Research Spotlight

Packer, M. (2018). “Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis.” Diabetes Obes Metab 20(6): 1361-1366.

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Sodium-glucose co-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 probably 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 favourably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin.

Packer, M. (2018). “The Alchemist’s Nightmare: Might Mesenchymal Stem Cells That Are Recruited to Repair the Injured Heart Be Transformed Into Fibroblasts Rather Than Cardiomyocytes?” Circulation 137(19): 2068-2073.

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The injection of mesenchymal stem cells into the injured myocardium to induce cardiac regeneration has yielded disappointing results, conceivably because cells with cardioreparative potential must be supplied for long periods of time to produce a salutary effect. Accordingly, investigators have devised ways of directing such cells to the heart on an ongoing basis: by enhancing the action of endogenous peptides that function as cardiac homing signals (eg, stromal cell-derived factor-1). Stromal cell-derived factor-1 is released during acute cardiac injury and heart failure, but it has a short half-life because of degradation by dipeptidyl peptidase-4. Inhibition of dipeptidyl peptidase-4 potentiates the actions of stromal cell-derived factor-1 and, theoretically, could enhance cardiac recovery. However, in large-scale trials in patients with type 2 diabetes mellitus, dipeptidyl peptidase-4 inhibitors have not reduced the risk of atherosclerotic ischemic events, and they have unexpectedly increased the risk of heart failure, most probably heart failure with a preserved ejection fraction. Such an outcome might be explained if the channeling of mesenchymal stem cells to the heart by the actions of stromal cell-derived factor-1 (especially from nearby adipose tissue) were followed by the transformation of these cells into fibroblasts rather than cardiomyocytes. This concern has been supported by experimental studies; the resulting fibrosis would be expected to exacerbate the pathophysiological derangements that lead to heart failure with a preserved ejection fraction. Given the widespread use of dipeptidyl peptidase-4 inhibitors, the possibility that these drugs potentiate the cardiac homing of mesenchymal stem cells that cause myocardial fibrosis (rather than repair) warrants further study.

Packer, M. (2018). “Contrasting effects on the risk of macrovascular and microvascular events of antihyperglycemic drugs that enhance sodium excretion and lower blood pressure.” Diabet Med 35(6): 707-713.

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Three classes of anti-hyperglycaemic medications are distinguished by their urinary sodium excretion-enhancing and blood pressure-lowering actions: long-acting glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors. Yet, these drugs exert different effects on macrovascular risk. Glucagon-like peptide-1 receptor agonists reduce atherosclerotic thromboembolic events, but have little effect on heart failure; sodium-glucose co-transporter-2 inhibitors decrease the occurrence of heart failure, but have minimal effect on myocardial infarction and stroke; and dipeptidyl peptidase-4 inhibitors do not ameliorate either atherosclerotic thromboembolic events or heart failure. Similarly, the three classes of drugs differ in their early effects on renal function. Dipeptidyl peptidase-4 inhibitors produce a small decrease in renal function that persists for the duration of treatment, and they do not prevent serious adverse renal events. For glucagon-like peptide-1 receptor agonists, a small early decrease in renal function persists for 2 years and is superseded by a small improvement in renal function, with no effect on renal outcomes. In contrast, an initial decrease in glomerular filtration with sodium-glucose co-transporter-2 inhibitors persists for only 1 year and is superseded by a durable improvement in renal function and a reduced risk of serious adverse renal events. These differences may be related to different actions on the proximal tubular reabsorption of sodium, and thereby, on glomerular hyperfiltration. Anti-hyperglycaemic drugs that have natriuretic actions differ markedly in their ability to modulate macrovascular and microvascular risk. These contrasting profiles cannot be predicted by their effects on blood glucose or blood pressure.

Ogola, G. O., M. L. Crandall and S. Shafi (2018). “High Volume Hospitals are Associated with Lower Mortality among High-risk Emergency General Surgery Patients.” J Trauma Acute Care Surg. May 21. [Epub ahead of print].

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INTRODUCTION: We have previously demonstrated that Emergency General Surgery (EGS) patients treated at high-volume hospitals experience lower mortality rates than those treated at low-volume hospitals. However, EGS comprises a wide spectrum of diseases. Our goal was to determine which EGS diseases had better outcomes at high volume hospitals. METHODS: We undertook a retrospective analysis of National Inpatient Sample database for 2013 (a nationwide representative sample). Patients with EGS diseases were identified using American Association for the Surgery of Trauma definitions. A hierarchical logistic regression model was used to measure risk-adjusted probability of death, adjusting for age, sex, race, ethnicity, insurance type, and comorbidities. Patients were then grouped into 16 risk groups based upon their predicted probability of death. We then compared observed mortality rates at high vs. low-volume hospitals within each risk-group. RESULTS: Nationwide, 3,006,615 patients with EGS diseases were treated at 4,083 hospitals in 2013. Patients with predicted risk of death of 4% or higher (275,615 patients, 9.2%) had lower observed mortality rates at high volume hospitals compared to low volume hospitals (7.7% versus 10.2%, p<0.001). We estimated that 1002 deaths were potentially preventable if high-risk patients that were treated in low-volume hospitals were instead transferred to high-volume hospitals. CONCLUSION: EGS patients with predicted risk of death of 4% or higher have experience lower mortality rates at high volume hospitals compared to low volume hospitals. A regional system of EGS care that enables rapid transfer of high risk patients to high volume hospitals may prevent several deaths. LEVEL OF EVIDENCE: Level III STUDY TYPE: prognostic and epidemiological.

Naziruddin, B., M. A. Kanak, C. A. Chang, M. Takita, M. C. Lawrence, A. R. Dennison, N. Onaca and M. F. Levy (2018). “Improved Outcomes of Islet Autotransplantation after Total Pancreatectomy by Combined Blockade of IL-1beta and TNFalpha.” Am J Transplant. Jun 4. [Epub ahead of print].

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The efficacy of islet transplantation is compromised by a significant loss of islet mass posttransplant due to an innate inflammatory reaction. Here we report the use of a combination of etanercept and anakinra to block inflammatory islet damage in 100 patients undergoing total pancreatectomy with islet autotransplantation. The patients were divided into three groups: no treatment (CTL), etanercept alone (ETA), or a combination of etanercept and anakinra (ANA+ETA). Peritransplant serum samples were analyzed for protein markers of islet damage and for inflammatory cytokines. Graft function was assessed by fasting blood glucose, basal C-peptide, SUITO index, and hemoglobin A1c. Administration of both antiinflammatory drugs was well tolerated without any major adverse events. Reductions in interleukin-6, interleukin-8, and monocyte chemoattractant protein 1 were observed in patients receiving ANA+ETA compared with the CTL group, while also showing a modest improvement in islet function as assessed by basal C-peptide, glucose, hemoglobin A1c, and SUITO index but without differences in insulin dose. Together these results suggest that double cytokine blockade (ANA+ETA) reduces peritransplant islet damage due to nonspecific inflammation and may represent a promising strategy to improve islet engraftment, leading to better transplant outcomes.