Peter A. McCullough M.D.

Lo, K. B., F. Gul, P. Ram, A. Y. Kluger, K. M. Tecson, P. A. McCullough and J. Rangaswami (2020). “The Effects of SGLT2 Inhibitors on Cardiovascular and Renal Outcomes in Diabetic Patients: A Systematic Review and Meta-Analysis.” Cardiorenal Med 10(1): 1-10.

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BACKGROUND: Previous meta-analyses demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) primarily on patients with established atherosclerotic cardiovascular disease (ASCVD), but with questionable efficacy on patients at risk of ASCVD. Additionally, evidence of beneficial cardiorenal outcomes in patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 with the CV outcomes trials remains unclear. Canagliflozin, one of the SGLT2i, has recently been studied in a large randomized controlled trial in diabetic patients with chronic kidney disease. Thus, there is a need to understand the combined outcomes on the population targeted for treatment with SGLT2i as a whole, regardless of ASCVD status. This meta-analysis will therefore assess the efficacy of SGLT2i in cardiovascular and renal outcomes in general, and in patients with eGFR under 60 mL/min/1.73 m2 in particular. METHODS: We searched PubMed and Cochrane databases for randomized, placebo-controlled studies involving SGLT2i. We examined composite cardiovascular outcomes of death from cardiovascular causes, nonfatal myocardial infarctions, nonfatal stroke, and heart failure hospitalizations. Renal composite outcomes and progression of albuminuria were also analyzed. Pooled relative risks (RR) and their 95% confidence intervals (CI) were calculated using a fixed-effects model. RESULTS: The search yielded a total of 252 articles. Four studies were ultimately included in the meta-analysis after exclusion of other irrelevant studies. The pooled RR (95% CI) for the composite cardiovascular outcome was 0.93 (0.87-0.99) with a number needed to treat (NNT) of 167 in the general study population and 0.89 (0.77-1.02) in patients with eGFR <60 mL/min/1.73 m2. The pooled RR for all-cause mortality was 0.9 (0.84-0.97) with NNT = 143. The pooled RR for death from cardiovascular causes alone was 0.89 (0.81-0.99) in the general population and 0.82 (0.62-1.07) in patients with eGFR <60 mL/min/1.73 m2. The pooled RR for heart failure hospitalizations was 0.71 (0.63-0.79) with NNT = 91. With respect to renal outcomes, the pooled RR for the composite renal outcome was 0.63 (0.56-0.71) with NNT = 67; this was true even in patients with eGFR <60 mL/min/1.73 m2 0.67 (0.59-0.76). Lastly, the pooled RR for progression of albuminuria was 0.80 (0.76-0.84). CONCLUSION: SGLT2i are associated with significantly lower major adverse cardiovascular events, heart failure hospitalizations, and all-cause mortality. The evidence is strongest in reducing heart failure hospitalizations. However, the evidence is weaker when it comes to the population subset with eGFR <60 mL/min/1.73 m2. SGLT2i are also associated with significantly lower adverse renal events, with these effects apparent even in the population with eGFR <60 mL/min/1.73 m2.

Vasudevan, A., J. W. Choi, G. A. Feghali, A. Y. Kluger, S. R. Lander, K. M. Tecson, M. Sathyamoorthy, J. M. Schussler, R. C. Stoler, R. C. Vallabhan, C. E. Velasco, A. Yoon and P. A. McCullough (2019). “First and recurrent events after percutaneous coronary intervention: implications for survival analyses.” Scand Cardiovasc J 53(6): 299-304.

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Objectives. Using composite endpoints and/or only first events in clinical research result in information loss and alternative statistical methods which incorporate recurrent event data exist. We compared information-loss under traditional analyses to alternative models. Design. We conducted a retrospective analysis of patients who underwent percutaneous coronary intervention (Jan2010-Dec2014) and constructed Cox models for a composite endpoint (readmission/death), a shared frailty model for recurrent events, and a joint frailty (JF) model to simultaneously account for recurrent and terminal events and evaluated the impact of heart failure (HF) on the outcome. Results. Among 4901 patients, 2047(41.8%) experienced a readmission or death within 1 year. Of those with recurrent events, 60% had >/=1 readmission and 6% had >4; a total of 121(2.5%) patients died during follow-up. The presence of HF conferred an adjusted Hazard ratio (HR) of 1.32 (95% CI: 1.18-1.47, p < .001) for the risk of composite endpoint (Cox model), 1.44 (95% CI: 1.36-1.52, p < .001) in the frailty model, and 1.34 (95% CI:1.22-1.46, p < .001) in the JF model. However, HF was not associated with death (HR 0.87, 95% CI: 0.52-1.48, p = .61) in the JF model. Conclusions. Using a composite endpoint and/or only the first event yields substantial loss of information, as many individuals endure >1 event. JF models reduce bias by simultaneously providing event-specific HRs for recurrent and terminal events.

Raju, B. and P. A. McCullough (2019). “Circulating plasma dipeptidyl dipeptidase 3 and the prognosis of cardiogenic shock.” Eur J Heart Fail Nov 28. [Epub ahead of print].

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The current management of cardiogenic shock after acute myocardial infarction (AMI) focuses on early revascularization, optimizing cardiac filling pressures, and inotropic or mechanical circulatory support (MCS). These interventions target two pathophysiologic processes underlying cardiogenic shock; myocardial ischaemia and low cardiac output. Despite advances in MCS and percutaneous coronary intervention that address both these mechanisms, in‐hospital mortality for cardiogenic shock remains high (27–51%). There are no approved in vitro diagnostic assays for the prognosis of cardiogenic shock. Over the past two decades the medical community has gained more knowledge about the myriad of other processes involved in the pathophysiology of cardiogenic shock and AMI. Biological pathways that affect systemic inflammation, neurohormonal modulation, and extracellular matrix remodelling are all altered in cardiogenic shock. Multiple studies have demonstrated the marked change in inflammatory markers and downstream mediators after myocardial infarction. Vasopressin and angiotensin II levels increase in the setting of cardiogenic shock, altering fluid and salt homeostasis. Alterations of the renin–angiotensin system also affects extracellular remodelling pathways. Understanding the downstream regulatory pathways associated with cardiogenic shock may allow for better prognostication, risk stratification, and targets for future therapies. Circulating plasma dipeptidyl dipeptidase 3 (cDPP3) is a protease that is ubiquitous in many organ systems throughout the human body. Although DPP3 has been identified and isolated as far back as 1967, its haemodynamic and cardiovascular relevance have only come to light more recently. cDPP3 has been implicated in pathophysiologic processes such as inflammation, blood pressure regulation, and pain modulation. Concentrations of cDDP3 have been found to be elevated in septic and cardiogenic shock. In vitro testing shows that cDPP3 is involved in angiotensin II regulation. In animal models cDPP3 inhibited angiotensin II‐induced hypertension, cardiac fibrosis, and hypertrophy. Animal studies have also shown cDPP3 significantly affects cardiac contractility and with a negative inotropic effect. Thus, cDPP3 clearly plays a role in cardiovascular physiology but the practical application of this knowledge is not yet clear. In the present issue of the Journal, Takagi et al. attempt to delineate a clinical role for DPP3 and confirm the relationship between cDPP3 and clinical outcomes measured in patients with ST‐ elevation myocardial infarction (STEMI) and cardiogenic shock from the OptimaCC trial. (Excerpt from text of this commentary on the article by K. Takagi et al., “Circulating dipeptidyl peptidase 3 and alteration in haemodynamics in cardiogenic shock: results from the OptimaCC trial” which appears in the same issue.)

Lo, K. B., F. Gul, P. Ram, A. Y. Kluger, K. M. Tecson, P. A. McCullough and J. Rangaswami (2019). “The Effects of SGLT2 Inhibitors on Cardiovascular and Renal Outcomes in Diabetic Patients: A Systematic Review and Meta-Analysis.” Cardiorenal Med Nov 19. [Epub ahead of print].

Full text of this article.

BACKGROUND: Previous meta-analyses demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) primarily on patients with established atherosclerotic cardiovascular disease (ASCVD), but with questionable efficacy on patients at risk of ASCVD. Additionally, evidence of beneficial cardiorenal outcomes in patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 with the CV outcomes trials remains unclear. Canagliflozin, one of the SGLT2i, has recently been studied in a large randomized controlled trial in diabetic patients with chronic kidney disease. Thus, there is a need to understand the combined outcomes on the population targeted for treatment with SGLT2i as a whole, regardless of ASCVD status. This meta-analysis will therefore assess the efficacy of SGLT2i in cardiovascular and renal outcomes in general, and in patients with eGFR under 60 mL/min/1.73 m2 in particular. METHODS: We searched PubMed and Cochrane databases for randomized, placebo-controlled studies involving SGLT2i. We examined composite cardiovascular outcomes of death from cardiovascular causes, nonfatal myocardial infarctions, nonfatal stroke, and heart failure hospitalizations. Renal composite outcomes and progression of albuminuria were also analyzed. Pooled relative risks (RR) and their 95% confidence intervals (CI) were calculated using a fixed-effects model. RESULTS: The search yielded a total of 252 articles. Four studies were ultimately included in the meta-analysis after exclusion of other irrelevant studies. The pooled RR (95% CI) for the composite cardiovascular outcome was 0.93 (0.87-0.99) with a number needed to treat (NNT) of 167 in the general study population and 0.89 (0.77-1.02) in patients with eGFR <60 mL/min/1.73 m2. The pooled RR for all-cause mortality was 0.9 (0.84-0.97) with NNT = 143. The pooled RR for death from cardiovascular causes alone was 0.89 (0.81-0.99) in the general population and 0.82 (0.62-1.07) in patients with eGFR <60 mL/min/1.73 m2. The pooled RR for heart failure hospitalizations was 0.71 (0.63-0.79) with NNT = 91. With respect to renal outcomes, the pooled RR for the composite renal outcome was 0.63 (0.56-0.71) with NNT = 67; this was true even in patients with eGFR <60 mL/min/1.73 m2 0.67 (0.59-0.76). Lastly, the pooled RR for progression of albuminuria was 0.80 (0.76-0.84). CONCLUSION: SGLT2i are associated with significantly lower major adverse cardiovascular events, heart failure hospitalizations, and all-cause mortality. The evidence is strongest in reducing heart failure hospitalizations. However, the evidence is weaker when it comes to the population subset with eGFR <60 mL/min/1.73 m2. SGLT2i are also associated with significantly lower adverse renal events, with these effects apparent even in the population with eGFR <60 mL/min/1.73 m2.

McCullough, P. A., M. Ostermann, L. G. Forni, A. Bihorac, J. L. Koyner, L. S. Chawla, J. Shi, J. P. Kampf, P. McPherson and J. A. Kellum (2019). “Serial Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor-Binding Protein 7 and the Prognosis for Acute Kidney Injury over the Course of Critical Illness.” Cardiorenal Med Oct 16: 1-12.[Epub ahead of print].

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INTRODUCTION: Over the course of critical illness, there is a risk of acute kidney injury (AKI), and when it occurs, it is associated with increased length of stay, morbidity, and mortality. The urinary cell-cycle arrest markers tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) have been utilized to predict the risk of AKI over the next 12 h from the time of sampling. The aim of this analysis was to evaluate the utility of [TIMP-2] x [IGFBP7] measured serially to anticipate the occurrence of AKI over the first 7 days of critical illness. METHODS: This analysis is from a prospective, blinded, observational, international study of patients admitted to intensive care units. We designed the analysis to emulate a clinician-driven serial testing strategy. Urine samples collected every 12 h up to 3 days from 530 patients were considered for analysis. We evaluated [TIMP-2] x [IGFBP7] results for the first 3 measurements (baseline, 12 and 24 h) and continued to evaluate additional results if any of the first 3 were positive >0.3 (ng/mL)2/1,000. Patients were stratified by number of [TIMP-2] x [IGFBP7] results >0.3 (ng/mL)2/1,000 and number of results >2.0 (ng/mL)2/1,000. The primary endpoint was AKI stage 2-3 defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. RESULTS: The median (interquartile range) age was 64 (53-74) years, 61% were men, and 79% were Caucasian. The median APACHE III score was 71 (51-93), and 82% required mechanical ventilation. Baseline serum creatinine was 0.8 mg/dL and 164/530 (31%) developed the primary endpoint by day 7 with a median time from baseline to stage 2/3 AKI of 26 (8-56) h. In patients with negative values for the first 3 tests (2.0 (ng/mL)2/1,000), the cumulative incidence for the primary endpoint at 7 days was 57.7, 75.0, and 94.4%, respectively, p < 0.001 for trend. There were 3.4% with test results between 0.3 and 2.0 (ng/mL)2/1,000 at all measurements; one third of those patients developed the primary endpoint. We observed a graded increase in the primary endpoint in Kaplan-Meier plots for successively positive test results over time. CONCLUSION: Serial urinary [TIMP-2] x [IGFBP7] at baseline, 12 and 24 h, and up through 3 days are prognostic for the occurrence of stage 2/3 AKI over the course of critical illness. Three consecutive negative values (2.0 [ng/mL]2/1,000] predict very high incidence rates (up to 94.4%) of stage 2/3 AKI. There was a low rate of test results between 0.3 and 2.0 (ng/mL)2/1,000, where the primary endpoint was observed in a third of cases.