Research Spotlight

Packer, M. (2018). “Is metformin beneficial for heart failure in patients with type 2 diabetes?” Diabetes Res Clin Pract 136: 168-170.

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Heart failure is a common and serious cardiovascular complication of type 2 diabetes. Many antihyperglycemic drugs can increase the risk of heart failure. However, it is commonly believed that metformin – the first-line treatment for type 2 diabetes – reduces the risk of and improves the clinical course of heart failure. It is estimated that 20-25% of patients taking metformin have heart failure. Metformin has been shown to have favorable effects on the course of heart failure in experimental models. Furthermore, when compared with other antihyperglycemic medications in nonrandomized epidemiological studies, metformin users had a lower risk of new-onset heart failure and a lower risk of death if they already had heart failure. However, these reports are difficult to interpret, given the potential for prescribing bias and the likelihood that comparator agents caused cardiovascular harm. Meta-analyses of randomized controlled clinical trials have not demonstrated benefits of metformin on the risk of or the clinical course of heart failure. Given metformin’s importance in the management of type 2 diabetes and its widespread use in heart failure, the current confidence in its benefits in high-risk patients needs to be re-evaluated.

Packer, M. (2018). “Have dipeptidyl peptidase-4 inhibitors ameliorated the vascular complications of type 2 diabetes in large-scale trials? The potential confounding effect of stem-cell chemokines.” Cardiovasc Diabetol 17(1): 9.

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Drugs that inhibit dipeptidyl peptidase-4 (DPP-4) are conventionally regarded as incretin-based agents that signal through the glucagon-like peptide-1 (GLP-1) receptor. However, inhibition of DPP-4 also potentiates the stem cell chemokine, stromal cell-derived factor-1 (SDF-1), which can promote inflammation, proliferative responses and neovascularization. In large-scale cardiovascular outcome trials, enhanced GLP-1 signaling has reduced the risk of atherosclerotic ischemic events, potentially because GLP-1 retards the growth and increases the stability of atherosclerotic plaques. However, DPP-4 inhibitors have not reduced the risk of major adverse cardiovascular events, possibly because potentiation of SDF-1 enhances plaque growth and instability, activates deleterious neurohormonal mechanisms, and promotes cardiac inflammation and fibrosis. Similarly, trials with GLP-1 agonists and sodium-glucose cotransporter 2 inhibitors have reported favorable effects on renal function, even after only 3-4 years of treatment. In contrast, no benefits on the rate of decline in glomerular filtration rate have been seen in trials of DPP-4 inhibitors, perhaps because the renal actions of DPP-4 inhibitors are primarily mediated by potentiation of SDF-1, not GLP-1. Experimentally, SDF-1 can promote podocyte injury and glomerulosclerosis. Furthermore, the natriuretic action of SDF-1 occurs primarily in the distal tubules, where it cannot utilize tubuloglomerular feedback to modulate the deleterious effects of glomerular hyperfiltration. Potentiation of SDF-1 in experimental models may also exacerbate both retinopathy and neuropathy. Therefore, although DPP-4 inhibitors have attractive clinical features, the benefits that might be expected from GLP-1 signaling may be undermined by their actions to enhance SDF-1.

Packer, M. (2018). “Do Sodium-Glucose Cotransporter-2 Inhibitors Prevent Heart Failure With a Preserved Ejection Fraction by Counterbalancing the Effects of Leptin? A Novel Hypothesis.” Diabetes Obes Metab. Jan 23. [Epub ahead of print].

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Sodium-glucose transporter-2 (SGLT2) inhibitors reduce the risk of serious heart failure events in patients with type 2 diabetes, but little is known about mechanisms that might mediate this benefit. The most common heart failure phenotype in type 2 diabetes is obesity-related heart failure with a preserved ejection fraction (HFpEF). It has been hypothesized that the synthesis of leptin in this disorder leads to sodium retention and plasma volume expansion as well as to cardiac and renal inflammation and fibrosis. Interestingly, leptin-mediated neurohormonal activation appears to enhance the expression of SGLT2 in the renal tubules, and SGLT2 inhibitors exert natriuretic actions at multiple renal tubular sites in a manner that can oppose the sodium retention produced by leptin. In addition, SGLT2 inhibitors reduce the accumulation and inflammation of perivisceral adipose tissue, thus minimizing the secretion of leptin and its paracrine actions on the heart and kidneys to promote fibrosis. Such fibrosis likely contributes to the impairment of cardiac distensibility and glomerular function that characterizes obesity-related HFpEF. Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favorably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin.

Ogola, G. O., M. L. Crandall and S. Shafi (2018). “Variations in outcomes of emergency general surgery patients across hospitals: A call to establish emergency general surgery quality improvement program.” J Trauma Acute Care Surg 84(2): 280-286.

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BACKGROUND: National Surgical Quality Improvement Program and Trauma Quality Improvement Program have shown variations in risk-adjusted outcomes across hospitals. Our study hypothesis was that there would be similar variation in risk-adjusted outcomes of emergency general surgery (EGS) patients. METHODS: We undertook a retrospective analysis of the National Inpatient Sample database for 2010. Patients with EGS diseases were identified using American Association for the Surgery of Trauma definitions. A hierarchical logistic regression model was used to model in-hospital mortality, accounting for patient characteristics, including age, sex, race, ethnicity, insurance type, and comorbidities. Predicted-to-expected mortality ratios with 90% confidence intervals were used to identify hospitals as low mortality (ratio significantly lower than 1), high mortality (ratio significantly higher than 1), or average mortality (ratio overlapping 1). RESULTS: Nationwide, 2,640,725 patients with EGS diseases were treated at 943 hospitals in 2010. About one-sixth of the hospitals (139, 15%) were low mortality, a quarter were high mortality (221, 23%), and the rest were average mortality. Mortality ratio at low mortality hospitals was almost four times lower than that of high mortality hospitals (0.57 vs. 2.03, p < 0.0001). If high and average mortality hospitals performed at the same level as low mortality hospitals, we estimate 16,812 (55%) more deaths than expected. CONCLUSION: There are significant variations in risk-adjusted outcomes of EGS patients across hospitals, with several thousand higher than expected number of deaths nationwide. Based on the success of National Surgical Quality Improvement Program and Trauma Quality Improvement Program, we recommend establishing EGS quality improvement program for risk-adjusted benchmarking of hospitals for EGS patients. LEVEL OF EVIDENCE: Care management, level III.

Moffatt-Bruce, S., S. Clark, M. DiMaio and J. Fann (2018). “Leadership Oversight for Patient Safety Programs: An Essential Element.” Ann Thorac Surg 105(2): 351-356.

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Leadership in the realm of quality oversight and endorsing a culture of safety is paramount. The stakeholders, ranging from the surgeons to the Chair of the Board have to be engaged and really understand the importance of leadership support. Clarity of leadership support, innovation in process improvement as well as performance management and accountability are the foundational components of a strong culture of safety. Alignment of all stakeholders and continuous improvement that is supported by leadership will ensure the best outcomes for surgical patients.