2 Minute Medicine Rewind September 4, 2017

Liraglutide and Renal Outcomes in Type 2 Diabetes

Diabetic kidney disease is the leading cause of dialysis-dependent chronic kidney disease (CKD) in most countries. Previous studies have shown that liraglutide, a human glucagon-like peptide 1 analogue, has beneficial effects on diabetic nephropathy and its progression; long-term effects of liraglutide, however, are unknown. In this randomized control trial, 9340 patients with type 2 diabetes mellitus and a high cardiovascular risk were randomized to receive liraglutide or matching placebo to study the effect on renal outcomes. The authors reported on a composite renal outcome, comprised of new-onset persistent macroalbuminuria, persistent doubling of serum creatinine level, the need for continuous renal-replacement disease, or death due to renal disease. Researchers found that the prespecified composite renal outcome occurred in fewer patients from the liraglutide group compared to the placebo group (HR 0.78, 95% CI 0.67 to 0.92, p = 0.003). Differences in the occurrence of new-onset persistent macroalbuminuria were most striking between liraglutide and placebo groups (HR 0.74, 95% CI 0.60 to 0.91, p= 0.004), while there was a non-significant lowering in the doubling of serum creatinine level and end-stage renal disease for patients in the liraglutide group. These findings indicate that liraglutide lowers the risk of adverse renal outcomes in patients with type 2 diabetes mellitus, primarily by reducing the likelihood of developing of macroalbuminuria. The trial design, however, was limited in that it followed patients for a maximum of five years and did not allow for analysis of other direct or indirect drug effects, leaving room for further study.

Trends in Adult Cancer–Related Emergency Department Utilization

Despite a currently estimated 15.5 million people living with cancer or a history of cancer in the U.S., there is a lack of information about emergency department (ED) utilization by adult cancer patients. In this retrospective cohort study, investigators examined data from the National Emergency Department Sample database (2006-2012), the largest nationally representative ED database, to characterize ED visits made by adults with a cancer diagnosis and examine factors related to inpatient admission within this population. Researchers found that of approximately 696 million ED visits, 4.2% were made by patients with a cancer diagnosis. The most common cancers associated with an ED visit were breast, prostate, and lung cancer. Patients with a cancer-related visit were more likely to be admitted as an inpatient than those visiting for non-cancer related reasons (59.7% vs. 16.3%, p<0.001). While the reasons for cancer-related ED visits differed depending on cancer type, the most common primary reasons included pneumonia, non-specific chest pain and urinary tract infection. The results of this study provide an important starting point in understanding ED utilization by patients with cancer. Further research is required in better describing cancer-related ED visits as part of identifying individuals at risk and improving quality of cancer care in the ED setting.

Association of Neighborhood Demographics With Out-of-Hospital Cardiac Arrest Treatment and Outcomes

Out-of-hospital cardiac arrest (OHCA) survival rates in the US range between 8.3% and 10%. The incidence of OHCA has been found to be consistently higher in black individuals compared to white individuals. While notable disparities exist in cardiopulmonary resuscitation (CPR) training and the use of bystander CPR, there is limited data on whether the racial composition of residents in a neighbourhood is associated with other bystander treatments, emergency medical services (EMS) processes of care and OHCA outcomes. In this retrospective cohort study, investigators used data from the Resuscitation Outcomes Consortium (ROC) Cardiac Arrest Epidemiologic Registry to examine the association between bystander treatments (CPR, automatic external defibrillation) and timing of EMS personnel on OHCA outcomes according to the racial composition of the neighborhood where the OHCA event occurred. Based on an analysis of 22,816 patients with OHCA from 2543 census tracts, researchers found that patients who experienced OHCA in neighborhoods with a higher percentage of black residents were less likely to receive bystander CPR and lay AED use (p<0.001 across quartiles for percentage of black residents). OHCAs occurring in neighborhoods with >75% black residents had the shortest time from call to dispatch to emergency medical service (EMS) arrival (p< 0.001), as well as the shortest transport times to the hospital (p<0.001). Results also showed, however, that the average time of EMS arrival-to-first defibrillation was significantly longer in predominantly black neighborhoods, and the average time for resuscitation was shorter (p<0.001). In comparison to OHCAs occurring in neighborhoods with less than 25% black residents, OHCAs occurring in neighborhoods with more than 75% black residents had a lower rate of survival to hospital discharge (OR 0.65, 95% CI 0.51 to 0.82). This study therefore shows that OHCAs in predominantly black neighbourhoods are associated with low rates of bystander CPR and automatic external defibrillation, and lower survival rates when compared to predominantly white neighbourhoods. The results of this study support the need for education surrounding the management of OHCA in predominantly black neighborhoods.

Addiction Potential of Cigarettes With Reduced Nicotine Content in Populations With Psychiatric Disorders and Other Vulnerabilities to Tobacco Addiction

It is currently unclear whether reducing the maximum nicotine content of cigarettes would be beneficial in reducing the addiction potential of cigarettes. While related studies have been previously conducted in psychiatrically and socioeconomically stable individuals, little data on this possible intervention exists for individuals with psychiatric conditions, who are particularly vulnerable to tobacco addiction and its adverse health effects. In this multisite, double-blind, within-participant assessment, 169 adult smokers with psychiatric disorders and other vulnerabilities to tobacco addiction were exposed to cigarettes with varying nicotine doses to study the effect of reducing nicotine on addiction potential. Researchers found that participants consistently chose to smoke cigarettes with the highest doses of nicotine compared with lowest nicotine content (30% vs. 70%, p<0.001). This preference, however, could be reversed by increasing the cost necessary to obtain the higher dose (p<0.001). Participants estimated that they would have less demand for cigarettes with lower nicotine doses, while results showed that each of the nicotine doses significantly reduced nicotine withdrawal symptoms and craving (p <0.001 for each dose), although higher doses had a more durable effect (p <0.05). This study therefore shows that reducing the maximum nicotine content of cigarettes may decrease the addiction potential of cigarettes in vulnerable populations, especially more effort is required in purchasing cigarettes with higher doses.

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

There is a need for better treatment of hemophilia, as current treatment requires frequent intravenous transfusion of clotting factors that can become ineffective if patients develop inhibitor alloantibodies to factor-replacement products. Evidence has suggested that reducing antithrombin levels can alleviate the hemophilia phenotype by improving thrombin generation. Fitusiran (ALN-AT3SC) is an investigational RNA interference therapy that targets the antithrombin messenger RNA and suppresses hepatic production of antithrombin. In this multicenter, open-label, dose-escalation study, 4 healthy volunteers and 25 participants with hemophilia A or B without inhibitory alloantibodies were given fitusiran to study the effect on plasma antithrombin levels and thrombin generation. Healthy volunteers were given a single subcutaneous dose or placebo. Participants with hemophilia received 3 injections of increasing dose, administered either once weekly or once monthly. Researchers found that in participants who received 3 weekly subcutaneous injections, a dose-dependent lowering of antithrombin levels from baseline was observed, with a mean maximum lowering of 61±8% at the highest dose of 0.075 mg/kg. Participants that received 3 monthly subcutaneous injections also exhibited a dose-dependent mean maximum lowering of antithrombin ranging from 70±9% at 0.225 mg/kg to 89±1% at 1.8 mg/kg. Lowering of antithrombin level was associated with a rise in thrombin level in patients with hemophilia A and B. No thromboembolic events or antidrug antibodies were observed during the study. This study therefore shows that fitusiran may be used in increasing thrombin levels in patients with hemophilia A and B.

Image: PD

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