobre esperanza de vida, una mayor prevalencia de cáncer, insuficiencia cardíaca e inadaptación social. El objetivo de este artículo es revisar los recientes avances clínicos en campos de investigación relacionados con la esteatosis hepática, el metabolismo de ferritina y el metabolismo del colesterol. La esteatosis hepática, también llamada hígado graso abarca una serie de las enfermedades con diferente pronóstico y relevancia clínica. El Hígado Graso No Alcohólico (NAFLD siglas en ingles) se correlaciona con la aterosclerosis, resistencia a la insulina y diabetes mellitus. Hoy en día existen evidencias de que la pérdida de peso que se obtiene a través de la dieta o cirugía restrictiva, reduce la prevalencia (y la gravedad) de la NAFLD. Otro tema de estudio incluye las concentraciones de ferritina sérica, que están fuertemente asociadas con la fibrosis e inflamación lobular y portal en pacientes con NAFLD, especialmente en presencia de obesidad. El exceso de hierro corporal en obesos contribuye a un aumento del estrés oxidativo debido a una sobrecarga en su concentración. Por otra parte, la ferritina sérica es un indicador importante e independiente del desarrollo de la diabetes. La pérdida de peso se acompaña de una disminución de la ferritina. Esta disminución es más evidente tras una cirugía restrictiva que tras una malabsortiva. Los cambios metabólicos son mayores después de una cirugía malabsortiva o mixta que tras una cirugía puramente restrictiva, y esto se ha atribuido a una mayor pérdida de peso. Estudios que comparan los dos tipos de cirugía indican que, para la mismo índice de pérdida de peso, la disminución de colesterol es mayor con las primeras técnicas que con las últimas, y esta diferencia se debe principalmente a una mayor reducción de la absorción intestinal del colesterol. En la elección de la cirugía para un paciente concreto, entre otros aspectos, la cirugía de malabsorción parece estar más indicada en sujetos con hiperlipemia, especialmente con altos niveles de colesterol.

Increased intestinal permeability precedes clinical onset of type 1 diabetes.

AIMS/HYPOTHESIS: Recent observations have shown subclinical intestinal abnormalities in human type 1 diabetes. Whether these are related to the pathogenetic process or secondary to the diabetes remains to be clarified. The aim of this study was to investigate this issue by examining intestinal permeability to sugars in subjects at different stages of type 1 diabetes: preclinical, new-onset and long-term established disease. METHODS: Eighty-one subjects with islet autoimmunity (18 preclinical, 28 new-onset and 35 long-term type 1 diabetes) and 40 healthy control subjects were investigated by a lactulose-mannitol test, consisting of oral administration of the two sugars and measurement of their urinary excretion. RESULTS: All groups of subjects with islet autoimmunity showed an increase in intestinal permeability (p < or = 0.009 vs controls) to the disaccharide lactulose, indicative of a damaged barrier, but a similar permeability to the monosaccharide mannitol (NS vs controls), indicative of an integral surface mucosa; consequently there was an increase in the lactulose:mannitol excretion ratio (p < or = 0.025 vs controls). CONCLUSIONS/INTERPRETATION: These findings indicate the presence of a subclinical enteropathy associated with type 1 diabetes that is already detectable before clinical onset of the disease, and suggest that the small intestine is an organ participating in the pathogenetic process of type 1 diabetes.