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Background A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). Methods We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease). Results GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79–0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67–0.82, P < 0.001). Conclusions GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.

Background It has been suggested that sodium–glucose cotransporter 2 (SGLT-2) inhibitors reduce the cardiorenal risk in patients with type 2 diabetes (T2D). The purpose of this study is to provide an update of all large cardiovascular outcome trials (CVOTs) with SGLT-2 inhibitors to assess their cardiorenal efficacy in patients with and without T2D. Methods An electronic search up to 30 September 2021 was conducted in PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. to determine eligible trials. We included CVOTs comparing any SGLT-2 inhibitor with placebo, reporting desired cardiovascular or renal outcomes and with a follow-up duration of at least 6 months. Results Eleven CVOTs, with data from five SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) and 77,541 participants, were included. In the overall analysis, the risk of the composite CV mortality or hospitalization for heart failure (HF) was reduced by 23% (HR = 0.77, 95% CI 0.73–0.82, P < 0.001) compared with placebo, with not significant heterogeneity (I 2  = 26%, P = 0.20), and irrespective of the presence of T2D (P for interaction = 0.81) and age (> 65 vs ≤ 65 years, P for interaction = 0.78). The risk of CV mortality, total mortality and hospitalization for HF was significantly reduced by 16%, 13%, and 32%, respectively; similarly, the risk of the composite renal outcome was reduced by 35% (HR = 0.65, 95% CI 0.56–0.75), with moderate heterogeneity (I 2  = 32%). In the analysis of 6 CVOTs reporting the data, the risk of major cardiovascular events (MACE) was reduced by 12%, with low heterogeneity (I 2  = 21.2%, P = 0.19) and irrespective of the presence of established CV disease at baseline (P for interaction = 0.46). Conclusions Therapy with SGLT-2 inhibitors in patients with cardiometabolic and renal diseases results in a sustained to moderate reduction of the composite CV death or hospitalization for HF, robust reduction of HF and renal outcomes, moderate reduction of CV mortality, total mortality and MACE.

Background Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. Methods An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. Results The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P < 0.001), with significant heterogeneity between studies (I 2  = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta =  − 0.298, P = 0.007), with significant heterogeneity (I 2  = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta =  − 0.531, R 2  = 100%), without heterogeneity (I 2  = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death. Conclusions The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R 2  = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.

Background: Acute kidney injury (AKI) is notoriously associated with adverse outcomes and mortality in patients with acute coronary syndrome. However, using the general cutoff of 0.3 mg/dL increase from baseline for AKI definition and neglecting smaller changes could result in late diagnosis and impaired prognostication. We aimed to assess the prognostic utility of minor creatinine changes (“twitches”) in a large cohort of ST-segment-elevation myocardial infraction (STEMI) patients and determine an optimal cutoff value for future use. Methods: This retrospective analysis of a prospective database included 2,933 consecutive patients admitted with STEMI between 2008 and 2022 to the cardiac intensive care unit of a large tertiary medical center. Renal function was assessed upon admission and at least once daily thereafter. Creatinine twitches were defined as a change from baseline to peak creatinine level of between 0.1 and 0.3 mg/dL. Thirty-day and 1-year mortality rates were the main outcomes. Results: From the study cohort (mean age 62 ± 13, 19% female, 16% with prior MI), 551 (19%) subjects presented creatinine twitches and 254 (9%) developed AKI. Compared to subjects with stable creatinine, those with creatinine twitches had higher rates of 30-day (1% vs. 2.5%, p < 0.001) and 1-year (1.6% vs. 4.4%, p < 0.001) mortality. In cox multivariate analysis, creatinine twitches had a higher hazard for 1-year mortality (HR 1.87, 95% CI: 1.1–3.2) and only a trend for 30-day mortality (HR 1.52, 95% CI: 0.96–2.96). Creatinine rise had an area under the curve of 0.780 (95% CI: 0.73–0.83) for 1-year mortality prediction, and 0.12 mg/dL was the optimal cutoff for prediction, with a sensitivity of 71%, specificity of 79%. In subgroup multivariate analysis, only twitches that did not resolve during hospitalization had higher hazard for mortality (HR 3.42, 95% CI: 1.65–7.05). Conclusion: Serum creatinine twitches are common among STEMI patients and correlate with elevated 30-day and 1-year mortality. These seemingly minor changes should prompt renal protective strategies for early detection and treatment.

Background The 2022 Canadian Cardiovascular Society (CCS) cardiorenal guideline provided clinical recommendations on sodium-glucose co-transport 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) use. Since then, additional trials of relevance for SGLT2i have been published. This update re-evaluates the clinical recommendations for using SGLTi and their indirect comparison with existing evidence on GLP-1RA as compared to the standard of care to reduce cardiorenal morbidity and mortality. Methods We updated our existing search and screening of the literature from September 2021 to April 2023 for randomized controlled trials of SGLT2i and GLP-1RA with placebo control. We conducted risk of bias assessment, data extraction and updated our meta-analysis of studies with similar interventions and components. The certainty of the evidence was determined using GRADE. Results Evidence from three new trials and additional results from an updated existing trial on SGLT2i met our inclusion criteria after an updated search. Across all the included studies, the total sample size was 151,023 adults, with 90,943 in SGLT2i trials and 60,080 in GLP-1 RA trials. The mean age ranged from 59.9 to 68.4 years. Compared with standard care, the use of SGLT2i and GLP-1 RA showed significant reductions in the outcomes of cardiovascular (CV) mortality (14% & 13%), any-cause mortality (12% & 12%), major adverse CV events (MACE) (11% & 14%), heart failure (HF) hospitalization (30% & 9%), CV death or HF hospitalization (23% & 11%), and kidney composite outcome (32% & 22%). In participants with T2D, both classes demonstrated significant cardiorenal protection. But, only GLP-1RA showed a reduction in non-fatal stroke (16%) and only SGLT2i showed a reduction in HF hospitalization (30%) in this population of people living with T2D. Conclusions This updated and comprehensive meta-analysis substantiates and strengthens the clinical recommendations of the CCS cardiorenal guidelines.

Background Randomized 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. Methods Members 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 m 2 ; 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. Results Between 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 [HR 95%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. Conclusions Our 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.

Chronic kidney disease (CKD) prevalence is rising worldwide and is projected to become the fifth leading cause of death globally by 2040. The high proportion of undiagnosed early-staged CKD and delayed diagnosis is of significant concern. The access to diagnosis and treatment is also limited in low-resource settings. The majority of individuals with kidney disease succumb to cardiovascular disease complications. Furthermore, heart failure and CKD are closely interconnected, with each condition significantly increasing the risk of developing the other. They share common risk factors, such as high blood pressure and diabetes, and their coexistence worsens prognosis and raises mortality rates. The bidirectional relationship between the heart and kidneys becomes even more complex and challenging in the context of cardiorenal syndrome. Emerging medications, such as sodium–glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists, have shown remarkable efficacy in slowing the progression of kidney disease, surpassing the benefits of traditional treatments. This article summarizes the evidence on the early detection of CKD and real-world opportunities to slow the progression of CKD by optimizing cardiorenal guideline-directed medical therapy.

Aims Left ventricular hypertrophy (LVH) has been associated with an increased risk of cardiovascular (CV) disease and linked to increased morbidity and mortality. In patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), hypertension is common, and patients with these co‐morbidities additionally have a high prevalence of LVH. This analysis of the prespecified pooled FIDELITY analysis comprising the randomized, double‐blind, placebo‐controlled, multicentre FIDELIO‐DKD and FIGARO‐DKD phase III studies aimed to explore the CV and kidney effects of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in patients with CKD and T2D stratified by a diagnosis of LVH at baseline. Methods and results A diagnosis of LVH in the FIDELITY patient population was determined at baseline using investigator‐reported electrocardiogram (ECG) findings. The two efficacy outcomes, assessed by baseline LVH, were the composite CV outcome of time to CV death, non‐fatal myocardial infarction, non‐fatal stroke, or hospitalization for heart failure (HHF), and a composite kidney outcome of time to onset of kidney failure, a sustained decrease in estimated glomerular filtration rate (eGFR) ≥57% from baseline over ≥4 weeks, or kidney‐related death. Safety outcomes by baseline LVH were reported as treatment‐emergent adverse events. At baseline out of 13 026 patients in FIDELITY, 96.5% had hypertension and 9.6% had investigator‐reported LVH. The relative risk reduction for the composite CV and kidney outcomes with finerenone versus placebo was lower in the LVH subgroup; however, the treatment effect of finerenone was not modified by baseline LVH for either outcome (Pinteraction = 0.1075 for composite CV outcome and Pinteraction = 0.1782 for composite kidney outcome). Analysis of the composite CV outcome components showed a greater reduction in the risk of HHF versus placebo for patients with baseline LVH compared with those without (Pinteraction = 0.0024). Overall safety events were comparable between the LVH subgroups and treatment arms. Treatment‐emergent hyperkalaemia was observed more frequently with finerenone versus placebo, but discontinuation rates were low in both treatment arms and between LVH subgroups. Conclusions In conclusion, the overall CV and kidney benefits of finerenone versus placebo were not modified by the presence of LVH at baseline, with overall safety findings being similar between LVH subgroups. A greater benefit was observed for HHF in patients with versus without LVH, suggesting that LVH may be a predictor of the treatment effect of finerenone on HHF.

Sodium‒glucose cotransporter-2 (SGLT2) inhibitors offer glycaemic and cardiorenal benefits in the early stage of chronic kidney disease (CKD). However, the use of SGLT2 inhibitors may increase the risk of genitourinary tract infection (GUTI). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may also cause deterioration of kidney function. The long-term follow-up of cardiorenal outcomes and GUTI incidence in patients with advanced CKD receiving SGLT2 inhibitors combined with ACEIs/ARBs should be further investigated. We analysed data from 5,503 patients in Taiwan's Taipei Medical University Research Database (2016-2020) who were part of a pre-end-stage renal disease (ESRD) program (CKD stages 3-5) and received ACEIs/ARBs. SGLT2 inhibitor users were matched 1:4 with nonusers on the basis of sex, CKD, and program entry duration. The final cohort included 205 SGLT2 inhibitor users and 820 nonusers. SGLT2 inhibitor users experienced a significant reduction in ESRD/dialysis risk (aHR = 0.35, 95% CI = 0.190.67), and SGLT2 inhibitor use was not significantly associated with acute kidney injury or acute kidney disease risk. Among SGLT2 inhibitor users, those with a history of cardiovascular disease (CVD) had greater CVD rates. Conversely, those without a CVD history had lower rates of congestive heart failure, arrhythmia, acute pulmonary oedema, and acute myocardial infarction, although the differences were not statistically significant. Notably, SGLT2 inhibitor usage was associated with a greater GUTI incidence (aHR = 1.78, 95% CI = 1.122.84) shortly after initiation, irrespective of prior GUTI history status. Among patients with CKD stages 3-5, SGLT2 inhibitor use was linked to increased GUTI incidence, but it also significantly reduced the ESRD/dialysis risk without an episodic AKI or AKD risk. Clinical physicians should consider a personalized medicine approach by balancing GUTI episodes and cardiorenal outcomes for advanced CKD patients receiving SGLT2 inhibitors.

The population with concomitant heart and kidney disease (often termed ‘cardiorenal’ disease) is expected to grow, significantly impacting public health and healthcare utilization. Moreover, the cardiorenal nexus encompasses a bidirectional relationship that worsens prognosis and may complicate pharmacological management in often elderly and frail patients. Therefore, a more cohesive multidisciplinary team approach aiming to provide holistic, coordinated and specialized care would be a positive shift towards improving patient outcomes and optimizing healthcare resources. This article aims to define the organizational aspects and key elements for setting up a multidisciplinary cardiorenal clinical program as a potential healthcare model adapted to the particular characteristics of patients with cardiorenal disease. Graphical Abstract Graphical Abstract