Treatment of hyperglycemia in ischemic stroke (THIS): a randomized pilot trial.

BACKGROUND AND PURPOSE: Hyperglycemia may worsen brain injury during acute cerebral infarction. We tested the feasibility and tolerability of aggressive hyperglycemia correction with intravenous insulin compared with usual care during acute cerebral infarction. METHODS: We conducted a randomized, multicenter, blinded pilot trial for patients with cerebral infarction within 12 hours after onset, a baseline glucose value >or=8.3 mmol/L (>or=150 mg/dL), and a National Institutes of Health Stroke Scale score of 3 to 22. Patients were randomized 2:1 to aggressive treatment with continuous intravenous insulin or subcutaneous insulin QID as needed (usual care). Target glucose levels were <7.2 mmol/L (<130 mg/dL) in the aggressive-treatment group and <11.1 mmol/L (<200 mg/dL) in the usual-care group. Glucose was monitored every 1 to 2 hours, and the protocol treatments continued for up to 72 hours. Final clinical outcomes were assessed at 3 months. RESULTS: We randomized 46 patients (31 to aggressive treatment and 15 to usual care). All patients in the aggressive-treatment group and 11 (73%) in the usual-care group had diabetes (P=0.008). Glucose levels were significantly lower in the aggressive-treatment group throughout protocol treatment (7.4 vs 10.5 mmol/L [133 vs 190 mg/dL], P<0.001). Hypoglycemia <3.3 mmol/L (<60 mg/dL) occurred only in the aggressive-treatment group (11 patients, 35%), 4 (13%) of whom had brief symptoms, including only 1 (3%) neurologic. Final clinical outcomes were nonsignificantly better in the aggressive-treatment group. CONCLUSIONS: The intravenous insulin protocol corrected hyperglycemia during acute cerebral infarction significantly better than usual care without major adverse events and should be investigated in a clinical efficacy trial.

Prenatal and postnatal pathways to obesity: different underlying mechanisms, different metabolic outcomes.

Obesity and type 2 diabetes are worldwide health issues. The present paper investigates prenatal and postnatal pathways to obesity, identifying different metabolic outcomes with different effects on insulin sensitivity and different underlying mechanisms involving key components of insulin receptor signaling pathways. Pregnant Wistar rats either were fed chow ad libitum or were undernourished throughout pregnancy, generating either control or intrauterine growth restricted (IUGR) offspring. Male offspring were fed either standard chow or a high-fat diet from weaning. At 260 d of age, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and other metabolic parameters were measured. As expected, high-fat feeding caused diet-induced obesity (DIO) and insulin resistance. Importantly, the insulin sensitivity of IUGR offspring was similar to that of control offspring, despite fasting insulin hypersecretion and increased adiposity, irrespective of postnatal nutrition. Real-time PCR and Western blot analyses of key markers of insulin sensitivity and metabolic regulation showed that IUGR offspring had increased hepatic levels of atypical protein kinase C zeta (PKC zeta) and increased expression of fatty acid synthase mRNA. In contrast, DIO led to decreased expression of fatty acid synthase mRNA and hepatic steatosis. The decrease in hepatic PKC zeta with DIO may explain, at least in part, the insulin resistance. Our data suggest that the mechanisms of obesity induced by prenatal events are fundamentally different from those of obesity induced by postnatal high-fat nutrition. The origin of insulin hypersecretion in IUGR offspring may be independent of the mechanistic events that trigger the insulin resistance commonly observed in DIO.

Description of anti-diabetic drug utilization pre- and post-formulary restriction of sitagliptin: findings from a national health plan.

OBJECTIVE: Multi-tiered formularies are commonly used for controlling costs of prescription medications. Focused on type 2 diabetes mellitus (T2DM), this database study assessed drug utilization before and after a formulary restriction (2nd-3rd tier), and compared demographic and clinical characteristics of patients affected vs not by the restriction. METHODS: Formulary restriction of sitagliptin (SITA) occurred July 1, 2012. The 'pre-period' was defined from January 1-June 30, 2012, the 'grace period' from July 1-September 30, 2012, and the 'post-period' from October 1, 2012-March 31, 2013. Patients from the OptumInsight database were included if diagnosed with T2DM, ≥18 years, had continuous enrollment, and had ≥2 prescriptions of SITA in the pre-period. Those who died or were aged ≥65 years in the post-period were excluded. Patients were grouped into SITA continuer and discontinuer cohorts based on SITA use in the post-period. Descriptive analyses assessed baseline patient characteristics and anti-hyperglycemic drug utilization in the pre- and post-periods. RESULTS: In total, 23,477 patients met inclusion criteria. In the post-period, 36.1% (n = 8480) of patients discontinued SITA. Among SITA discontinuers, 44.1% switched to a preferred DPP-4 inhibitor, 9.2% switched to glucagon-like peptides-1 (GLP-1) or insulin, and 2.4% switched to metformin or sulfonylurea. Of the SITA discontinuers, 21.6% dropped SITA without replacement and 8.4% discontinued all diabetes medications. In the post-period, a greater proportion of SITA discontinuers used GLP-1 (12.6% vs 5.8%) and insulin (29.1% vs 20.9%) than continuers, or had some change in anti-hyperglycemic treatment (67.5% vs 22.1%). Baseline demographic and clinical characteristics were similar between SITA continuers and discontinuers, indicating a lack of an association with SITA discontinuation. LIMITATIONS: This descriptive study used a non-controlled observational approach. CONCLUSIONS: Following formulary change, 1/3 of patients discontinued SITA and 30% of discontinuers received less intensive anti-hyperglycemic treatment in the post-restriction period. Meanwhile, 44% of discontinuers switched to a new preferred DPP-4 inhibitor.