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.

A b b re v i a t i o n s : AUC, area under the curve; 1st PH, first-phase insulin release; Gluc, plasma glucose concentration during the OGTT; HOMA, homeostasis model assessment; IGT, impaired glucose tolerance; Ins, plasma insulin concentration during the OGTT; IR, insulin resistance index; ISI, insulin sensitivity index; ISI(comp), composite insulin sensitivity index; MCR, metabolic clearance rate; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; 2nd PH, second-phase insulin release; Secr, insulin release index; SI, sensitivity index; S y x , residual error of re g ression; WHR, waist-to-hip ratio.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Use of the Oral Glucose Tolerance Test to Assess Insulin Release and Insulin S e n s i t i v ity O R I G I N A L A R T I C L E O B J E C T I V E -The oral glucose tolerance test (OGTT) has often been used to evaluate a p p a rent insulin release and insulin resistance in various clinical settings. However, because insulin sensitivity and insulin release are interdependent, to what extent they can be pre d i c t e d f rom an OGTT is unclear.RESEARCH DESIGN AND METHODS -We studied insulin sensitivity using the euglycemic-hyperinsulinemic clamp and insulin release using the hyperglycemic clamp in 104 nondiabetic volunteers who had also undergone an OGTT. Demographic parameters (BMI, waist-to-hip ratio, age) and plasma glucose and insulin values from the OGTT were subjected to multiple linear re g ression to predict the metabolic clearance rate (MCR) of glucose, the insulin sensitivity index (ISI), and first-phase (1st PH) and second-phase (2nd PH) insulin release as measured with the respective clamps. R E S U LT S -The equations predicting MCR and ISI contained BMI, insulin (120 min), and glucose (90 min) and were highly correlated with the measured MCR (r = 0.80, P 0 . 0 0 0 0 5 ) and ISI (r = 0.79, P 0.00005). The equations predicting 1st PH and 2nd PH contained insulin (0 and 30 min) and glucose (30 min) and were also highly correlated with the measured 1st PH (r = 0.78, P 0.00005) and 2nd PH (r = 0.79, P 0.00005). The parameters predicted by our equations correlated better with the measured parameters than homeostasis model assessment for secretion and resistance, the 30-min insulin/ 30-min glucose ratio for secretion and insulin (120 min) for insulin resistance taken from the OGTT. C O N C L U S I O N S E p i d e m i o l o g y / H e a l t h S e r v i c e s / P s y c h o s o c i a l R e s e a r c h 296DIABETES CARE, VOLUME 23, NUMBER 3, MARCH 2000Insulin release and insulin sensitivity 0.5 kg/m 2 (19.7-45.8), and waist-to-hip ratio (WHR) 0.84 ± 0.10 (0.67-1.03); 65 had normal glucose tolerance (NGT), and the remainder had impaired glucose tolerance (IGT) according to the World Health O rganization criteria (1). Within 2 months, all subjects underwent a 75-g OGTT, a h y p e rglycemic clamp study in which the a rterialized venous plasma glucose concentration was increas...

Impaired glucose tolerance, the precursor of NIDDM, results primarily from reduced suppression of hepatic glucose output due to abnormal pancreatic islet-cell function. The late hyperinsulinemia may be the consequence of an inadequate early beta-cell response rather than of insulin resistance.

To define glycemic thresholds for activation of counterregulatory hormone secretion, initiation of symptoms (autonomic and neuroglycopenic), and onset of deterioration of cognitive function, we measured indexes of these responses during glycemic plateaus of 90, 78, 66, 54, and 42 mg/dl in 10 normal volunteers, with the use of the hyperinsulinemic glucose clamp technique. Activation of glucagon, epinephrine, norepinephrine, and growth hormone secretion began at arterialized venous plasma glucose concentrations of 68 +/- 1, 68 +/- 1, 65 +/- 1, and 67 +/- 2 (SE) mg/dl, respectively. Autonomic symptoms (anxiety, palpitations, sweating, irritability, and tremor) began at 58 +/- 2 mg/dl, which was significantly (P = 0.0001) lower. Neuroglycopenic symptoms (hunger, dizziness, tingling, blurred vision, difficulty thinking, and faintness) and deterioration in cognitive function tests began at 51 +/- 3 and 49 +/- 2 mg/dl, respectively, values that were both significantly (P = 0.018 and 0.004, respectively) lower than that for initiation of autonomic symptoms. We therefore conclude that there is a distinct hierarchy of responses to decrements in plasma glucose, such that the threshold for activation of counterregulatory hormone secretion occurs at higher plasma glucose levels than that for initiation of autonomic warning symptoms, which in turn occurs at higher plasma glucose levels than that for onset of neuroglycopenic symptoms and deterioration in cerebral function. Such a hierarchy would maximize the opportunity to avoid incapacitating hypoglycemia.