Sodium glucose co-transporter inhibitors for the management of diabetes mellitus: an opinion paper from the Endocrine and Metabolism Practice and Research Network of the American College of Clinical Pharmacy

Type 2 diabetes mellitus (T2DM) carries a high prevalence in the United States and worldwide. Therefore, the number of medication classes being developed and studied has grown. The individualized management of diabetes is accomplished by evaluating a medication’s efficacy, safety, and cost, along with the patient’s preference and tolerance to the medication. Sodium glucose co-transporter 2 inhibitors are a new therapeutic class indicated for the treatment of diabetes and have a unique mechanism of action, independent of beta-cell function. The first agent approved by the Food and Drug Administration (FDA) was canagliflozin in March 2013. Two agents – dapagliflozin and empagliflozin – were FDA-approved in January and July 2014, respectively. A clear understanding of the new class is needed to identify its appropriate use in clinical practice. Members of the American College of Clinical Pharmacy Endocrine and Metabolism Practice and Research Network reviewed available literature regarding this therapeutic class. The article addresses the advantages, disadvantages, emerging role, and patient education for sodium glucose co-transporter 2 inhibitors. Key limitations for this article include limited access to clinical trial data not published by the pharmaceutical company and limited data on products produced outside the United States.     

Percutaneous coronary intervention versus coronary bypass graft surgery for patients with medically refractory myocardial ischemia and risk factors for adverse outcomes with bypass: The VA AWESOME multicenter registry: comparison with the randomized clinical trial.

OBJECTIVES: This study was designed to compare the three-year survival after percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) in physician-directed and patient-choice registries with the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) randomized trial results. BACKGROUND: The AWESOME multicenter randomized trial and registry compared the long-term survival after PCI and CABG for the treatment of patients with medically refractory myocardial ischemia and at least one additional risk factor for adverse outcome with CABG. The randomized trial demonstrated comparable three-year survival. METHODS: Over a five-year period (1995 to 2000), 2,431 patients with medically refractory myocardial ischemia and at least one of five risk factors (prior heart surgery, myocardial infarction within seven days, left ventricular ejection fraction <0.35, age >70 years, intra-aortic balloon required to stabilize) were identified. By physician consensus, 1,650 patients formed a physician-directed registry assigned to CABG (692), PCI (651) or further medical therapy (307), and 781 were angiographically eligible for random allocation; 454 of these patients constitute the randomized trial, and the remaining 327 constitute a patient choice registry. Survival for CABG and PCI was compared using Kaplan-Meier curves and log-rank tests. RESULTS: The CABG and PCI 36-month survival rates for randomized patients were 79% and 80%, respectively. The CABG and PCI 36-month survival rates were both 76% for the physician-directed subgroup; comparable survival rates for the patient-choice subgroup were 80% and 89%, respectively. None of the global log-rank tests for survival demonstrated significant differences. CONCLUSIONS: Both registries support the randomized trial conclusion: PCI is an alternative to CABG for some medically refractory high-risk patients.     

Alcohol septal ablation versus surgical septal myectomy: comparison of effects on atrioventricular conduction tissue

OBJECTIVES: This study was designed to evaluate the effect of septal reduction therapies on the conduction system for patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: Heart block is a potential complication of both catheter-based and surgical procedures to relieve left ventricular outflow tract obstruction in HCM, but it is important to understand the different effects of these treatments on the conduction system. METHODS: The electrocardiograms and postoperative course of patients who underwent percutaneous alcohol septal ablation or surgical myectomy at Mayo Clinic between 1999 and 2003 were reviewed. RESULTS: For the 58 patients who underwent alcohol septal ablation, 21 (36%) developed right bundle branch block. Six patients (12%) developed complete heart block requiring permanent pacing, three of whom had left bundle branch block before the procedure. Among the 117 patients who underwent surgical septal myectomy, 47 (40%) developed left bundle branch block. Four patients (3%) developed heart block requiring permanent pacing after the procedure, three of whom had right bundle branch block preoperatively. CONCLUSIONS: Percutaneous septal ablation selectively produces transmural infarction of the basal mid-septum and adjacent right bundle tissue, whereas surgical myectomy affects the endocardial portion of the basal anterior septum and adjacent left bundle tissue. These observations may help identify patients at risk for complete heart block after septal reduction procedures for HCM.     

Clustering Individuals as a Way of Dealing with Multiple Predictors in Occupational Stress Research

Abstract

As the number and type of variables thought to affect the amount of stress experienced by an individual in the workplace increase, and as these effects are often found to be nonlinear and to interact with each other, the forms of statistical analyses employed present different costs and benefits. The use of cluster analysis as a preliminary means of categorizing individuals is described as the least artificial and empirically most accurate means of deriving groups that can lead to hypotheses and hypothesis testing using the more conventional means of analysis of variance. Such a methodology is described as it was applied to an investigation of the effects of demands, attitudes to demands, supports-constraints, and trait neuroticism upon job satisfaction and scores on the General Health Questionnaire for a sample of psychiatric nurses.     

VEGF-A165b Is an Endogenous Neuroprotective Splice Isoform of Vascular Endothelial Growth Factor A in?Vivo and in?Vitro

Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A₁₆₅a and VEGF-A₁₆₅b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A₁₆₅a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeability, vasodilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A₁₆₅b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A₁₆₅b was detected in hippocampal and cortical neurons. VEGF-A₁₆₅b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A₁₆₅b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3–kinase activation. Recombinant human VEGF-A₁₆₅b is a neuroprotective agent that effectively protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A₁₆₅b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A₁₆₅b expression suggests that non–isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons.Vascular endothelial growth factor (VEGF) A, originally described as a potent vascular permeability and growth factor for endothelial cells, is up-regulated in the brain during stroke and ischemic episodes¹ and has been linked with many neuronal diseases. The most widely studied isoform of VEGF-A, VEGF-A₁₆₅a, is up-regulated in hypoxia, induces increased vascular permeability in neuronal vasculature, and can stimulate angiogenesis after ischemic episodes. The resulting edema and hyperemia can be damaging, but VEGF-A₁₆₅a has also been found to have direct anticytotoxic effects on neurons, raising the possibility that it may act as an endogenous neuroprotective agent in neurodegenerative pathologies. VEGF-A exerts neurotrophic (survival) and neurotropic (neurogenesis and axon outgrowth) actions, which, although initially thought to be a function of increased angiogenesis and perfusion after neuronal injury,² are now appreciated as direct effects of VEGF-A on neurons.The vegfa gene encodes numerous products by differential splicing, but not all isoforms exert the same effects.³ Alternative splicing of exon 8 leads to two functionally distinct families: the proangiogenic VEGF-A_xxxa family and the counteracting VEGF-A_xxxb family.^4,5 VEGF-A₁₆₅b prevents the VEGF-A₁₆₅a effects on increased vascular permeability, blood vessel growth, and vasodilatation.^4–7The therapeutic potential of VEGF-A and anti–VEGF-A treatments are now widely recognized, and effective anti–VEGF-A treatments are available in ophthalmology⁸ and oncology.⁹ The finding that VEGF-A is implicated in neuronal disorders (eg, Alzheimer disease, Parkinson disease, Huntington disease, diabetic neuropathy, and amyotrophic lateral sclerosis¹⁰) provides a rationale for the use of VEGF-A as a therapeutic agent in neurodegenerative conditions. Although this rationale is supported by preclinical evidence,¹¹ the identification of the VEGF-A_xxxb family requires reexamination of VEGF-A isoforms in these contexts to allow for the clear evidence that VEGF-A splicing variants are not functionally equivalent³ and to determine whether augmentation of the proangiogenic isoform family (VEGF-A_xxxa) alone may have deleterious effects (eg, in occult malignancy and carcinoma in situ).The neuroprotective profile of the exon 8 alternatively spliced isoforms VEGF-A_xxxb remains unexplored. Interestingly, VEGF-A_xxxb isoforms do not exhibit the vascular effects seen with VEGF-A_xxxa isoforms, such as a sustained increase in capillary permeability or hypotension.^5,12 The lack of these potential adverse effects may make VEGF-A_xxxb isoforms more amenable as therapeutic agents in neurodegenerative diseases.We therefore tested the hypothesis that VEGF-A₁₆₅b is neuroprotective for central and peripheral neurons. We found that VEGF-A₁₆₅b is expressed in central neurons and is neuroprotective in vitro and in vivo. This finding indicates that VEGF-A₁₆₅b may prove to be a suitable therapeutic agent in neurodegenerative disorders, exhibiting fewer adverse effects than VEGF-A₁₆₅a.     

Should culture affect practice? A comparison of prognostic discussions in consultations with immigrant versus native-born cancer patients

Objective

Poor prognosis is difficult to impart, particularly across a cultural divide. This study compared prognostic communication with immigrants (with and without interpreters) versus native-born patients in audio-taped oncology consultations.

Methods

Ten oncologists, 78 patients (31 Australian-born, 47 immigrants) and 115 family members participated. The first two consultations after diagnosis of incurable disease were audiotaped, transcribed and coded. 142 consultations were included in the analysis.

Results

Fifty percent of doctor and 59% of patient prognostic speech units were not interpreted or interpreted non-equivalently when an interpreter was present. Immigrant status predicted few prognostic facts, and oncologist characteristics no prognostic facts, disclosed. Oncologists were significantly less likely to convey hope to immigrants (p = 0.0004), and more likely to use medical jargon (p = 0.009) than with Australian-born patients. Incurable disease status and a limited life span were commonly acknowledged, generally with no timeframe provided. Physical issues were discussed more commonly than emotional aspects.

Conclusions

While culture did not appear to influence doctor speech, interpreters filtered or blocked much prognostic communication.

Practice implications

Initiatives to empower all patients to attain needed information, optimise communication when an interpreter is present and train cancer health professionals in culturally appropriate care, are urgently required.     

A Post‐Hoc Comparison of the Utility of Sanger Sequencing and Exome Sequencing for the Diagnosis of Heterogeneous Diseases

The advent of massive parallel sequencing is rapidly changing the strategies employed for the genetic diagnosis and research of rare diseases that involve a large number of genes. So far it is not clear whether these approaches perform significantly better than conventional single gene testing as requested by clinicians. The current yield of this traditional diagnostic approach depends on a complex of factors that include gene‐specific phenotype traits, and the relative frequency of the involvement of specific genes. To gauge the impact of the paradigm shift that is occurring in molecular diagnostics, we assessed traditional Sanger‐based sequencing (in 2011) and exome sequencing followed by targeted bioinformatics analysis (in 2012) for five different conditions that are highly heterogeneous, and for which our center provides molecular diagnosis. We find that exome sequencing has a much higher diagnostic yield than Sanger sequencing for deafness, blindness, mitochondrial disease, and movement disorders. For microsatellite‐stable colorectal cancer, this was low under both strategies. Even if all genes that could have been ordered by physicians had been tested, the larger number of genes captured by the exome would still have led to a clearly superior diagnostic yield at a fraction of the cost.     

Adaptation and evaluation of a child-friendly patient reported outcome measure for use in Australia

BackgroundUse of Patient Reported Outcomes (PROs) to assess symptoms in children are not routinely used in clinical practice, yet children with complex conditions experience a significant number of symptoms.AimTo adapt and evaluate the Symptom Screening in Pediatrics Tool (SSPedi), a PRO measure developed in Canada for use with Australian children.MethodsSSPedi wording was adapted and item relevance assessed by an expert clinical group (N = 7) resulting in the Australian version (SSPedi-Aus). Cognitive interviewing with children with cancer (N = 10, 8–18 years) established understanding and difficulty with completing. A second group of child-parent dyads (N = 30) were recruited to evaluate psychometric properties (content validity, test-retest reliability, and parent-proxy) measured with Intraclass Correlation Coefficients (ICC) with 95% Confidence Intervals (CI). Acceptability and usefulness of SSPedi-Aus were also assessed.FindingsConstruct validity was confirmed across all items by 30 children. Child test-retest achieved excellent concordance (ICC 0.98, 95% CI 0.91 to 0.99). Symptoms causing the most distress as reported by children were different to those identified by parents. Although children and parents returned a similar mean total score (13.43 vs. 13.80), there was weak overall interrater reliability (ICC 0.37, 95% CI ?0.26 to 0.70, p = 0.12).ConclusionChildren are distressed by symptoms that may not be identified by parents or reported to clinicians, yet these symptoms are amendable to intervention. The SSPedi-Aus is useful to assess the level of distress caused by symptoms in children.