Research Spotlight

Wesson, D. E., V. Mathur, N. Tangri, Y. Stasiv, D. Parsell, E. Li, G. Klaerner and D. A. Bushinsky (2019). “Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension.” Lancet 394(10196): 396-406.

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BACKGROUND: Metabolic acidosis, a complication of chronic kidney disease, causes protein catabolism and bone demineralisation and is associated with adverse kidney outcomes and mortality. Veverimer, a non-absorbed, counterion-free, polymeric drug candidate selectively binds and removes hydrochloric acid from the gastrointestinal lumen. METHODS: We did a multicentre, randomised, blinded, placebo-controlled, 40-week extension of a 12-week parent study at 29 sites (hospitals and specialty clinics) in seven countries (Bulgaria, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA). Eligible patients were those with chronic kidney disease (estimated glomerular filtration rate 20-40 mL/min per 1.73 m(2)) and metabolic acidosis (serum bicarbonate 12-20 mmol/L), who had completed the 12-week parent study, for which they were randomly assigned (4:3) to veverimer (6 g/day) or placebo as oral suspensions in water with food. Participants in the extension continued with the same treatment assignment as in the parent study. The primary endpoint was safety; the four secondary endpoints assessed the long-term effects of veverimer on serum bicarbonate concentration and physical functioning. The safety analysis set was defined as all patients who received any amount of study drug. This trial is registered at ClinicalTrials.gov, number NCT03390842, and has now completed. FINDINGS: Participants entered the study between Dec 20, 2017, and May 4, 2018. Of the 217 patients randomly assigned to treatment in the parent study (124 to veverimer and 93 to placebo), 196 patients (114 veverimer and 82 placebo) continued on their blinded randomised treatment assignment into this 40-week extension study. Compared with placebo, fewer patients on veverimer discontinued treatment prematurely (3% vs 10%, respectively), and no patients on veverimer discontinued because of an adverse event. Serious adverse events occurred in 2% of veverimer-treated patients and in 5% of placebo patients (two of whom died). Renal system adverse events were reported in 8% and 15% in the veverimer and placebo groups, respectively. More patients on veverimer than placebo had an increase in bicarbonate (>/=4 mmol/L or normalisation) at week 52 (63% vs 38%, p=0.0015) and higher bicarbonate concentrations were observed with veverimer than placebo at all timepoints starting at week 1 (p<0.001). Veverimer resulted in improved patient-reported physical functioning (Kidney Disease and Quality of Life-Physical Function Domain) versus placebo with a mean placebo-subtracted change at end of treatment of 12.1 points (SE 3.3; p<0.0001). Time to do the repeat chair stand test improved by 4.3 s (1.2) on veverimer versus 1.4 s (1.2) on placebo (p<0.0001). INTERPRETATION: In patients with chronic kidney disease and metabolic acidosis, veverimer safely and effectively corrected metabolic acidosis and improved subjective and objective measures of physical function. FUNDING: Tricida.

Wesson, D. E., C. R. Lucey and L. A. Cooper (2019). “Building Trust in Health Systems to Eliminate Health Disparities.” JAMA 322(2): 111-112.

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Health systems are critical, but not sufficient, to successfully eliminating health disparities within the populations they serve. Health system leaders should adopt evidence-based strategies to build the trusting relationships needed to address this complex social problem that robs people of their health and lives. Such strategies include: 1) Seek, develop, and continuously nurture trust-based relationships with community institutions around improving health outcomes. 2) Establish institutional commitments with appropriate operational strategies, resources, and accountability systems to address health disparities in the community. This includes a willingness to discuss fundamental changes in operations (e.g., focus on health in addition to health care delivery). 3) Adopt co-production models that engage and empower community institutions to work as co-equals in the identification and design of interventions and dissemination of results. 4) Establish, monitor, and share progress on metrics that measure progress toward agreed on areas of focus. 5) Establish supporting systems for, and measure compliance with, an institutional commitment that all interactions with the community undertaken by the institution’s health professionals, administrators, faculty, and learners are conducted in alignment with respectful practices for community engagement. Eventual transition to systems that reward good health outcomes will require health systems to proactively partner with patient populations and communities to eliminate health disparities as a shared value, using strategies that incentivize healthy outcomes for the whole population while also addressing the unique needs of disadvantaged populations. Eliminating health and health care disparities is a necessary step on the journey to VBC and health equity, where “everyone has a fair and just opportunity to be as healthy as possible.” (Excerpt from text, p. 112; no abstract available.)

Que, J., K. S. Garman, R. F. Souza and S. J. Spechler (2019). “Pathogenesis and Cells of Origin of Barrett’s Esophagus.” Gastroenterology 157(2): 349-364.e341.

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In patients with Barrett’s esophagus (BE), metaplastic columnar mucosa containing epithelial cells with gastric and intestinal features replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease. This condition is estimated to affect 5.6% of adults in the United States, and is a major risk factor for esophageal adenocarcinoma. Despite the prevalence and importance of BE, its pathogenesis is incompletely understood and there are disagreements over the cells of origin. We review mechanisms of BE pathogenesis, including transdifferentiation and transcommitment, and discuss potential cells of origin, including basal cells of the squamous epithelium, cells of esophageal submucosal glands and their ducts, cells of the proximal stomach, and specialized populations of cells at the esophagogastric junction (residual embryonic cells and transitional basal cells). We discuss the concept of metaplasia as a wound-healing response, and how cardiac mucosa might be the precursor of the intestinal metaplasia of BE. Finally, we discuss shortcomings in current diagnostic criteria for BE that have important clinical implications.

Ailawadi, G., D. S. Lim and P. A. Grayburn (2019). “Response by Ailawadi et al to Letter Regarding Article, ‘One-Year Outcomes After MitraClip for Functional Mitral Regurgitation.’” Circulation 140(5): e175-e176.

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We thank Gul and Haseeb for the thoughtful insights into our report that documented 1-year outcomes after MitraClip implantation for functional mitral regurgitation (FMR) for patients enrolled in the EVEREST II study (Endovascular Valve Edge-to-Edge Repair Study). Gul and Haseeb note that left ventricular dyssynchrony occurs in the setting of ventricular remodeling, which can lead to mitral regurgitation (MR). They note that cardiac resynchronization therapy (CRT) as part of an aggressive optimal medical management strategy can improve MR and should be first-line therapy. Our study spanned the early experience with MitraClip in the United States from 2007 to 2013 and included >600 patients with functional MR, many of whom were not surgical candidates. Our understanding of the role of CRT has evolved during the last decade. Therefore, our study did not capture nor did it require CRT before enrollment. With greater understanding of optimal medical therapy, the COAPT study (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) did require CRT in appropriate patients before assessment of MR severity as part of optimal medical therapy. More than 35% of patients who were in COAPT had CRT placed previously yet still had significant MR. Although the denominator of patients who were referred for treatment of their FMR in COAPT and were then treated and responded to CRT is unknown, other studies have evaluated the impact of CRT on FMR. Van der Bijl and colleagues3 reported the effect of FMR on outcomes after CRT. Of 518 patients with grade 2 to 4+ FMR, only 40% had improvement following CRT, whereas the remaining 60% had no improvement in their MR severity. Nonresponse to CRT was independently associated with mortality (hazard ratio, 1.77; P<0.001). Moreover, other studies have documented a worsening of MR severity after CRT in 10% to 15% of patients. Data such as these have called into question which therapy, MitraClip or CRT, should be first-line therapy for significant functional MR even in patients who meet criteria for CRT. According to Kienemund and colleagues, roughly one-third of patients with an indication for CRT have moderate to severe FMR, which can be caused by altered ventricular geometry/size or the dyssynchrony itself. Some have suggested that MitraClip may be a preferred approach over CRT in selected patients.4 Because current guidelines support the use of CRT as first-line treatment before evaluation for FMR, limited data remain. Unfortunately, the ongoing trial of MitraClip versus medical therapy for nonresponders to CRT to which Gul and Haseeb refer will not answer the important question of which should be first-line treatment: MitraClip or CRT for FMR. (Text of response to a comment about author’s article, Ailawadi G, Lim DS, Mack MJ, Trento A, Kar S, Grayburn PA, Glower DD, Wang A, Foster E, Qasim A, et al.; EVEREST II Investigators. One-year outcomes after MitraClip for functional mitral regurgitation. Circulation. 2019; 139:37–47.)

Packer, M. (2019). “Reconceptualization of the Molecular Mechanism by Which Sodium-Glucose Cotransporter 2 Inhibitors Reduce the Risk of Heart Failure Events.” Circulation 140(6): 443-445.

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Two sodium-glucose cotransporter 2 (SGLT2) inhibitors (ie, empagliflozin and canagliflozin) are currently approved by the Food and Drug Administration to reduce cardiovascular death or major adverse thromboembolic events in patients with type 2 diabetes mellitus. Yet, the current labeling for this class of drugs is misleading. The Food and Drug Administration indication reflects certain design features of the major cardiovascular outcome safety trials with these drugs, but it does not accurately describe the most important efficacy findings of these studies. In none of the 3 major cardiovascular trials did SGLT2 inhibitors reduce the risk of myocardial infarction and stroke.1 Instead, the primary benefit of SGLT2 inhibitors was a 25% to 35% decrease in the risk of heart failure hospitalizations, which was seen consistently across the trials. The additional benefit of empagliflozin to decrease the risk of cardiovascular death is primarily driven by an effect on pump failure deaths and sudden deaths: the 2 most common modes of death in patients with heart failure. How can inhibition of glucose transport in the proximal renal tubule lead to such a striking decrease in the risk of heart failure events? The effect of these drugs to block glucose reabsorption is accompanied by a lowering of hemoglobin A1c, body weight, and blood pressure. However, the magnitude of these effects is modest, and these changes are not well correlated with the observed decrease in the risk of heart failure deaths or hospitalizations. Furthermore, most drugs that lower blood glucose, body weight, and blood pressure do not have beneficial effects on, and they often adversely influence, the course of heart failure. Inhibition of SGLT2 in the proximal renal tubule causes a meaningful natriuresis, and the resulting decrease in plasma volume could conceivably lead to a decrease in cardiac dimensions and pressures, resulting in favorable effects on ventricular remodeling. However, it is difficult to ascribe the benefits of these drugs primarily to an increase in urinary sodium excretion, because the reduction in heart failure events was seen in patients already receiving diuretics. Intensification of diuretic therapy has not led to a dramatic decrease in cardiovascular mortality or sudden death in patients with heart failure. Similarly, the increase in hemoglobin (that is typically seen with SGLT2 inhibitors) does not lead to clinical benefits in patients with heart failure. (Excerpt from text, p. 443; no abstract available.)