Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS Program

This study compared initiation of insulin and other antihyperglycaemic agents (AHAs) with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year, fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs. 16%), insulin (3% vs. 9%) or any non-insulin AHA (5% vs. 12%) (P < .001 for all); overall AHA initiation rates increased over time but were consistently lower with canagliflozin compared with placebo. During the study, the likelihood of initiating insulin was 2.7 times lower for participants treated with canagliflozin compared with placebo (hazard ratio, 0.37; 95% CI: 0.31, 0.43; P < .001). The time difference between 10% of patients in the canagliflozin and placebo groups being initiated on insulin from the beginning of the trial was about 2 years. Time to initiation of other AHAs, including metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sulphonylureas, was also delayed for canagliflozin versus placebo (P < .001 for each). Compared with placebo, canagliflozin delayed the need for initiation of other AHAs and delayed time to insulin therapy, an outcome that is important to many people with diabetes.     

USING MENDELIAN RANDOMISATION TO INFER CAUSALITY IN DEPRESSION AND ANXIETY RESEARCH

Depression and anxiety co‐occur with substance use and abuse at a high rate. Ascertaining whether substance use plays a causal role in depression and anxiety is difficult or impossible with conventional observational epidemiology. Mendelian randomisation uses genetic variants as a proxy for environmental exposures, such as substance use, which can address problems of reverse causation and residual confounding, providing stronger evidence about causality. Genetic variants can be used instead of directly measuring exposure levels, in order to gain an unbiased estimate of the effect of various exposures on depression and anxiety. The suitability of the genetic variant as a proxy can be ascertained by confirming that there is no relationship between variant and outcome in those who do not use the substance. At present, there are suitable instruments for tobacco use, so we use that as a case study. Proof‐of‐principle Mendelian randomisation studies using these variants have found evidence for a causal effect of smoking on body mass index. Two studies have investigated tobacco and depression using this method, but neither found strong evidence that smoking causes depression or anxiety; evidence is more consistent with a self‐medication hypothesis. Mendelian randomisation represents a technique that can aid understanding of exposures that may or may not be causally related to depression and anxiety. As more suitable instruments emerge (including the use of allelic risk scores rather than individual single nucleotide polymorphisms), the effect of other substances can be investigated. Linkage disequilibrium, pleiotropy, and population stratification, which can distort Mendelian randomisation studies, are also discussed.     

Role of adenosine A2A receptor in organ-specific vascular reactivity following hemorrhagic shock in rats

Background

Previous studies have demonstrated differences among organs in terms of shock-induced vascular reactivity and a role for adenosine A2A receptors (A2ARs) in protection against ischemia/reperfusion injury. However, the contributions of A2ARs to organ-specific vascular reactivity and the protection of vascular responsiveness following shock are currently unknown.

Methods

We investigated the role of A2ARs in different arteries, including the left femoral artery (LFA), thoracic aorta (TA), superior mesenteric artery (SMA), right renal artery (RRA), pulmonary artery (PA), and middle cerebral artery (MCA), in hemorrhagic-shock rats.

Results

The vascular reactivities of the LFA, SMA, RRA, and MCA increased slightly during early shock and then gradually decreased, whereas those of the PA and TA decreased from the start of shock. Different blood vessels lost vascular reactivity at different rates compared with controls; the LFA had the highest rate of loss (64.51%), followed by the SMA (44.69%), TA (36.06%), PA (37.83%), and RRA (32.33%), whereas the MCA had the lowest rate (18.45%). The rate of loss of vascular reactivity in the different vessels was negatively correlated with A2AR expression levels in normal and shock conditions. The highly selective A2AR agonist CGS 21680 significantly improved vascular reactivity, hemodynamic parameters, and animal survival, whereas the specific antagonist SCH58261 further decreased the shock-induced reduction in vascular reactivity and hemodynamic parameters.

Conclusions

A2ARs are involved in the regulation and protection of vascular reactivity following shock. A2AR activation may have a beneficial effect on hemorrhagic shock by improving vascular reactivity and hemodynamic parameters.     

Temporal trends in the relative prevalence of dysphagia etiologies from 1999-2009

AIM: To examine the relative prevalence and temporal variation of dysphagia etiologies in patients undergoing upper endoscopy (EGD) over the past decade.METHODS: EGDs with the indication of dysphagia at an urban, university medical center in 1999, 2004 and 2009 were retrospectively identified from the electronic medical record. The entire patient chart, including EGD, pathology, manometry, radiographic and clinician reports, was reviewed for demographic and clinical data and to determine the etiology of dysphagia. The number of EGDs in which an esophageal biopsy was performed was also noted. Gastroesophageal reflux disease (GERD) as a cause of dysphagia independent of peptic stricture was defined by symptoms with erosive esophagitis or symptom response to proton pump inhibition (PPI). Cases of eosinophilic esophagitis (EoE) were defined by an appropriate clinical history and histological criteria of ≥ 15 eosinophils per high powered field. PPI-responsive esophageal eosinophilia was not routinely reported prior to 2008. Statistical analysis was performed using one-way analysis of variance to analyze for trends between 1999, 2004 and 2009 and a post-hoc Tukey analysis was performed following a significant main effect.RESULTS: A total of 1371 cases (mean age 54 years, 43% male) met pre-specified inclusion criteria with 191, 504 and 675 cases in 1999, 2004 and 2009, respectively. Patients were older in 2004 compared to 2009 (mean ± SD, 54.0 ± 15.7 years vs 52.3 ± 16.8 years, P = 0.02) and there were more males in 1999 compared to 2004 (57.5% vs 40.8%, P = 0.005). Overall, GERD (27.6%) and EoE (7.7%) were the most common identifiable causes of dysphagia. An unspecified diagnosis accounted for 21% of overall cases. There were no significant differences in the relative prevalence of achalasia or other motility disorders, peptic stricture, Schatzki’s ring, esophageal cancer or unspecified diagnoses over the 10-year time period. There was, however, a decrease in the relative prevalence of GERD (39.3% vs 24.1%, P < 0.001) and increases in the relative prevalence of EoE (1.6% vs 11.2%, P < 0.001) and oropharyngeal disorders (1.6% vs 4.2%, P = 0.02) from 1999 to 2009. Post-hoc analyses determined that the increase in relative prevalence of EoE was significant between 1999 and 2009 as well as 2004 and 2009 (5.4% vs 11.6%, P < 0.001), but not between 1999 and 2004 (1.6% P 5.4%, P = 0.21). On the other hand, the decrease in relative prevalence of GERD was significant between 1999 and 2009 and 1999 and 2004 (39.3% vs 27.7%, P = 0.006), but not between 2004 and 2009 (27.7% vs 24.1%, P = 0.36). There were also significantly more EGDs in which a biopsy was obtained in 1999 compared to 2009 (36.7% vs 68.7%, P < 0.001) as well as between 2004 and 2009 (37.5% vs 68.7%, P < 0.001). While total EGD volume did increase over the 10-year time period, the percentage of EGDs for the indication of dysphagia remained stable making increasing upper endoscopy an unlikely reason for the observed increased prevalence of EoE.CONCLUSION: EoE has emerged as a dominant cause of dysphagia in adults. Whether this was due to a rise in disease incidence or increased recognition is unclear.     

Repeat percutaneous coronary revascularization: Indications and outcomes in a “Real World” cohort

Objectives : To investigate rates of and reasons for second and subsequent stent procedures in an unselected, “real‐world” population. Background : Repeat stenting is the primary difference reported in clinical trials of alternative revascularization strategies. The incidence, indication, and outcome for repeat stenting in contemporary practice outside the more selective populations of trials and registries has not been described. Method : All patients undergoing a first percutaneous coronary intervention (PCI) procedure with stenting from January 2001 to August 2009 (10,509) from a large UK tertiary referral and district general hospital were identified. Mortality and the incidence, timing, and indication for repeat revascularization in this population were investigated from patient records. Results : Of 10,509 patients undergoing a first PCI and stent implant 23.5% underwent repeat angiography of which 11.2% required repeat PCI and 2% coronary artery bypass grafting (median follow‐up of 3.8 years). A total of 1.3% went on to a third PCI. The commonest indication for repeat stenting was disease progression remote from the original stent (46%) and planned staged PCI (23%); 21% had a stent‐related indication. Functional assessment before repeat stenting was used in one‐third of stable patients. Mortality was 2.5% per annum. Conclusions : In contemporary practice, patients undergoing a first stenting procedure have a low subsequent mortality, and the substantial majority (86.4%) requires no further revascularization over a median 3.8 year follow‐up. For those who do require repeat stenting, this is most commonly at a site remote from the first stent. © 2012 Wiley Periodicals, Inc.