Finerenone Reduces Risk of Incident Heart Failure in Patients With Chronic Kidney Disease and Type 2 Diabetes: Analyses from the FIGARO-DKD Trial

Background: Chronic kidney disease (CKD) and type 2 diabetes (T2D) are independently associated with heart failure (HF), a leading cause of morbidity and mortality. In the FIDELIO-DKD and FIGARO DKD trials, finerenone (a selective, nonsteroidal mineralocorticoid receptor antagonist) improved cardiovascular outcomes in patients with albuminuric CKD and T2D. These prespecified analyses from FIGARO-DKD assessed the impact of finerenone on clinically important HF outcomes. Methods: Patients with T2D and albuminuric CKD (urine albumin-to-creatinine ratio [UACR] ≥30 to <300 mg/g and estimated glomerular filtration rate [eGFR] ≥25 to ≤90 ml/min/1.73 m 2 , or UACR ≥300 to ≤5000 mg/g and eGFR ≥60 ml/min/1.73 m 2 ,), without symptomatic HF with reduced ejection fraction, were randomized to finerenone or placebo. Time-to-first event outcomes included: new-onset HF (first hospitalization for HF [HHF] in patients without a history of HF at baseline); cardiovascular death or first HHF; HF-related death or first HHF; first HHF; cardiovascular death or total (first or recurrent) HHF; HF-related death or total HHF; and total HHF. Outcomes were evaluated in the overall population and in prespecified subgroups categorized by baseline HF history (as reported by the investigators). Results: Overall, 7352 patients were included in these analyses; 571 (7.8%) had a history of HF at baseline. New-onset HF was significantly reduced with finerenone versus placebo (1.9% versus 2.8%; hazard ratio [HR], 0.68 [95% CI 0.50-0.93]; P =0.0162). In the overall population, the incidences of all HF outcomes analyzed were significantly lower with finerenone than placebo, including a 18% lower risk of cardiovascular death or first HHF (HR, 0.82 [95% CI 0.70-0.95]; P =0.011), a 29% lower risk of first HHF (HR, 0.71 [95% CI 0.56-0.90]; P =0.0043) and a 30% lower rate of total HHF (rate ratio, 0.70 [95% CI, 0.52- 0.94]). The effects of finerenone on improving HF outcomes were not modified by a history of HF. The incidence of treatment-emergent adverse events was balanced between treatment groups. Conclusions: The results from these FIGARO-DKD analyses demonstrate that finerenone reduces new-onset HF and improves other HF outcomes in patients with CKD and T2D, irrespective of a history of HF.

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Finerenone and Cardiovascular Outcomes in Patients with Chronic Kidney Disease and Type 2 Diabetes

Circulation ◽

10.1161/circulationaha.120.051898 ◽

2020 ◽

Cited By ~ 1

Author(s):

Gerasimos Filippatos ◽

Stefan D. Anker ◽

Rajiv Agarwal ◽

Bertram Pitt ◽

Luis M. Ruilope ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Renin Angiotensin System ◽

Mineralocorticoid Receptor Antagonist ◽

Angiotensin System ◽

Renin Angiotensin ◽

History Of

Background: The FIDELIO-DKD trial evaluated the effect of the nonsteroidal, selective mineralocorticoid receptor antagonist finerenone on kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) with optimized renin-angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and CV outcomes. We report the effect of finerenone on individual CV outcomes and in patients with and without history of atherosclerotic CV disease (CVD). Methods: This randomized, double-blind, placebo-controlled trial included patients with T2D and urine albumin-to-creatinine ratio 30-5000 mg/g and an estimated glomerular filtration rate (eGFR) ≥25-<75 mL/min/1.73 m 2 , treated with optimized renin-angiotensin system blockade. Patients with a history of heart failure with reduced ejection fraction were excluded. Patients were randomized 1:1 to receive finerenone or placebo. The composite CV outcome included time to CV death, myocardial infarction, stroke, or hospitalization for heart failure. Prespecified CV analyses included analyses of the components of this composite and outcomes according to CVD history at baseline. Results: Between September 2015 and June 2018, 13,911 patients were screened and 5674 were randomized; 45.9% of patients had CVD at baseline. Over a median follow-up of 2.6 years (interquartile range, 2.0-3.4 years), finerenone reduced the risk of the composite CV outcome compared with placebo (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.99; P=0.034), with no significant interaction between patients with and without CVD (HR, 0.85; 95% CI, 0.71-1.01 in patients with a history of CVD; HR, 0.86; 95% CI, 0.68-1.08 in patients without a history of CVD; P-value for interaction, 0.85). The incidence of treatment-emergent adverse events was similar between treatment arms, with a low incidence of hyperkalemia-related permanent treatment discontinuation (2.3% with finerenone vs 0.8% with placebo in patients with CVD and 2.2% with finerenone vs 1.0% with placebo in patients without CVD). Conclusions: Among patients with CKD and T2D, finerenone reduced incidence of the composite CV outcome, with no evidence of differences in treatment effect based on pre-existing CVD status. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02540993 (Funded by Bayer AG)

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Effects of SGLT2 inhibitors on cardiovascular death and all-cause death in patients with type 2 diabetes and chronic kidney disease: an updated meta-analysis including the SCORED trial

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/20420188211044945 ◽

2021 ◽

Vol 12 ◽

pp. 204201882110449

Author(s):

Li-Min Zhao ◽

Ze-Lin Zhan ◽

Mei Qiu

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Meta Analysis ◽

Cardiovascular Death ◽

Sglt2 Inhibitors ◽

Ckd Progression ◽

Meta Analyses

Background: The effects of sodium-glucose transporter 2 (SGLT2) inhibitors on cardiovascular death (CV death) and all-cause death (AC death) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) are currently under intensive investigation. We intended to conduct an updated meta-analysis including the SCORED trial to evaluate the effects of SGLT2 inhibitors on death and cardiorenal events in this vulnerable population. Methods: Cardiorenal outcome trials of SGLT2 inhibitors were included. Primary outcomes were CV death and AC death, while secondary outcomes were hospitalization for heart failure (HHF), myocardial infarction (MI), CKD progression, cardiovascular death or hospitalization for heart failure (CV death or HHF), major adverse cardiovascular events (MACE), and stroke. Meta-analysis was conducted for each outcome. Results: Eight trials were included for meta-analysis. Compared with placebo, SGLT2 inhibitors significantly lowered the risk of CV death (HR = 0.86, 95% CI = 0.75–0.98), AC death (HR = 0.87, 95% CI = 0.79–0.96), HHF (HR = 0.64, 95% CI = 0.56–0.74), MI (HR = 0.76, 95% CI = 0.65–0.89), CKD progression (HR = 0.62, 95% CI = 0.54–0.72), and CV death or HHF (HR = 0.73, 95% CI = 0.67–0.80). No heterogeneity existed in the above meta-analyses (all I2 values = 0%), whereas moderate heterogeneity existed in the meta-analyses for MACE and stroke (I2 = 31.6% and 44.5%, respectively). Conclusions: Our findings suggest that SGLT2 inhibitors versus placebo significantly lower death, heart failure, renal failure, and MI events in patients with T2D and CKD. Head-to-head trials are needed to examine the possible differences in the effects of various gliflozins on MACE and stroke.

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Dapagliflozin and new-onset type 2 diabetes in patients with chronic kidney disease or heart failure: pooled analysis of the DAPA-CKD and DAPA-HF trials

The Lancet Diabetes & Endocrinology ◽

10.1016/s2213-8587(21)00295-3 ◽

2021 ◽

Author(s):

Peter Rossing ◽

Silvio E Inzucchi ◽

Priya Vart ◽

Niels Jongs ◽

Kieran F Docherty ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Pooled Analysis ◽

Onset Type ◽

New Onset

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Cardiovascular and mortality benefits of sodium–glucose co-transporter-2 inhibitors in patients with type 2 diabetes mellitus: CVD-Real Catalonia

Cardiovascular Diabetology ◽

10.1186/s12933-021-01323-5 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Jordi Real ◽

Bogdan Vlacho ◽

Emilio Ortega ◽

Joan Antoni Vallés ◽

Manel Mata-Cases ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Propensity Score ◽

Lower Risk ◽

Previous History ◽

Incidence Rates ◽

Real World Data

Abstract Background Evidence from prospective cardiovascular (CV) outcome trials in type 2 diabetes (T2DM) patients supports the use of sodium–glucose co-transporter-2 inhibitors (SGLT2i) to reduce the risk of CV events. In this study, we compared the risk of several CV outcomes between new users of SGLT2i and other glucose-lowering drugs (oGLDs) in Catalonia, Spain. Methods CVD-REAL Catalonia was a retrospective cohort study using real-world data routinely collected between 2013 and 2016. The cohorts of new users of SGLT2i and oGLDs were matched by propensity score on a 1:1 ratio. We compared the incidence rates and hazard ratio (HR) for all-cause death, hospitalization for heart failure, chronic kidney disease, and modified major adverse CV event (MACE; all-cause mortality, myocardial infarction, or stroke). Results After propensity score matching, 12,917 new users were included in each group. About 27% of users had a previous history of CV disease. In the SGLT2i group, the exposure time was 60% for dapagliflozin, 26% for empagliflozin and 14% for canagliflozin. The use of SGLT2i was associated with a lower risk of heart failure (HR: 0.59; 95% confidence interval [CI] 0.47–0.74; p < 0.001), all-cause death (HR = 0.41; 95% CI 0.31–0.54; p < 0.001), all-cause death or heart failure (HR = 0.55; 95% CI 0.47–0.63; p < 0.001), modified MACE (HR = 0.62; 95% CI 0.52–0.74; p < 0.001), and chronic kidney disease (HR = 0.66; 95% CI 0.54–0.80; p < 0.001). Conclusions In this large, retrospective observational study of patients with T2DM from a Catalonia, initiation of SGLT-2i was associated with lower risk of mortality, as well as heart failure and CKD.

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Metformin Use and Clinical Outcomes Among Patients With Diabetes Mellitus With or Without Heart Failure or Kidney Dysfunction

Circulation ◽

10.1161/circulationaha.119.040144 ◽

2019 ◽

Vol 140 (12) ◽

pp. 1004-1014 ◽

Cited By ~ 17

Author(s):

Brian A. Bergmark ◽

Deepak L. Bhatt ◽

Darren K. McGuire ◽

Avivit Cahn ◽

Ofri Mosenzon ◽

...

Keyword(s):

Diabetes Mellitus ◽

Heart Failure ◽

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Type 2 Diabetes Mellitus ◽

Kidney Disease ◽

Cardiovascular Death ◽

Inverse Probability ◽

All Cause Mortality

Background: Metformin is first-line therapy for type 2 diabetes mellitus, although its effects on the cardiovascular system are unproved. Methods: In this post hoc analysis, patients in SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) with baseline biomarker samples (n=12 156) were classified as ever versus never taking metformin during the trial period. Associations between metformin exposure and outcomes were estimated with inverse probability of treatment weighting Cox modeling for the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, as well as cardiovascular death and all-cause mortality, with biomarkers included as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models. Results: Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) had at least moderate chronic kidney disease (estimated glomerular filtration rate ≤45 mL·min −1 ·1.73 m −2 ). Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting, 0.92 [95% CI, 0.76–1.11]) but lower risk of all-cause mortality (hazard ratio for inverse probability of treatment weighting, 0.75 [95% CI, 0.59–0.95]). There was no significant relationship between metformin use and these end points in patients with prior heart failure or moderate to severe chronic kidney disease. Conclusions: In a cohort of 12 156 patients with type 2 diabetes mellitus and high cardiovascular risk, metformin use was associated with lower rates of all-cause mortality, including after adjustment for clinical variables and biomarkers, but not lower rates of the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01107886.

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Effects of Canagliflozin on Cardiovascular, Renal, and Safety Outcomes in Participants With Type 2 Diabetes and Chronic Kidney Disease According to History of Heart Failure: Results From the CREDENCE Trial

American Heart Journal ◽

10.1016/j.ahj.2020.12.008 ◽

2020 ◽

Author(s):

Ashish Sarraju ◽

JingWei Li ◽

Christopher P. Cannon ◽

Tara I. Chang ◽

Rajiv Agarwal ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Safety Outcomes ◽

History Of

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Evidence-based use of newer agents in type 2 diabetes

Journal of Prescribing Practice ◽

10.12968/jprp.2021.3.6.224 ◽

2021 ◽

Vol 3 (6) ◽

pp. 224-234

Author(s):

David Morris

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Glycaemic Control ◽

Side Effect ◽

Atherosclerotic Cardiovascular Disease ◽

Disease Case ◽

The Impact

The DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors are newer agents for glycaemic control in type 2 diabetes that can offer additional health benefits. All three treatments carry a low risk of hypoglycaemia. GLP-1 RAs and SGLT-2 inhibitors are associated with weight loss and DPP-4 inhibitors are weight neutral. The GLP-1 RAs and SGLT-2 inhibitors offer protection against cardiovascular events. SGLT-2 inhibitors are the agents of choice to add on to metformin for glycaemic control in chronic kidney disease and heart failure, with GLP-1 RAs an alternative to be considered if SGLT-2 inhibitors are poorly tolerated or contraindicated. DPP-4 inhibitors are very well tolerated. Gastrointestinal side-effects can be problematic with GLP-1 RAs though frequently these settle with time. Genital thrush is a common side-effect with SGLT-2 inhibitors and diabetic ketoacidosis is a rare but serious side-effect. It is important that healthcare professionals with responsibility in diabetes familiarise themselves with these treatments in order to know when and how to safely and effectively deploy them. The selection of newer agents should be based on careful assessment of individual circumstances. Overall, the standpoint has shifted from a largely glucocentric approach to one considering the impact of treatments on weight, risk of hypoglycaemia, and co-morbidities (notably atherosclerotic cardiovascular disease, heart failure and chronic kidney disease). Case histories are used in the article to illustrate the pragmatic use of these agents.

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194SGLT-2 inhibitors versus GLP-1 receptor agonists and risk of mortality, chronic kidney disease and hospitalisation for heart failure in patients with type 2 diabetes

European Heart Journal ◽

10.1093/eurheartj/ehz747.0054 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

C Noergaard ◽

C Torp-Pedersen ◽

P Vestergaard ◽

N Wong ◽

T Gerds ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Lower Risk ◽

Cox Regression ◽

Receptor Agonists ◽

All Cause Mortality ◽

The Absolute

Abstract Background Two promising classes of second-line glucose-lowering drugs, the sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), have both been shown to lower the risk of cardiovascular (CV) outcomes in patients with type 2 diabetes, however no head-to-head comparisons exist. Purpose The aim of this study was to examine the risk of CV and all-cause mortality, incident chronic kidney disease (CKD) and hospitalisation for heart failure (HF) in association with SGLT-2i versus GLP-1RA use. Methods New users of SGLT-2i and GLP-1RA, with no prior use of drugs from the comparison class, were identified between 2012–2016, using individual-level linkage of Danish nationwide registries. The absolute risk of CV was calculated using the Aalen-Johansen Estimator with non-CV mortality as competing risk. The hazard ratios (HR) of CV and all-cause mortality, incident CKD and hospitalisation for HF were estimated using Cox regression and adjusted for age, sex, diabetes duration and other outcome specific risk factors. Results The study included a total of 8,304 SGLT-2i users (median age: 63 years [interquartile range (IQR): 54–70], males: 63%, dapagliflozin: 60.5%, empagliflozin: 36.5%) and 13,318 GLP-1RA users (median age: 60 years [IQR: 50–68], males: 54%, liraglutide: 97.4%) with a median follow-up time of 2.0 [(IQR): 1.5–2.9] years and 3.6 [IQR: 2.1–5.0] years, respectively. At baseline 29% of SGLT-2i and 30% of GLP-1RA users had CV disease. The absolute risks are shown in Figure 1. Compared with GLP-1RA, initiation of SGLT-2i was in adjusted analyses associated with a lower risk of CV mortality (HR: 0.49 [confidence interval (CI): 0.37–0.65]), all-cause mortality [HR: 0.79 [CI: 0.68–0.93], incident CKD (HR: 0.42 [CI: 0.34–0.53] and hospitalisation for HF (HR: 0.68 [CI: 0.59–0.78]). Figure 1 Conclusion SGLT-2i use was associated with a significantly lower risk of CV and all-cause mortality, incident CKD and hospitalisation for HF in comparison with GLP-1RA use. Acknowledgement/Funding The Danish Heart Foundation (18-R125-A8381-22082)

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