Research Spotlight

Packer, M. (2020). “Mitigation of the Adverse Consequences of Nutrient Excess on the Kidney: A Unified Hypothesis to Explain the Renoprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors.” Am J Nephrol Mar 3. [Epub ahead of print].

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The 2 most common causes of chronic kidney disease worldwide (type 2 diabetes and obesity) are states of nutrient excess, suggesting that fuel overabundance leads to deleterious effects on the structure and function of the kidneys. Three pathophysiological pathways may potentially explain this linkage. First, both obesity and type 2 diabetes are characterized by glomerular hyperfiltration, which may result from increased proximal tubular reabsorption of sodium (due to enhanced glucose and sodium transport) coupled with activation of the renin-angiotensin system. Second, both obesity and type 2 diabetes are characterized by adipose tissue expansion and inflammation, followed by the augmented synthesis and release of lipid intermediates and proinflammatory adipocytokines that can have deleterious effects on the kidney. Third, states of nutrient excess cause a diminution in the activation of the energy sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). The result is a suppression of autophagy, a lysosomal degradative pathway that is responsible for the clearance of damaged organelles that are an important source of oxidative and endoplasmic reticulum stress and inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors induces a transcriptional paradigm that mimics fasting, which leads to the amelioration of glomerular hyperfiltration and adipose tissue inflammation as well as augmentation of AMPK/SIRT1 signaling and autophagy, thereby acting to mute organellar and cellular stress in the kidney. Therefore, SGLT2 inhibitors are positioned to antagonize all 3 pathways by which nutrient excess can lead to nephropathy.

Packer, M. (2020). “Epicardial Adipose Tissue Inflammation Can Cause the Distinctive Pattern of Cardiovascular Disorders Seen in Psoriasis.” Am J Med 133(3): 267-272.

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Psoriasis is a systemic inflammatory disorder that can target adipose tissue; the resulting adipocyte dysfunction is manifest clinically as the metabolic syndrome, which is present in approximately 20%-40% of patients. Epicardial adipose tissue inflammation is likely responsible for a distinctive pattern of cardiovascular disorders consisting of 1) accelerated coronary atherosclerosis leading to myocardial infarction, 2) atrial myopathy leading to atrial fibrillation and thromboembolic stroke, and 3) ventricular myopathy leading to heart failure with a preserved ejection fraction. If cardiovascular inflammation drives these risks, then treatments that focus on blood pressure, lipids, and glucose will not ameliorate the burden of cardiovascular disease in patients with psoriasis, especially in those who are young and have severe inflammation. Instead, interventions that alleviate systemic and adipose tissue inflammation may not only minimize the risks of atrial fibrillation and heart failure but may also have favorable effects on the severity of psoriasis. Viewed from this perspective, the known link between psoriasis and cardiovascular disease is not related to the influence of the individual diagnostic components of the metabolic syndrome.

Packer, M. (2020). “Does Metformin Interfere With the Cardiovascular Benefits of SGLT2 Inhibitors? Questions About Its Role as the Cornerstone of Diabetes Treatment.” Am J Med Feb 12. [Epub ahead of print].

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Metformin is widely used as first-line therapy to lower blood glucose in type 2 diabetes, because it is inexpensive and does not cause weight gain. However, the evidentiary basis for the primacy of metformin is not persuasive. A clinical trial performed >20 years ago reported that initial therapy with metformin reduced the risk of myocardial infarction when compared with other glucose-lowering drugs. However, this finding represented a subgroup analysis that relied only a small number of events, with confidence intervals that did not exclude a neutral effect. Furthermore, the benefit of metformin was not confirmed in a parallel trial in which the drug was used as second-line therapy. Importantly, there is little evidence to support a benefit of metformin to prevent the most serious cardiovascular complication of type 2 diabetes — heart failure. Observational studies have reported that metformin use is associated with a lower risk of heart failure and its adverse consequences; however, these reports are difficult to interpret, since it is likely that physicians selectively prescribed metformin to low-risk patients, due to fears that its use causes lactic acidosis in patients with left ventricular dysfunction. Furthermore, in these studies, metformin was compared with insulin-signaling antihyperglycemic drugs that have themselves been linked to an increased risk of heart failure; thus, the finding of a lower risk of heart failure in metformin users may have been due to an adverse effect of the comparator rather than a benefit of the biguanide. Importantly, in two large meta-analyses of randomized controlled trials, metformin did not did not influence the risk or consequences of heart failure, and the use of metformin with sulfonylureas has been accompanied by an increased risk of death both in observational studies and clinical trials. In light of these observations, there is no reliable evidence that metformin prevents or ameliorates the clinical course of heart failure in type 2 diabetes. (Excerpt from text, n.p.; no abstract available.)

Packer, M. (2020). “Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium-glucose cotransporter 2 inhibitors.” Eur J Heart Fail Feb 10. [Epub ahead of print].

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In five large-scale trials involving >40 000 patients, sodium-glucose cotransporter 2 (SGLT2) inhibitors decreased the risk of serious heart failure events by 25-40%. This effect cannot be explained by control of hyperglycaemia, since it is not observed with antidiabetic drugs with greater glucose-lowering effects. It cannot be attributed to ketogenesis, since it is not causally linked to ketone body production, and the benefit is not enhanced in patients with diabetes. The effect cannot be ascribed to a natriuretic action, since SGLT2 inhibitors decrease natriuretic peptides only modestly, and they reduce cardiovascular death, a benefit that diuretics do not possess. Although SGLT2 inhibitors increase red blood cell mass, enhanced erythropoiesis does not favourably influence the course of heart failure. By contrast, experimental studies suggest that SGLT2 inhibitors may reduce intracellular sodium, thereby preventing oxidative stress and cardiomyocyte death. Additionally, SGLT2 inhibitors induce a transcriptional paradigm that mimics nutrient and oxygen deprivation, which includes activation of adenosine monophosphate-activated protein kinase, sirtuin-1, and/or hypoxia-inducible factors-1alpha/2alpha. The interplay of these mediators stimulates autophagy, a lysosomally-mediated degradative pathway that maintains cellular homeostasis. Autophagy-mediated clearance of damaged organelles reduces inflammasome activation, thus mitigating cardiomyocyte dysfunction and coronary microvascular injury. Interestingly, the action of hypoxia-inducible factors-1alpha/2alpha to both stimulate erythropoietin and induce autophagy may explain why erythrocytosis is strongly correlated with the reduction in heart failure events. Therefore, the benefits of SGLT2 inhibitors on heart failure may be mediated by a direct cardioprotective action related to modulation of pathways responsible for cardiomyocyte homeostasis.

Ordonez, A. A., H. Wang, G. Magombedze, C. A. Ruiz-Bedoya, S. Srivastava, A. Chen, E. W. Tucker, M. E. Urbanowski, L. Pieterse, E. Fabian Cardozo, M. A. Lodge, M. R. Shah, D. P. Holt, W. B. Mathews, R. F. Dannals, J. V. S. Gobburu, C. A. Peloquin, S. P. Rowe, T. Gumbo, V. D. Ivaturi and S. K. Jain (2020). “Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions.” Natture Medicine Feb 17. [Epub ahead of print].

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Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments. In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans. Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study using dynamic [(11)C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [(11)C]rifampin PET-CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET-CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET-CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development.