Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Awakening responses and diurnal fluctuations of salivary cortisol, DHEA-S and alpha-amylase in healthy male subjects

OBJECTIVES: Because the cortisol awakening response (CAR) has received increasing attention as a useful index of adrenocortical activity, the primary objective of this study was to investigate the presence of an awakening response for various salivary biomarkers of adrenocortical activity, including dehydroepiandrosterone-sulphate (DHEA-S), which acts as a cortisol antagonist, and alpha-amylase, which is a predictor of circulating catecholamine activity. Salivary biological indicators are considered to be valuable markers of hypothalamus-pituitary-adrenal (HPA) axis diurnal activity. METHODS: In an attempt to overcome problems associated with non-adherence to the requested sampling protocol, only young, healthy males with a physiological CAR value (defined as a 50% increase in salivary cortisol within 30 mm after waking) were included in the study (67 out of 102 who initially enrolled met this criterion). RESULTS: Our results suggested that, as is already known for cortisol, DHEA-S and alpha-amylase have significant awakening responses. In addition, daily profile of salivary cortisol, alpha-amylase and DHEA-S fluctuations were analysed. Significant correlations were found between salivary cortisol, DHEA-S and alpha-amylase levels. The results showed that cortisol and DHEA-S concentrations were inversely correlated with alpha-amylase levels. DISCUSSION: This correlation confirmed the distinctiveness of the two regulatory systems: salivary cortisol and DHEA-S concentrations reflect the activity of the HPA axis, whereas alpha-amylase activity is more closely related to sympathetic activity. In addition, the present study emphasizes the potential value of saliva collection (which is both easy and stress-free) in monitoring changes of adrenal function, confirming that multiple sampling (especially within 1 h after awakening) is necessary to reliably characterise biomarker activity when investigating neuroendocrine changes under various conditions

Mortality after surgery in Europe: a 7 day cohort study

Background: Clinical outcomes after major surgery are poorly described at the national level. Evidence of heterogeneity between hospitals and health-care systems suggests potential to improve care for patients but this potential remains unconfirmed. The European Surgical Outcomes Study was an international study designed to assess outcomes after non-cardiac surgery in Europe.Methods: We did this 7 day cohort study between April 4 and April 11, 2011. We collected data describing consecutive patients aged 16 years and older undergoing inpatient non-cardiac surgery in 498 hospitals across 28 European nations. Patients were followed up for a maximum of 60 days. The primary endpoint was in-hospital mortality. Secondary outcome measures were duration of hospital stay and admission to critical care. We used χ² and Fisher’s exact tests to compare categorical variables and the t test or the Mann-Whitney U test to compare continuous variables. Significance was set at p&lt;0·05. We constructed multilevel logistic regression models to adjust for the differences in mortality rates between countries.Findings: We included 46 539 patients, of whom 1855 (4%) died before hospital discharge. 3599 (8%) patients were admitted to critical care after surgery with a median length of stay of 1·2 days (IQR 0·9–3·6). 1358 (73%) patients who died were not admitted to critical care at any stage after surgery. Crude mortality rates varied widely between countries (from 1·2% [95% CI 0·0–3·0] for Iceland to 21·5% [16·9–26·2] for Latvia). After adjustment for confounding variables, important differences remained between countries when compared with the UK, the country with the largest dataset (OR range from 0·44 [95% CI 0·19 1·05; p=0·06] for Finland to 6·92 [2·37–20·27; p=0·0004] for Poland).Interpretation: The mortality rate for patients undergoing inpatient non-cardiac surgery was higher than anticipated. Variations in mortality between countries suggest the need for national and international strategies to improve care for this group of patients.Funding: European Society of Intensive Care Medicine, European Society of Anaesthesiology