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OBJECTIVECompare the efficacy and safety of monotherapy with dulaglutide, a once-weekly GLP-1 receptor agonist, to metformin-treated patients with type 2 diabetes. The primary objective compared dulaglutide 1.5 mg and metformin on change from baseline glycosylated hemoglobin A 1c (HbA 1c ) at 26 weeks. RESEARCH DESIGN AND METHODSThis 52-week double-blind study randomized patients to subcutaneous dulaglutide 1.5 mg, dulaglutide 0.75 mg, or metformin. Patients (N = 807) had HbA 1c ‡6.5% ( ‡48 mmol/mol) and £9.5% (£80 mmol/mol) with diet and exercise alone or low-dose oral antihyperglycemic medication (OAM) monotherapy; OAMs were discontinued at beginning of lead-in period. RESULTSAt 26 weeks, changes from baseline HbA 1c (least squares [LS] mean 6 SE) were: dulaglutide 1.5 mg, 20.78 6 0.06% (28.5 6 0.70 mmol/mol); dulaglutide 0.75 mg, 20.71 6 0.06% (27.8 6 0.70 mmol/mol); and metformin, 20.56 6 0.06% (26.1 6 0.70 mmol/mol). Dulaglutide 1.5 and 0.75 mg were superior to metformin (LS mean difference): 20.22% (22.4 mmol/mol) and 20.15% (21.6 mmol/mol) (one-sided P < 0.025, both comparisons), respectively. Greater percentages reached HbA 1c targets <7.0% (<53 mmol/mol) and £6.5% (£48 mmol/mol) with dulaglutide 1.5 and 0.75 mg compared with metformin (P < 0.05, all comparisons). No severe hypoglycemia was reported. Compared with metformin, decrease in weight was similar with dulaglutide 1.5 mg and smaller with dulaglutide 0.75 mg. Over 52 weeks, nausea, diarrhea, and vomiting were the most common adverse events; incidences were similar between dulaglutide and metformin. CONCLUSIONSDulaglutide improves glycemic control and is well tolerated as monotherapy in patients with early stage type 2 diabetes.Muscle and liver insulin resistance and b-cell failure represent the core pathophysiologic defects in type 2 diabetes. In addition, there is increasing evidence that the gastrointestinal (GI) tract plays an essential role in the development of carbohydrate intolerance of type 2 diabetes (1). The incretin concept suggests that ingested glucose results in a considerably larger and more sustained insulin secretion compared with glucose administered intravenously due to the release of two intestinal-derived

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Patients' reports of hypoglycaemic symptoms are common in European outpatients with type 2 diabetes and are associated with significantly lower treatment satisfaction and with barriers to adherence. In addition, being at HbA1C goal is associated with treatment satisfaction and adherence.

Objective: To evaluate insulin-secretion kinetics and insulin sensitivity in cystic fibrosis (CF) patients with normal glucose tolerance (CF-NGT), impaired glucose tolerance (CF-IGT) or CF-related diabetes (CFRD), and the potential effects of moderate hyperglycemia on clinical and nutritional status. Design and methods: Cross-sectional study including 50 outpatients with CF. Patients underwent both oral (OGGT) and intravenous (IVGTT) glucose tolerance tests in order to assess insulin secretion and peripheral insulin sensitivity. Homeostasis assessment model and OGGT were used to investigate insulin sensitivity. Forced expiratory volume in the first second (FEV 1 ) and forced vital capacity (FVC) were measured to evaluate pulmonary function. Body mass index (BMI) was determined to assess nutritional status. Results: Insulin secretion was significantly decreased (and delayed at OGTT) in the CFRD group (n ¼ 9) versus the CF-IGT group (n ¼ 10) and the CF-IGT versus the CF-NGT group (n ¼ 31). Insulin sensitivity was significantly different in the CF-IGT and CFRD groups versus the CF-NGT group. FEV 1 , FVC and BMI presented a significant linear correlation with plasma glucose value at 120 min at OGTT and were significantly lower in both CF-IGT and CFRD versus the CF-NGT group, whereas no differences were found between the CF-IGT and CFRD groups. Conclusions: CF patients with IGT present diminished insulin secretion and increased peripheral insulin resistance, correlating with a worse clinical status, undernutrition and impaired pulmonary function. These findings open the question of whether early treatment of mild alterations of glucose metabolism with insulin secretagogues or short-action insulin may lead to improvement of clinical status in CF patients.European Journal of Endocrinology 152 241-247

Summary Aims To evaluate in a real‐world setting the effectiveness and tolerability of available GLP‐1 RA drugs in patients with type 2 diabetes after a prolonged follow‐up. Materials and methods Observational, retrospective, single‐centre study in patients starting GLP‐1 RA therapy. Change in HbA1c, fasting plasma glucose (FPG) and body mass index (BMI) along with gastrointestinal (GI) adverse events and withdrawal from GLP‐1 RA therapy were evaluated. Lack of efficacy of GLP‐1 RA therapy according to prespecified goals was also measured. Results A total of 735 patients were included, mean age 59.7 years, duration of diabetes 9.01 years, HbA1c 8.18% and BMI 38.56 kg/m 2 . Average follow‐up was 18.97 months (range 4.2‐39.09). All HbA1c (0.93%; P < 0.01), FPG (24 mg/dL; P < 0.01) and BMI (1.55 kg/m 2 ; P < 0.05) were significantly reduced from baseline and maintained throughout follow‐up, regardless of prescribed GLP‐1 RA. GI adverse events were present in 13.81% of patients at first follow‐up visit, 37.07% of patients discontinued GLP‐1 RA treatment, and 38.63% did not meet efficacy goals. Conclusions In a real‐world setting, GLP‐1 RA therapy is largely prescribed in severely obese patients with a long‐standing and poorly controlled diabetes. All prescribed GLP‐1 RAs significantly decreased HbA1c, FPG and BMI. GI adverse events affected a low proportion of patients. Inversely, a high proportion of patients did not meet efficacy goals and/or discontinued GLP‐1 RA treatment. Baseline characteristics of patients and lack of adherence may represent important issues underlying differences in effectiveness in real‐world studies versus randomized trials.

Objective: To investigate the relationship between chemical structure and physiological effect, the efficacy and the molecular mechanisms involved in the reduction of body weight by C18 fatty acids (stearic, elaidic, oleic, linoleic and 2-hydroxyoleic acids (2-OHOA)). Design: Ad libitum fed, lean Wistar Kyoto rats treated orally with up to 600 mg kg À1 of the fatty acids or vehicle every 12 h for 7 days. Besides, starved rats and rats pairfed to the 2-OHOA-treated group served as additional controls under restricted feeding conditions. Measurements: Body weight, food intake, weight of various fat depots, plasma leptin, hypothalamic neuropeptides, uncoupling proteins (UCP) in white (WAT) and brown adipose tissue (BAT) and phosphorylation level of cyclic AMP (cAMP) response element-binding protein (CREB) in WAT. Results: Only treatment with oleic acid and 2-OHOA induced body weight loss (3.3 and 11.4%, respectively) through reduction of adipose fat mass. Food intake in these rats was lower, although hypothalamic neuropeptide and plasma leptin levels indicated a rise in orexigenic status. Rats pairfed to the 2-hydroxyoleic group only lost 6.3% body weight. UCP1 expression and phosphorylation of CREB was drastically increased in WAT, but not BAT of 2-OHOA-treated rats, whereas no UCP1 expression could be detected in WAT of rats treated with oleic acid. Conclusion: Both cis-configured monounsaturated C18 fatty acids (oleic acid and 2-OHOA) reduce body weight, but the introduction of a hydroxyl group in position 2 drastically increases loss of adipose tissue mass. The novel molecular mechanism unique to 2-hydroxyoleic, but not oleic acid, implies induction of UCP1 expression in WAT by the cAMP/PKA pathwaydependent transcription factor CREB, most probably as part of a transdifferentiation process accompanied by enhanced energy expenditure.

Ambulatory blood pressure monitoring (ABPM) allows determining of the nocturnal blood pressure fall (NBPF). An NBPF below 10% (nondipper pattern) has been related to increased cardiovascular risk, and it is a common finding in type 2 diabetic hypertensive patients. The authors evaluated the impact on 24-hour blood pressure, NBPF, and albuminuria of olmesartan 40 mg, administered in a morning-vs a nocturnal-based dosing scheme, in type 2 diabetic patients with newly diagnosed hypertension. Using a crossover design, 40 patients (42.1% men) received olmesartan 40 mg once daily at wake up or bedtime for 8 weeks. Patients underwent 24-hour ABPM at baseline and at weeks 8 and 16, and albumin to creatinine ratio was measured at baseline and 8 weeks. Night systolic blood pressure (BP) (P=.007) and mean BP (P=.012) were significantly reduced following the bedtime dose, compared with morning dosing. Night BP fall (%) was significantly reduced by bedtime dosing, compared with morning dosing (P=.0001). No differences were seen for urinary albumin excretion between both arms at week 8. Without affecting 24-hour BP control, night dosing of olmesartan increases nocturnal BP fall significantly more than conventional morning dosing, increasing the number of dipper diabetic hypertensive patients. J Clin Hypertens (Greenwich). 2009;11:426-431. B lood pressure (BP) and heart rate in humans are characterized by cyclic changes during 24 hours that parallel the rest ⁄ activity state. 1Along with this observation, it has been demonstrated that the extent of the nocturnal BP decline and the subsequent morning BP rate of rise along with the awakening and starting of diurnal activity are both independent risk factors for stroke and other cardiovascular (CV) events.