Cardiorenal Outcomes Research Articles

Abstract P242: The Role Of Kappa Opioid Receptors In The Development Of Hypertension And Kidney Injury In Sprague-Dawley Rats

The extensive use of opioid-based pain management strongly correlates with poor cardiovascular and cardiorenal outcomes. Our recent studies suggest that treatment with kappa opioid receptor (KOR) agonist BRL 52537 leads to the progression of chronic kidney disease (CKD) and aggravation of salt-sensitive hypertension. We hypothesize that stimulation of KORs leads to blood pressure elevation, albuminuria, and kidney damage in healthy Sprague-Dawley (SD) rats. To characterize the effect of the KOR agonist BRL 52537 on the development of blood pressure and kidney function in vivo , SD rats were treated with a daily i.v. bolus infusion of BRL 52537 or a corresponding vehicle. To test the contribution of KOR stimulation on calcium homeostasis in podocytes, BRL 52537 was used on freshly isolated glomeruli from SD rats. Single-channel analysis was applied to assess the effect of KORs stimulation on TRPC6 channel activity in the human immortalized podocytes. Chronic treatment with BRL 52537 leads to increased mean arterial pressure (88±1 vs 101±4 mmHg, vehicle vs treated, p<0.05), podocyte basal calcium (90±12 vs 216±16 a.u., vehicle vs treated, p<0.05), and GFB impairment in SD rats which is reflected by a transient increase in albumin excretion (Alb/cre ratio 0.35±0.1 vs 0.72±0.2, vehicle vs treated, p<0.05). Cumulative probability distribution analysis of the glomerular injury score revealed a rightward shift toward a high glomerular injury score in the group treated with BRL 52537 (p<0.05). Angiotensin II level was higher in a BRL-treated group (156±17 vs 232±59 pmol, vehicle vs treated, p=0.065); however, it did not reach a statistical difference. Acute application of BRL 52537 resulted in sustained calcium response (0.23±0.01 a.u., Fluo4/FuraRed, maximum calcium response) in freshly isolated glomeruli from SD rats. Furthermore, patch-clamp experiments in human immortalized podocytes (cell-attached configuration) revealed that BRL 52537 activated TRPC6 channels. Taken together, these data support the hypothesis that administration of opioids in SD rats leads to activation of the KOR/TRPC6 pathway, which in turn led to glomerular filtration barrier impairment, increased glomerular damage, and blood pressure elevation.

Outcomes of patients with type 2 diabetes treated with SGLT-2 inhibitors versus DPP-4 inhibitors. An Italian real-world study in the context of other observational studies

AimsWe compared cardiovascular outcomes of patients with type 2 diabetes (T2D) receiving sodium glucose cotransporter-2 inhibitors (SGLT2i) or dipeptidyl peptidase-4 inhibitors (DPP4i) under routine care. MethodsFrom an administrative claims database of >5.2M citizen, we identified patients with T2D who initiated SGLT2i or DPP4i from 2014 to 2018. Patients were matched by propensity scores. The primary outcome was the 3-point major adverse cardiovascular events (3P-MACE). ResultsAfter matching, we included 3216 patients/group, with mean age of 63 years, diabetes duration of 8.7 years, and 20% had cardiovascular disease. During a median follow-up of 18 months, the rate of 3P-MACE was lower among patients who initiated SGLT2i versus DPP4i (HR 0.74; 95 %C.I. 0.58–0.94). Initiators of SGLT2i also showed significantly lower rates of myocardial infarction (HR 0.75; 95 %C.I. 0.56–1.00), hospitalization for heart failure (HR 0.44; 95 %C.I. 0.25–0.95) or cardiovascular causes (HR 0.72; 95 %C.I. 0.60–0.87), and all-cause death (HR 0.49; 95 %C.I. 0.25–0.95). Renal failure was less common with SGLT2i than with DPP4i. Results were consistent to those obtained in a meta-analysis of 10 observational studies on ~1.5M patients. ConclusionsPatients with T2D who initiated SGLT2i under routine care had better cardio-renal outcomes and lower all-cause mortality than similar patients who initiated DPP4i.

Association between blood and urine manganese levels and cardiorenal outcomes in adolescents: NHANES 2013-2018

BACKGROUND AND AIM: Manganese (Mn), an essential mineral, is naturally present in many foods; however, deficiency or excess exposure may have potential adverse health effects. The kidneys are a major organ of Mn site-specific toxicity because of their unique role in filtration, metabolism, and excretion of xenobiotics. Limited evidence has identified the effects of Mn on renal or cardiovascular dysfunction, especially in adolescents. We hypothesized that Mn concentrations were associated with poorer cardiorenal outcomes such as estimated glomerular filtration rate (eGFR), blood pressure (BP), and blood urea nitrogen (BUN). METHODS: We conducted a cross-sectional analysis of 2,002 US adolescents aged 10-19 years participating in NHANES cycles 2013-2014, 2015-2016, and 2017-2018. Blood Mn concentrations were measured using inductively coupled plasma mass spectrometry. Systolic (SBP) and diastolic (DBP) BP was calculated as the average of available readings. eGFR was calculated from serum creatinine using the Bedside Schwartz equation. We performed multiple linear regression, adjusted for race, age, gender, BMI, race/ethnicity, and poverty income ratio. RESULTS:The average age of participants was 15.4 years. Median blood Mn concentration was 10.4 ug/L (IQR: 8.4, 13.1 ug/L). We observed that a log10-unit increase in blood Mn ug/L was marginally associated with a 6.41 mL/min higher eGFR (95% CI: -0.32, 13.14). We observed null relationships for BP and BUN outcomes. There were no significant differences when stratified by sex. CONCLUSIONS:Our findings suggest that Mn exposure may have implications for kidney health reflecting potential hyperfiltration. Additional analyses will examine non-linear relationships. We cautiously interpret these findings, as reverse causality cannot be ruled out. These findings warrant further investigation in longitudinal studies. KEYWORDS: Environmental Epidemiology, Heavy Metals, Cardiovascular Disease, Outcomes

Cardiorenal outcomes with sodium/glucose cotransporter-2 inhibitors in patients with type 2 diabetes and low kidney risk: real world evidence

BackgroundRandomized controlled trials showed that sodium/glucose cotransporter-2 inhibitors (SGLT2i) protect the heart and kidney in an array of populations with type 2 diabetes (T2D) and increased cardiorenal risk. However, the extent of these benefits also in lower kidney-risk T2D populations needs further investigation.MethodsMembers of Maccabi Healthcare Systems listed in their T2D registry who initiated new glucose lowering agents (GLA), were divided into SGLT2i initiators and other GLAs (oGLAs). Groups were propensity score-matched by baseline demographic and medical characteristics. Two composite cardiovascular outcomes were defined: all-cause mortality (ACM) or hospitalization for heart failure (hHF); and ACM, myocardial infraction (MI) or stroke. The cardiorenal outcome was: ACM, new end-stage kidney disease (ESKD) or ≥ 40% reduction from baseline estimated glomerular filtration rate (eGFR). Renal-specific outcome was new ESKD or ≥ 40% eGFR reduction. Single components of cardiovascular and kidney outcomes were also assessed. Three subgroup definitions of low baseline kidney-risk were used: eGFR > 90 ml/min/1.73 m2; urinary albumin below detectable levels; and low risk according to Kidney Disease: Improving Global Outcomes (KDIGO) classification. Analyses were performed utilizing an unadjusted model, and a model adjusted to baseline eGFR and urinary albumin-to-creatinine ratio.ResultsBetween April 1, 2015 and June 30, 2018; 68,187 patients initiated new GLAs — 11,321 SGLT2i initiators and 42,077 oGLAs initiators were eligible. Propensity score-matching yielded two comparable cohorts; each included 9219 participants. Median follow-up was 1.7 years. Compared to oGLAs, SGLT2i initiators had lower incidence of ACM or hHF [HR95%CI = 0.62(0.51–0.75)]; ACM, MI or stroke [0.67(0.57–0.80)]; the cardiorenal outcome [0.65(0.56–0.76)]; and the renal-specific outcome [0.70(0.57–0.85)]. SGLT2i initiators also had lower risk for ACM, hHF and ≥ 30%, ≥ 40%, ≥ 50%, ≥ 57% eGFR reduction. No difference between groups was observed for MI or stroke. In the low baseline kidney-risk subgroups, SGLT2i initiation was generally associated with lower risk of the cardiovascular and cardiorenal outcomes, driven mainly by lower ACM incidence.ConclusionsOur findings in the general population of patients with T2D demonstrates lower risk of cardiorenal outcomes associated with initiation of SGLT2i compared with oGLAs, including specifically in patients with low baseline kidney-risk.

Emerging Treatments of Cardiorenal Syndrome: An Update on Pathophysiology and Management.

Cardiorenal syndrome refers to combined cardiac and renal dysfunction that adversely impacts both organs and is also associated with severe clinical outcomes. The pathophysiology is believed to be multifactorial and complex. Increased central venous pressure and intra-abdominal pressure, overactivation of the Renin-Angiotensin-Aldosterone System (RAAS), systemic illnesses like sepsis, amyloidosis, diabetes are important factors in developing the cardiorenal syndrome. Our review article attempts to review the pathophysiology and treatment aspect of cardiorenal syndrome and explores potential therapeutic strategies that can be adopted for the management.We searched PubMed, EMBASE, Google Scholar for relevant articles using different keywords and Medical Subject Headings, and finalized 38 articles to be included in our study. Cardiorenal syndrome management aims to eliminate venous congestion and fluid retention, which leads to improved cardiorenal status. This is usually achieved using pharmacologic agents like diuretics, vasodilators, inotropes, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs), neprilysin inhibitors, and extracorporeal methods like ultrafiltration. The use of therapeutic agents such as sodium-glucose co-transporter 2 inhibitors and tolvaptan (a vasopressin V2 receptor antagonist), and cardiac resynchronization therapy has also been shown to have potential benefits in managing the disease. These agents can be instrumental in the management and require large-scale clinical trials specifically aimed at improving cardiorenal outcomes based on severity and type of cardiorenal syndrome.

Comparative efficacy of 5 sodium glucose cotransporter 2 inhibitor and 7 glucagon-like peptide 1 receptor agonists interventions on cardiorenal outcomes in type 2 diabetes patients: A network meta-analysis based on cardiovascular or renal outcome trials.

Background:Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been demonstrated to be able to improve the cardiovascular and renal prognosis in patients with type 2 diabetes (T2D). However, the relative efficacy of various SGLT2 inhibitors and GLP-1 RAs on cardiorenal outcomes is unestablished.Methods:We searched PubMed and Embase for relevant cardiovascular or renal outcome trials (CVOTs). Endpoints of interest were major adverse cardiovascular events (MACE), stroke, myocardial infarction (MI), cardiovascular death (CVD), all-cause death (ACD), kidney function progression (KFP), and hospitalization for heart failure (HHF). Bayesian network meta-analysis was conducted to produce pooled hazard ratio (HR) and 95% confidence interval (CI). We calculated the probability values of surface under the cumulative ranking curve to rank active and placebo interventions.Results:Fourteen COVTs were included in analysis. Sotagliflozin (HR 0.76, 95% CI 0.61–0.94), subcutaneous semaglutide, and albiglutide lowered MACE versus lixisenatide among others. Sotagliflozin (HR 0.59, 95% CI 0.40–0.89), canagliflozin, and empagliflozin lowered HHF versus subcutaneous semaglutide among others. Dapagliflozin and empagliflozin lowered KFP versus exenatide among others. Empagliflozin and oral semaglutide lowered CVD versus dapagliflozin among others. Sotagliflozin (HR 0.65, 95% CI 0.47–0.91) and albiglutide lowered MI versus ertugliflozin among others. Sotagliflozin (HR 0.56, 95% CI 0.37–0.85) and subcutaneous semaglutide lowered stroke versus empagliflozin among others. Oral semaglutide and empagliflozin lowered ACD versus subcutaneous semaglutide among others. The maximum surface under the cumulative ranking curve values followed sotagliflozin, subcutaneous semaglutide, and albiglutide in lowering MACE; sotagliflozin, canagliflozin, and empagliflozin in lowering HHF; dapagliflozin and empagliflozin in lowering KFP; empagliflozin and oral semaglutide in lowering CVD; sotagliflozin and albiglutide in lowering MI; sotagliflozin and subcutaneous semaglutide in lowering stroke; and oral semaglutide and empagliflozin in lowering ACD.Conclusions:This updated network meta-analysis reproduced the findings in the first network meta-analysis, and moreover revealed that sotagliflozin was one of the most effective drugs as for lowering MI, stroke, MACE, and HHF, whereas ertugliflozin was not. These findings will provide the according evidence regarding the usage of specific SGLT2 inhibitors and GLP-1 RAs in T2D patients for prevention of specific cardiorenal endpoints.

Evolution of Type 2 Diabetes Management from a Glucocentric Approach to Cardio-Renal Risk Reduction: The New Paradigm of Care.

For many years, clinical studies could not show that lowering glucose in patients with type 2 diabetes leads to better macrovascular outcomes. In the past few years, new data have shown that treatment with two classes of dugs developed as "glucose-lowering agents," SGLT2 inhibitors and GLP-1 receptor agonists, can reduce macrovascular and renal complications. These studies have prompted debate about the main aim of type 2 diabetes management. In this review, three eras of diabetes management are described according to the treatment recommendations, such as the ADA/EASD consensus, moving from a pure glucocentric view into the present cardio-renal outcome-oriented approach, this has been endorsed by major diabetes and cardiology societies. While in the first era normalizing HbA1c was the only focus (e.g., UK Prospective Diabetes Study), failing to show a reduction in cardiovascular morbidity and mortality, further studies analyzing the pros and cons of intensified control such as ACCORD, VADT, ADVANCE recognized that treatment intensification was associated with weight gain and hypoglycemia, thereby potentially reducing the benefits of glycemic control. Therefore, the focus in the second area was on controlling HbA1c without these unwanted effects. The consistent beneficial results of several cardiovascular outcome trials with SGLT2 inhibitors and GLP-1 receptor agonists showing significantly improved cardio-renal outcomes, induced a paradigm shift: a change from (only) control of HbA1c to an organ-protective approach with the main focus now on cardio-renal risk; this is now considered as the third era. Recent data indicating beneficial effects of glucose-lowering agents in particular SGLT2 inhibitors even in subjects without diabetes, improving hospitalization for heart failure and renal outcomes might reveal another new era, which could then be considered a fourth era. While current international guidelines call for this paradigm shift, registry data show that we are still far from translating this objective into real-world practice.

Use of chronic kidney disease blind spot to prevent cardiorenal outcomes.

Use of chronic kidney disease blind spot to prevent cardiorenal outcomes.

Comparative Efficacy of Five SGLT2i on Cardiorenal Events: A Network Meta-analysis Based on Ten CVOTs.

The relative efficacy of different sodium-glucose transporter 2 inhibitors (SGLT2i) on cardiorenal outcomes is unclear. We included cardiovascular outcome trials (CVOTs) of SGLT2i. The eight endpoints of interest were major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, cardiovascular death (CVD), CVD or hospitalization for heart failure (HHF), HHF, kidney function progression (KFP), and all-cause death (ACD). We conducted a Bayesian network meta-analysis and calculated the surface under the cumulative ranking curve (SUCRA) probability to rank treatments. We included ten CVOTs involving five SGLT2i. Canagliflozin (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.53-0.77), dapagliflozin (HR 0.70; 95% CI 0.62-0.79), empagliflozin (HR 0.68; 95% CI 0.59-0.78), ertugliflozin (HR 0.70; 95% CI 0.54-0.90), and sotagliflozin (HR 0.66; 95% CI 0.56-0.77) versus placebo reduced HHF, whereas none reduced MI and stroke. Empagliflozin reduced CVD or HHF (HR 0.81; 95% CI 0.67-0.99) and KFP (HR 0.65; 95% CI 0.45-0.93), and dapagliflozin reduced KFP (HR 0.69; 95% CI 0.52-0.92), versus ertugliflozin. Canagliflozin had the greatest SUCRA values for the reduction of MACE, stroke, and HHF, whereas empagliflozin had the greatest SUCRA values for the reduction of MI, CVD, CVD or HHF, KFP, and ACD. Canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin versus placebo reduce HHF but none reduces MI and stroke. Canagliflozin is most effective in reducing MACE and HHF, and empagliflozin is most effective in reducing CVD, CVD or HHF, KFP, and ACD. These findings will guide the use of specific SGLT2i in the prevention of different cardiorenal events.

Sodium-Glucose Transporter Inhibition in Adult and Pediatric Patients with Type 1 Diabetes Mellitus.

Adjunctive therapies to insulin for treatment of type 1 diabetes mellitus (T1D) have gained popularity in efforts to achieve glycemic targets, and sodium-glucose transporter (SGLT) inhibitors are an appealing option due to associated weight loss, low risk of hypoglycemia, and improved cardiorenal outcomes seen in persons with type 2 diabetes mellitus. The increased risk of diabetic ketoacidosis (DKA), including euglycemic DKA, has led many to be wary of their use in T1D, especially given limited pediatric data and data regarding cardiorenal protection in this population. The phase 3 trials of these agents in T1D have yielded lower HbA1c, decreased total daily insulin dose, and small but significant weight loss with no increase in hypoglycemia. These trials also reported increased risks of genital mycotic infection and DKA. SGLT inhibitors have been approved as adjunctive therapy to insulin in adults with T1D in Europe and Japan, but the United States Food and Drug Administration has rejected similar applications. Although approaches to mitigate the risk of DKA have been developed, no randomized trials using such tools have been conducted. More research is needed to minimize the risk of DKA and to better evaluate the cardiorenal impact of these agents in persons with T1D.

The Association of Serum Lactate Level with the Occurrence of Contrast-Induced Acute Kidney Injury and Long-Term Prognosis in Patients Undergoing Emergency Percutaneous Coronary Intervention.

ObjectiveThe association of lactate and contrast-induced acute kidney injury (CI-AKI) has not been well established. This prospective study was planned to identify the effects of lactate level on the occurrence of CI-AKI and long-term prognosis with acute myocardial infarction (AMI) patients undergoing emergency percutaneous coronary intervention (PCI).MethodsA total of 280 patients with AMI who underwent emergency PCI were selected from March 2018 to March 2019. A receiver operating characteristic (ROC) curve was used to analyze the optimal cut-off value of lactate on predicting CI-AKI after PCI. A multivariable logistic regression model was used to explore the significant predictors that might affect the occurrence of CI-AKI after univariate analysis. The primary endpoints were clinical outcomes including events: a combined endpoint of major adverse cardiovascular events, re-hospitalization due to heart failure, and worsening renal function. The Cox regression model was further used to analyze the predictors of the long-term prognosis after PCI.ResultsAmong the 280 patients, 64 patients (22.9%) developed CI-AKI after emergency PCI procedure. Multivariable logistic regression analysis revealed that baseline lactate level was the independent risk factor for the development of CI-AKI (OR, 3.657; 95% CI, 2.237–5.978; p<0.001). The area under the ROC curve for predicting CI-AKI of lactate was 0.786, and the optimum cut-off point of lactate was 3.02 mmol/L, with sensitivity of 65.6% and specificity of 85.2%. The incidence of primary endpoints in the high lactate group (lactate ≥3.02mmol/L) was significantly increased compared with the control group [26.3% (42/160) vs 15.8% (19/120), χ2=4.430, p=0.035]. Cox regression analysis also confirmed high lactate was an independent predictor for primary endpoint outcomes at 1-year follow-up (HR, 1.916; 95% CI, 1.118–3.285; p=0.018).ConclusionOur study demonstrates that baseline high lactate levels may be associated with an increased risk of CI-AKI and are the important predictors of long-term poor cardiorenal outcomes in AMI patients undergoing emergency PCI.

Safety and Efficacy of SGLT2 Inhibitors: A Multiple-Treatment Meta-Analysis of Clinical Decision Indicators.

To jointly assess the safety and effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiorenal outcomes and all-cause mortality in type 2 diabetes mellitus (T2DM) with or at high risk of cardiovascular disease (CVD). We performed a systematic review and network meta-analysis, systematically searching the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science databases up to September 2020. Primary outcomes were composite major adverse cardiovascular events (MACEs), hospitalization for heart failure, all-cause mortality and a composite renal outcome. We performed a random effects network meta-analysis estimating the pooled hazard ratio (HR), risk ratio and number needed to treat (NNT). Six trials evaluating empagliflozin, canagliflozin, dapagliflozin and ertugliflozin met the inclusion/exclusion criteria, which comprised 46,969 patients, mostly with established CVD. Pooled estimates (95% CI) of benefits of SGLT2i in terms of HR and NNT were as follows: for all-cause mortality, 0.85 (0.75, 0.97) and 58 (28, 368); for MACE, 0.91 (0.85, 0.97) and 81 (44, 271); for hospitalization for heart failure, 0.70 (0.62, 0.78) and 32 (20, 55); and for composite renal outcome, 0.61 (0.50, 0.74) and 20 (11, 44). Pooled estimates for serious adverse events were 0.92 (95% CI 0.89, 0.95). In patients with T2DM at cardiovascular risk, ertugliflozin is a less potent drug than empagliflozin, canagliflozin or dapagliflozin to prevent cardiorenal events and all-cause mortality. In addition, our data endorse that empagliflozin is the best treatment option among SGLT2i for this type of patient, but the evidence is not consistent enough.

Effect of empagliflozin on cardiorenal outcomes and mortality according to body mass index: A subgroup analysis of the EMPA-REG OUTCOME trial with a focus on Asia.

AimTo investigate whether the cardiorenal benefits of the sodium‐glucose co‐transporter‐2 inhibitor empagliflozin are affected by body mass index (BMI) in type 2 diabetes patients with established cardiovascular (CV) disease, including Asians.MethodsIn this exploratory analysis of the EMPA‐REG OUTCOME trial, we used Cox regression to evaluate the effects of empagliflozin on all‐cause mortality, hospitalization for heart failure (HHF) or CV death, and incident or worsening nephropathy by baseline BMI category.ResultsOf the 7020 participants (1517 Asians [21.6%]), 934 (13.3%), 2465 (35.1%) and 3621 (51.6%) had a BMI of less than 25, 25 to less than 30, and 30 kg/m2 or higher, respectively. Overall, hazard ratios for empagliflozin versus placebo for all‐cause mortality, HHF or CV death, and incident or worsening nephropathy were 0.68 (95% CI 0.57, 0.82), 0.66 (0.55, 0.79) and 0.61 (0.53, 0.70), respectively, and were consistent across BMI categories (P values for interaction between treatment and BMI were .6772, .3087 and .6265, respectively). Results were similar in Asians using these BMI categories and categories of less than 24, 24 to less than 28, and 28 kg/m2 or higher.ConclusionEmpagliflozin reduced cardiorenal and mortality risk regardless of BMI at baseline, including in Asians with a lower BMI.

319-OR: Effects of Empagliflozin on Markers of Liver Steatosis and Fibrosis and Their Relation to Cardiorenal Outcomes in the EMPA-REG OUTCOME Trial

Treatment with empagliflozin (EMPA) improves cardiorenal outcomes, but also reduces liver fat content in individuals with both type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Thus, we evaluated the effects of EMPA vs. placebo (PLAC) on NAFLD-related steatosis and fibrosis risks and the relation of fibrosis risk to cardiorenal outcomes in individuals with T2D in the randomized controlled trial EMPA-REG OUTCOME. The trial enrolled 7020 people with T2D and cardiovascular disease for treatment with 10 or 25 mg daily EMPA or PLAC. Post-hoc, we derived the Dallas Steatosis Index (DSI) and NAFLD fibrosis score (NFS) to assess the risks of steatosis and fibrosis from baseline to week 164 of treatment, respectively. Changes from baseline in DSI and NFS were examined by mixed model repeated measures analysis, and effects on cardiovascular and all-cause death, hospitalization for heart failure and nephropathy by Cox regression across fibrosis risk categories. At baseline, 72% of participants had high risk of steatosis (DSI probability of &amp;gt;50%; mean, 0.74±0.00 and 23% had high risk of advanced fibrosis (NFS &amp;gt;0.675; mean, 1.26±0.01. Overall DSI (logit) decreased with EMPA compared to PLAC at all timepoints (p&amp;lt;0.001; placebo-corrected change -0.13±0.03 at 164 weeks) and also in the subgroup at high steatosis risk. Despite comparable overall NFS over time in EMPA and PLAC groups, NFS was lower in the EMPA-treated advanced fibrosis subgroup at weeks 12, 28 and 108 (placebo-corrected changes -0.08±0.03, -0.11±0.03 and -0.11±0.04, all timepoints p&amp;lt;0.01 vs. PLAC). Of note, effects of EMPA on cardiorenal and mortality outcomes were consistent across high and low fibrosis risk groups. In conclusion, EMPA may attenuate NAFLD-related steatosis as well as fibrosis progression specifically in individuals at risk of advanced fibrosis, and improves cardiorenal outcomes as well as all-cause mortality independent of fibrosis risk category. Disclosure S. Kahl: None. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. C. Wanner: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Speaker’s Bureau; Self; Eli Lilly and Company. E. Schueler: None. S. E. Inzucchi: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Esperion, Merck &amp; Co., Inc., Novo Nordisk. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH.

783-P: Cardiorenal Outcomes with Ertugliflozin by Baseline (BL) Glucose-Lowering Agent (GLA): An Analysis from VERTIS CV

VERTIS CV was the cardiovascular (CV) outcome trial for the SGLT2 inhibitor ertugliflozin, conducted in patients with type 2 diabetes (T2D) and atherosclerotic CV disease. In the overall population, ertugliflozin was noninferior to placebo for major adverse CV events (MACE). Although superiority for the composite endpoint of CV death or hospitalization for heart failure (HHF) and the renal composite (that included doubling of serum creatinine from BL) were not met, the prespecified secondary objective of HHF showed a 30% risk reduction and a prespecified exploratory renal composite (sustained ≥40% decrease in eGFR from BL, dialysis/transplantation, or renal death) showed improved kidney outcomes. This analysis assessed cardiorenal endpoints of VERTIS CV by BL GLA.Among 8246 patients in VERTIS CV, at BL 6292 (76%) used metformin, 3900 (47%) insulin, 3390 (41%) sulfonylureas (SU), and 911 (11%) dipeptidyl peptidase-4 inhibitors (DPP4i), alone or in combination therapy (67% used >1 GLA at BL). For each of the GLAs, metformin, insulin, SU, and DPP4i, no significant differences were observed for cardiorenal outcomes by BL use (yes, no) of the GLA (FIGURE; all interaction P values >0.05). Cardiorenal outcomes were generally similar across the BL GLA subgroups.In VERTIS CV, the effects of ertugliflozin on cardiorenal outcomes in patients with T2D were generally consistent regardless of BL GLA.View largeDownload slideView largeDownload slide DisclosureB. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. I. Gantz: Employee; Self; Merck & Co., Inc. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. W. J. Shih: None. J. Liu: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None.FundingMerck Sharp & Dohme Corp

791-P: Ertugliflozin in Older Patients with Type 2 Diabetes (T2D): An Analysis from VERTIS CV

VERTIS CV was a cardiovascular (CV) outcome trial of ertugliflozin vs. placebo in patients (pts) with T2D and atherosclerotic CV disease. Here we analyzed the cardiorenal outcomes and safety of ertugliflozin in older pts.Among 8238 pts randomized and treated with ertugliflozin 5 mg, 15 mg, or placebo, 4093 (49.7%) were <65 yrs, 4145 (50.3%) were ≥65 yrs, with 903 (11.0%) ≥75 yrs. Baseline characteristics were similar across treatment groups within each age group; mean eGFR was lower in older pts (82.2, 69.9, and 63.6 mL/min/1.73m2 for pts <65, ≥65, and ≥75 yrs, respectively). Cardiorenal outcomes for ertugliflozin vs. placebo did not differ between pts ≥65 and <65 yrs, with interaction P values >0.05 for all outcomes assessed (FIGURE). The incidences of adverse events (AEs), serious AEs (including deaths), and discontinuations due to an AE were higher in older vs. younger pts, but generally similar across treatment groups in pts ≥65 and ≥75 yrs. The incidence of renal-related AEs was similar across treatment groups in younger and older pts. The incidences of genital mycotic infection and urinary tract infection were higher with ertugliflozin vs. placebo in older pts. The incidences of hypovolemia AEs with ertugliflozin vs. placebo in pts ≥65 was 5.3% vs. 4.5% and in pts ≥75 yrs was 6.9% vs. 5.8%.Cardiorenal outcomes were similar in pts ≥65 and <65 yrs. Ertugliflozin was generally well tolerated in pts ≥65 and ≥75 yrs.View largeDownload slideView largeDownload slide DisclosureR. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. I. A. Adamsons: Employee; Self; Merck Sharp & Dohme Corp. D. Lawrence: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Becton, Dickinson and Company. W. J. Shih: None. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. M. N. Essex: Employee; Self; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc. P. L. S. Jones: Employee; Self; Pfizer Inc. J. Liu: Employee; Self; Merck Sharp & Dohme Corp.FundingMerck Sharp & Dohme Corp

410-P: Therapeutic Profile from the Canadian REgistry of Chronic Kidney Disease in Diabetes Outcomes (CREDO) Study

Background: Chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) is associated with an elevated risk of end stage renal disease, cardiovascular disease, hospitalizations, and death. As treatment options for patients with T2D and CKD continue to expand, an analysis of the current distribution of therapies and cardiorenal outcomes is warranted. Methods: The CREDO study was a retrospective cohort study of adults with T2D and CKD, who were seen by an endocrinologist in 2019. Data were retrieved from the Canadian LMC Diabetes Registry, one of the largest endocrine practice groups globally. A subgroup analysis of the CREDO study was performed to describe patients using an ACEi/ARB or an emerging renal therapy (MRA, SGLT2i or GLP-1 RA) for ≥ 6 months, or none of the therapies. Results: In this cohort of 11,816 patients with CKD and T2D, ACEi/ARBs were the most frequently used medication, followed by SGLT2i. Expectantly, a greater number of patients using an ACEi/ARB or MRA had hypertension, and more patients using GLP-1 RA suffered from obesity compared to other subgroups. Patients using ≥ 1 of the therapies showed higher mean eGFR and body weight, similar HbA1c and uACR, and a lower mean LDL-C compared to patients not using any therapy (Table 1). Conclusion: These descriptive findings improve our understanding of the current landscape and treatment patterns amongst patients with CKD and T2D in Canada. Disclosure L. Chu: None. M. Fuller: Employee; Self; Bayer Inc. K. Jervis: Employee; Self; Bayer Inc. S. K. Bhogal: None. A. Abitbol: Advisory Panel; Self; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk Canada Inc., Sanofi, Research Support; Self; Bayer Inc., Speaker’s Bureau; Self; Amgen Canada, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Funding Bayer Inc. (21190)

796-P: Cardiorenal Outcomes with Ertugliflozin by Baseline Cardiorenal Medications: An Analysis from VERTIS CV

VERTIS CV was a placebo-controlled cardiovascular (CV) outcome trial evaluating the SGLT2 inhibitor ertugliflozin. The aim of current analyses was to examine pre-specified CV and kidney outcomes by Cox proportional hazard assessment according to use of renin-angiotensin-aldosterone system inhibitors (RAASi), diuretics, and mineralocorticoid receptor antagonists (MRA) at baseline. Among 8246 randomized patients, at baseline 6686 (81%) were treated with RAASi, 3542 (43%) with diuretics, including 1252 (15%) with loop diuretics, and 674 (8%) with MRA. No significant interactions were observed for cardiorenal outcomes by baseline use of RAASi or MRA (Pinteraction > 0.05 for all; FIGURE). Nominally significant interactions for first event of hospitalization for heart failure (HHF) and HHF/CV death were observed with baseline use of diuretics, including loop diuretics, with an increased benefit of ertugliflozin vs. placebo. In VERTIS CV, baseline use of diuretics, including loop diuretics, appeared to be associated with greater benefit of ertugliflozin on first HHF and HHF/CV death, with no modification of effect based on baseline use of RAASi or MRA.View largeDownload slideView largeDownload slide DisclosureD. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. I. Gantz: Employee; Self; Merck & Co., Inc. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. U. Masiukiewicz: Employee; Self; Pfizer Inc. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. W. J. Shih: None. M. Maldonado: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None.

FC 090EFFECTS OF FINERENONE ON CARDIORENAL OUTCOMES IN BLOOD PRESSURE SUBGROUPS IN PATIENTS WITH CKD AND T2D

Abstract Background and Aims Finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA) that significantly reduced the risk of adverse kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the FIDELIO-DKD trial. In phase II studies, finerenone had modest effects on office blood pressure (BP) compared with the steroidal MRA spironolactone. We report an analysis of the relationship between baseline and changes in office systolic BP (SBP) and outcomes with finerenone in the FIDELIO-DKD trial. Method In FIDELIO-DKD, 5734 patients were randomised 1:1 to oral finerenone or placebo. Patients with T2D, urine albumin-to-creatine ratio (UACR) ≥30–&amp;lt;300 mg/g, estimated glomerular filtration rate (eGFR) ≥25–&amp;lt;60 ml/min/1.73 m2 and a history of diabetic retinopathy, or UACR ≥300–≤5000 mg/g and eGFR ≥25–&amp;lt;75 ml/min/1.73 m2, and treated with optimised renin–angiotensin system blockade were eligible. The primary endpoint was time to kidney failure, sustained eGFR decline ≥40% from baseline, or renal death. The key secondary endpoint was time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for heart failure. A Cox proportional hazards model was used to investigate the relationship between treatments and efficacy outcomes adjusted for baseline SBP and change in SBP from baseline to month 4. Results A total of 5669 patients with available baseline SBP data were analysed. At baseline, the mean SBP and diastolic BP were 138.0 and 75.8 mmHg, respectively. Patients treated for hypertension at baseline received an average of 3.3 antihypertensive therapies. The study population was stratified by quartiles (Q) of SBP at baseline: ≤128.7 mmHg (Q1); &amp;gt;128.7–≤138.3 mmHg (Q2); &amp;gt;138.3–≤148.0 mmHg (Q3); and &amp;gt;148.0 mmHg (Q4). Patients in higher SBP categories tended to be older, with higher median UACR, but similar mean eGFR at baseline. Effects of finerenone, estimated as hazard ratios (HRs), were consistent across the quartiles for the primary endpoint (HR [95% CI]: Q1, 0.87 [0.66–1.15]; Q2, 0.76 [0.59–0.98]; Q3, 0.81 [0.65–1.02]; Q4, 0.86 [0.70–1.07]; p-value for interaction=0.87) and the key secondary endpoint (HR [95% CI]: Q1, 0.95 [0.69–1.29]; Q2, 0.81 [0.60–1.10]; Q3, 0.79 [0.60–1.03]; Q4, 0.91 [0.70–1.18]; p-value for interaction=0.78) (Figure). Finerenone treatment resulted in a modest reduction in SBP; over the duration of the trial, overall mean difference in SBP between treatment groups was –2.7 mmHg. Maximum differences in SBP between finerenone and placebo were observed at month 4; the mean change in SBP from baseline to month 4 across SBP quartiles were: Q1: 4.99 and 9.01 mmHg; Q2: –0.85 and 2.43 mmHg; Q3: –5.63 and –2.40 mmHg; Q4: –11.76 and –6.44 mmHg, for finerenone and placebo, respectively. Adjusting for baseline SBP and SBP change to month 4 resulted in small changes in treatment effect for the primary endpoint and the key secondary endpoint, with only slightly increased HRs for treatment compared with the unadjusted primary analysis (primary endpoint: HR: 0.85 vs 0.82; key secondary endpoint: HR: 0.90 vs 0.86) and no strong indication of an interaction between treatment and SBP. Conclusion In FIDELIO-DKD, a small proportion of the effect of finerenone on cardiorenal outcomes can be attributed to BP. However, most of the effect appears to be via BP-independent mechanisms. (Funded by Bayer AG; FIDELIO-DKD ClinicalTrials.gov number, NCT02540993)

Abstract 066: Association Between Nocturnal Blood Pressure Dipping Magnitude And Chronic Kidney Disease Risk Among Patients With Controlled Office Blood Pressure

Although abnormal diurnal blood pressure (BP) patterns are associated with adverse cardiorenal outcomes, their risks are yet unquantified by BP dipping magnitude. We assessed chronic kidney disease risk across nocturnal BP dipping spectrum among patients with controlled hypertension without prior advanced kidney disease. Ambulatory BP measurements were collected from 995 middle-aged patients with controlled office BP (&lt;140/90 mmHg). The magnitude of dipping was defined as the difference between daytime and nighttime systolic BP divided by daytime systolic BP. Accordingly, patients were categorized as extreme-dipper (≥20%) dipper (10-&lt;20%), non-dipper (0-&lt;10%), or reverse-dipper (&lt;0%). We cross-sectionally analyzed continuous and categorical associations of dipping with albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) and decreased estimated glomerular filtration rate (&lt;60 ml/min/1.73m 2 ), adjusting for office/ambulatory BP, antihypertensive class, body mass index, total cholesterol, fasting glucose, socioeconomic status, and health behavior. The participants (mean age 60.2 years; 52.9% male) consisted of 13.5% (134 of 995) extreme-dippers, 43.1% (429 of 995) dippers, 34.7% (345 of 995) non-dippers, and 8.7% (87 of 995) reverse-dippers. In reference to dippers, odds ratios (95% confidence interval) for albuminuria were 1.73 (1.04-2.60) in reverse-dippers, 1.67 (1.20-2.32) in non-dippers, and 0.62 (0.38-1.04) in extreme-dippers; this reflects significantly lower risk (0.77, 0.55-0.95) per 10% dipping. Likewise, persons presenting reduced and reverse-directional dipping were at higher risk for decreased estimated glomerular filtration rate: reverse-dippers 2.02 (1.06-3.84); non-dippers 1.98 (1.07-3.08); extreme-dippers 0.69 (0.20-1.17), with lower risk (0.74, 0.22-1.02) per every 10%. In short, monitoring nocturnal BP patterns may identify chronic kidney disease risk otherwise overlooked based on office BP.