Research Spotlight

Packer, M. (2020). “Interplay of AMPK/SIRT1 Activation and Sodium Influx Inhibition Mediates the Renal Benefits of SGLT2 Inhibitors in Type 2 Diabetes: a Novel Conceptual Framework.” Diabetes Obes Metab. Jan 9. [Epub ahead of print].

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Long-term treatment with SGLT2 inhibitors slows the deterioration of renal function in patients with diabetes. This benefit cannot be ascribed to an action on blood glucose, ketone utilization, uric acid or systolic blood pressure. SGLT2 inhibitors produce a striking amelioration of glomerular hyperfiltration. Although initially ascribed to an action of these drugs to inhibit proximal tubular glucose reabsorption, SGLT2 inhibitors exert renoprotective effects even in patients with meaningfully impaired levels of glomerular function that are sufficient to abolish their glycosuric actions. Instead, the reduction in intraglomerular pressures may be related to an action of SGLT2 inhibitors to interfere with the activity of sodium-hydrogen exchanger isoform 3 (NHE-3), thereby inhibiting proximal tubular sodium reabsorption and promoting tubuloglomerular feedback. Yet, experimentally, such an effect may not be sufficient to prevent renal injury. It is therefore noteworthy that the diabetic kidney exhibits an important defect in AMPK and SIRT1 signaling, which may contribute to the development of nephropathy. These enzymes exert direct effects to mute oxidative stress and inflammation, and they also stimulate autophagy, a lysosomally-mediated degradative pathway that maintains cellular homeostasis in the kidney. SGLT2 inhibitors induce both AMPK and SIRT1, and they have been shown to stimulate autophagy, thereby ameliorating cellular stress and glomerular and tubular injury. Enhanced AMPK/SIRT1 signaling may also contribute to the action of SGLT2 inhibitors to interfere with sodium transport mechanisms. The dual effects of SGLT2 inhibitors on AMPK/SIRT1 activation and renal tubular sodium transport may explain their protective effects on the kidney in type 2 diabetes.

Packer, M. (2020). “Concerns about the use of metformin as a first-line agent to slow the progression of chronic kidney disease in diabetes.” Diabetes Res Clin Pract Jan 16. [Epub ahead of print].

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A major imperative in the treatment of diabetes is to slow the onset and prevent the progression of diabetes-related renal injury. Currently, metformin is used routinely as first-line therapy to lower blood glucose, and many physicians assume that the drug′s glycemic effects have important renoprotective benefits . . . [But] there is little evidence to suggest that glycemic control with metformin has favorable effects on the development of serious chronic kidney disease in patients with diabetes . . . Further work is needed to explore the potential interactions between metformin and SGLT2 inhibitors in clinical trials. If these analyses confirm that metformin attenuates the benefits of dapagliflozin and canagliflozin on the kidneys, then physicians should reconsider the current practice of using metformin as first-line treatment, given the fact that the effectiveness of metformin in preventing chronic kidney disease in patients with type 2 diabetes has not been established. (Excerpt from text, p. 1-2; no abstract available.)

Packer, M. (2020). “Atrial Fibrillation and Heart Failure With Preserved Ejection Fraction in Patients With Nonalcoholic Fatty Liver Disease.” Am J Med 133(2): 170-177.

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The most common causes of chronic liver disease in the developed world-nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)-are the hepatic manifestations of an insulin-resistant state that is linked to visceral adiposity and systemic inflammation. NAFLD and NASH lead to an expansion of epicardial adipose tissue and the release of proinflammatory adipocytokines that cause microcirculatory dysfunction and fibrosis of the adjoining myocardium, resulting in atrial fibrillation as well as heart failure with a preserved ejection fraction (HFpEF). Inflammatory changes in the left atrium lead to electroanatomical remodeling; thus, NAFLD and NASH markedly increase the risk of atrial fibrillation. Simultaneously, patients with NAFLD or NASH commonly show diastolic dysfunction or latent HFpEF. Interventions include 1) weight loss by caloric restriction, bariatric surgery, or intensive exercise, and 2) drugs that ameliorate fat-mediated inflammation in both the liver and heart (eg, statins, metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and pioglitazone). Patients with NAFLD or NASH commonly have an inflammation-related atrial and ventricular myopathy, which may contribute to symptoms and long-term outcomes.

Oberg, K., A. Califano, J. R. Strosberg, S. Ma, U. Pape, L. Bodei, G. Kaltsas, C. Toumpanakis, J. R. Goldenring, A. Frilling and S. Paulson (2020). “A meta-analysis of the accuracy of a neuroendocrine tumor mRNA genomic biomarker (NETest) in blood.” Ann Oncol 31(2): 202-212.

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BACKGROUND: The lack of an accurate blood biomarker in neuroendocrine tumor (NET) disease has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy-liquid biopsy-to facilitate real-time management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD). PATIENTS AND METHODS: A systematic review of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified ten original scientific papers that met the inclusion criteria. These were assessed by qualitative analysis and thereafter meta-analysis. Data were pooled and a median [95% confidence interval (CI)] diagnostic odds ratio (DOR), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) were calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and area under the curve (AUC) data. RESULTS: The ten studies exhibited moderate to high methodological quality. They evaluated NETest usage both as a diagnostic and as a monitoring tool. The meta-analysis identified the diagnostic accuracy of the NETest to be 95%-96% with a mean DOR of 5 853, +LR of 195, and -LR of 0.06. The NETest was 84.5%-85.5% accurate in differentiating stable disease from progressive disease. As a marker of natural history, the accuracy was 91.5%-97.8%. As an interventional/response biomarker, the accuracy was 93.7%-97.4%. The pooled AUC for the NETest was 0.954 +/- 0.005, with a z-statistic of 175.06 (P < 0.001). CONCLUSIONS: The NETest is an accurate biomarker suitable for clinical use in NET disease management. The meta-analysis supports the utility of the NETest as an IVD to establish a diagnosis and monitor therapeutic efficacy. The use of this as a biomarker provides information relevant to NET management consistent with observations regarding utility of liquid biopsies in other oncological disciplines.E

Nakase-Richardson, R., D. J. Schwartz, L. Drasher-Phillips, J. M. Ketchum, K. Calero, M. N. Dahdah, K. R. Monden, K. Bell, U. Magalang, J. M. Hoffman, J. Whyte, J. Bogner and J. M. Zeitzer (2020). “Comparative Effectiveness of Sleep Apnea Screening Instruments During Inpatient Rehabilitation Following Moderate to Severe TBI.” Arch Phys Med Rehabil 101(2): 283-296.

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OBJECTIVE: To determine the diagnostic sensitivity and specificity and comparative effectiveness of traditional sleep apnea screening tools in traumatic brain injury (TBI) neurorehabilitation admissions. DESIGN: Prospective diagnostic comparative effectiveness trial of sleep apnea screening tools relative to the criterion standard, attended level 1 polysomnography including encephalography. SETTING: Six TBI Model System Inpatient Rehabilitation Centers. PARTICIPANTS: Between May 2017 and February 2019, 449 of 896 screened were eligible for the trial with 345 consented (77% consented). Additional screening left 263 eligible for and completing polysomnography with final analyses completed on 248. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Area under the curve (AUC) of screening tools relative to total apnea hypopnea index>/=15 (AHI, moderate to severe apnea) measured at a median of 47 days post-TBI (interquartile range, 29-47). RESULTS: The Berlin high-risk score (receiving operating curve [ROC] AUC=0.634) was inferior to the Multivariable Apnea Prediction Index (MAPI) (ROC AUC=0.780) (P=.0211; CI, 0.018-0.223) and Snoring, Tired, Observed, Blood Pressure, Body Mass Index, Age, Neck Circumference, and Gender (STOPBANG) score (ROC AUC=0.785) (P=.001; CI, 0.063-0.230), both of which had comparable AUC (P=.7245; CI, -0.047 to 0.068). Findings were similar for AHI>/=30 (severe apnea); however, no differences across scales was observed at AHI>/=5. The pattern was similar across TBI severity subgroups except for posttraumatic amnesia (PTA) status wherein the MAPI outperformed the Berlin. Youden’s index to determine risk yielded lower sensitivities but higher specificities relative to non-TBI samples. CONCLUSION: This study is the first to provide clinicians with data to support a choice for which sleep apnea screening tools are more effective during inpatient rehabilitation for TBI (STOPBANG, MAPI vs Berlin) to help reduce comorbidity and possibly improve neurologic outcome.