Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

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These data show that type 2 diabetic patients with nonalbuminuric renal impairment exhibit distinct clinical features, suggesting predominance of macroangiopathy as underlying renal pathology, and that this phenotype is associated with significant CVD burden.

OBJECTIVE -The presence of an enhanced cortisol secretion in patients with type 2 diabetes is debated. In type 2 diabetic subjects, cortisol secretion was found to be associated with the complications and metabolic control of diabetes. We evaluated cortisol secretion in 170 type 2 diabetic subjects and in 71 sex-, age-, and BMI-matched nondiabetic subjects. RESEARCH DESIGN AND METHODS-In all subjects, we evaluated ACTH at 8:00 A.M. in basal conditions and serum cortisol levels at 12:00 P.M. (F24) and at 9:00 A.M. after a 1-mg overnight dexamethasone suppression test and 24-h urinary free cortisol (UFC). In diabetic patients, we evaluated the presence of chronic complications (incipient nephropathy, asymptomatic neuropathy, background retinopathy, and silent macroangiopathy). Patients were subdivided according to the absence (group 1, n ϭ 53) or presence (group 2, n ϭ 117) of diabetes complications.RESULTS -In group 2, UFC (125.2 Ϯ 4.6 nmol/24 h) and F24 (120.6 Ϯ 4.1 nmol/l) were higher than in group 1 (109.2 Ϯ 6.8 nmol/24 h, P ϭ 0.057, and 99.7 Ϯ 6.1 nmol/l, P ϭ 0.005, respectively) and in nondiabetic patients (101.7 Ϯ 5.9 nmol/24 h, P ϭ 0.002, and 100.3 Ϯ 5.3 nmol/l, P ϭ 0.003, respectively). In diabetic patients, the number of complications was associated with F24 (R ϭ 0.345; P Ͻ 0.0001) and diabetes duration (R ϭ 0.39; P Ͻ 0.0001). Logistic regression analysis showed that the presence of diabetes complications was significantly associated with F24, sex, duration of diabetes, and glycated hemoglobin.CONCLUSIONS -In type 2 diabetic subjects, hypothalmic-pituitary-adrenal activity is enhanced in patients with diabetes complications and the degree of cortisol secretion is related to the presence and number of diabetes complications. Diabetes Care 30:83-88, 2007I n patients with type 2 diabetes, glucocorticoid secretion has been suggested to be a possible link between insulin resistance and the features of the metabolic syndrome (hypertension, obesity, coronary heart disease, hyperlipidemia, and type 2 diabetes) (1-4). In fact, while glucocorticoid excess (overt or subclinical) has been demonstrated to lead to diabetes or to worsen metabolic control (5-7), the relationship between cortisol levels, insulin resistance, and chronic complications in type 2 diabetic patients without hypercortisolism is still a matter of debate.In past years, the hypothalamicpituitary-adrenal (HPA) axis secretion in patients with type 2 diabetes has been extensively investigated (8 -14). In particular, some studies reported in these subjects an elevation of ACTH (10,12), basal (9 -11) and after dexamethasone test serum cortisol (13,14), and late-night salivary cortisol levels (15). In contrast, other previous studies (16 -17) did not show any alteration of pituitary-adrenal axis secretion. The presence of chronic complications of type 2 diabetes (i.e., macroangiopathy, retinopathy, and neuropathy) has been associated to with HPA axis activity (9,18 -23), and an association between the degree of severity of several clinical measures of d...

OBJECTIVETo examine the association of hemoglobin (Hb) A1c variability with microvascular complications in the large cohort of subjects with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study.RESEARCH DESIGN AND METHODSSerial (3–5) HbA1c values collected in a 2-year period before enrollment were available from 8,260 subjects from 9 centers (of 15,773 patients from 19 centers). HbA1c variability was measured as the intraindividual SD of 4.52 ± 0.76 values. Diabetic retinopathy (DR) was assessed by dilated funduscopy. Chronic kidney disease (CKD) was defined based on albuminuria, as measured by immunonephelometry or immunoturbidimetry, and estimated glomerular filtration rate (eGFR) was calculated from serum creatinine.RESULTSMedian and interquartile range of average HbA1c (HbA1c-MEAN) and HbA1c-SD were 7.57% (6.86–8.38) and 0.46% (0.29–0.74), respectively. The highest prevalence of microalbuminuria, macroalbuminuria, reduced eGFR, albuminuric CKD phenotypes, and advanced DR was observed when both HbA1c parameters were above the median and the lowest when both were below the median. Logistic regression analyses showed that HbA1c-SD adds to HbA1c-MEAN as an independent correlate of microalbuminuria and stages 1–2 CKD and is an independent predictor of macroalbuminuria, reduced eGFR, and stages 3–5 albuminuric CKD, whereas HbA1c-MEAN is not. The opposite was found for DR, whereas neither HbA1c-MEAN nor HbA1c-SD affected nonalbuminuric CKD.CONCLUSIONSIn patients with type 2 diabetes, HbA1c variability affects (albuminuric) CKD more than average HbA1c, whereas only the latter parameter affects DR, thus suggesting a variable effect of these measures on microvascular complications.