scholarly journals Association Between Circulating GDF‐15 and Cardio‐Renal Outcomes and Effect of Canagliflozin: Results From the CANVAS Trial

Author(s):  
Taha Sen ◽  
Jingwei Li ◽  
Brendon L. Neuen ◽  
Clare Arnott ◽  
Bruce Neal ◽  
...  

Background Studies have suggested that sodium glucose co‐transporter 2 inhibitors exert anti‐inflammatory effects. We examined the association of baseline growth differentiation factor‐15 (GDF‐15), a marker of inflammation and cellular injury, with cardiovascular events, hospitalization for heart failure (HF), and kidney outcomes in patients with type 2 diabetes in the CANVAS (Canagliflozin Cardiovascular Assessment Study) and determined the effect of the sodium glucose co‐transporter 2 inhibitor canagliflozin on circulating GDF‐15. Methods and Results The CANVAS trial randomized 4330 people with type 2 diabetes at high cardiovascular risk to canagliflozin or placebo. The association between baseline GDF‐15 and cardiovascular (non‐fatal myocardial infarction, non‐fatal stroke, cardiovascular death), HF, and kidney (40% estimated glomerular filtration rate decline, end‐stage kidney disease, renal death) outcomes was assessed using multivariable adjusted Cox regression models. During median follow‐up of 6.1 years (N=3549 participants with available samples), 555 cardiovascular, 129 HF, and 137 kidney outcomes occurred. Each doubling in baseline GDF‐15 was significantly associated with a higher risk of cardiovascular (hazard ratio [HR], 1.2; 95% CI, 1.0‒1.3), HF (HR, 1.5; 95% CI, 1.2‒2.0) and kidney (HR, 1.5; 95% CI, 1.2‒2.0) outcomes. Baseline GDF‐15 did not modify canagliflozin’s effect on cardiovascular, HF, and kidney outcomes. Canaglifozin treatment modestly lowered GDF‐15 compared with placebo; however, GDF‐15 did not mediate the protective effect of canagliflozin on cardiovascular, HF, or kidney outcomes. Conclusions In patients with type 2 diabetes at high cardiovascular risk, higher GDF‐15 levels were associated with a higher risk of cardiovascular, HF, and kidney outcomes. Canagliflozin modestly lowered GDF‐15, but GDF‐15 reduction did not mediate the protective effect of canagliflozin.

2020 ◽  
Author(s):  
James L. Januzzi Jr ◽  
Javed Butler ◽  
Naveed Sattar ◽  
Jialin Xu ◽  
Wayne Shaw ◽  
...  

<b>Objective</b>: To analyze the association between concentrations of plasma insulin-like growth factor binding protein-7 (IGFBP7) with renal and cardiac outcomes among participants with type 2 diabetes and high cardiovascular risk. <p><b>Research Design and Methods</b>: Associations between IGFBP7 levels and clinical outcomes were assessed among participants in the Canagliflozin Cardiovascular Assessment Study (CANVAS) with type 2 diabetes and high cardiovascular risk. </p> <p><b>Results</b>: Among CANVAS participants, 3577 and 2898 had IGFBP7 measured at baseline and 1 year, respectively. Per log-unit higher concentration, baseline IGFBP7 was significantly associated with the composite renal endpoint of sustained 40% reduction in eGFR, need for renal replacement therapy, or renal death (hazard ratio [HR]=3.51; <i>P</i><0.001), and the composite renal endpoint plus cardiovascular death (HR=4.90; <i>P</i><0.001); other outcomes including development or progression of albuminuria were also predicted by baseline IGFBP7. <a>Most outcomes were improved by canagliflozin regardless of baseline IGFBP7; however, those with baseline concentrations ≥96.5 ng/mL appeared to benefit more from canagliflozin relative to first progression of albuminuria compared to those with lower baseline IGFBP7 (HR=0.64 vs 0.95; <i>P</i><sub>interaction </sub>=0.003). </a>Canagliflozin did not lower IGFBP7 concentrations by 1 year; however, at 1 year, higher IGFBP7 concentrations more strongly predicted the composite renal endpoint (HR=15.7; <i>P</i><0.001). Patients with rising IGFBP7 between baseline to 1 year had the highest number of composite renal events. </p> <p><b>Conclusions</b>: <a>Plasma IGFBP7 concentrations predicted renal and cardiac events among participants with type 2 diabetes and high cardiovascular risk. More data are needed regarding circulating IGFBP7 and progression of diabetic kidney disease and its complications. </a></p>


2020 ◽  
Author(s):  
James L. Januzzi Jr ◽  
Javed Butler ◽  
Naveed Sattar ◽  
Jialin Xu ◽  
Wayne Shaw ◽  
...  

<b>Objective</b>: To analyze the association between concentrations of plasma insulin-like growth factor binding protein-7 (IGFBP7) with renal and cardiac outcomes among participants with type 2 diabetes and high cardiovascular risk. <p><b>Research Design and Methods</b>: Associations between IGFBP7 levels and clinical outcomes were assessed among participants in the Canagliflozin Cardiovascular Assessment Study (CANVAS) with type 2 diabetes and high cardiovascular risk. </p> <p><b>Results</b>: Among CANVAS participants, 3577 and 2898 had IGFBP7 measured at baseline and 1 year, respectively. Per log-unit higher concentration, baseline IGFBP7 was significantly associated with the composite renal endpoint of sustained 40% reduction in eGFR, need for renal replacement therapy, or renal death (hazard ratio [HR]=3.51; <i>P</i><0.001), and the composite renal endpoint plus cardiovascular death (HR=4.90; <i>P</i><0.001); other outcomes including development or progression of albuminuria were also predicted by baseline IGFBP7. <a>Most outcomes were improved by canagliflozin regardless of baseline IGFBP7; however, those with baseline concentrations ≥96.5 ng/mL appeared to benefit more from canagliflozin relative to first progression of albuminuria compared to those with lower baseline IGFBP7 (HR=0.64 vs 0.95; <i>P</i><sub>interaction </sub>=0.003). </a>Canagliflozin did not lower IGFBP7 concentrations by 1 year; however, at 1 year, higher IGFBP7 concentrations more strongly predicted the composite renal endpoint (HR=15.7; <i>P</i><0.001). Patients with rising IGFBP7 between baseline to 1 year had the highest number of composite renal events. </p> <p><b>Conclusions</b>: <a>Plasma IGFBP7 concentrations predicted renal and cardiac events among participants with type 2 diabetes and high cardiovascular risk. More data are needed regarding circulating IGFBP7 and progression of diabetic kidney disease and its complications. </a></p>


2021 ◽  
Vol 9 (1) ◽  
pp. e002408
Author(s):  
João Pedro Ferreira ◽  
Diana Ferrao ◽  
Patrick Rossignol ◽  
Faiez Zannad ◽  
Abhinav Sharma ◽  
...  

IntroductionPatients with type 2 diabetes (T2D) have an increased risk of worsening kidney function (WKF) over time compared with patients without diabetes. Data evaluating the inter-relation between WKF, cardiovascular risk, and clinical events are scarce. We aim to study the association of WKF with subsequent cardiovascular events and the probabilities of transition from WKF to hospitalization or death according to patients’ risk. We have used a large population of patients with T2D and a high cardiovascular risk enrolled in the Action to Control Cardiovascular Risk in Diabetes Study.Research design and methodsTime-updated, joint, and multistate modeling were used. WKF was defined as an estimated glomerular filtration rate (eGFR) decline greater than 40% from baseline. A total of 10 251 patients were included, of whom 1213 (11.8%) presented WKF over a median (percentile25–75) follow-up time of 5.0 (4.1–5.7) years.ResultsPatients who experienced WKF were slightly older, more frequently women, and had longer diabetes duration. Patients experiencing WKF, regardless of baseline kidney function, had a higher risk of subsequent cardiovascular events, including the composite of cardiovascular death or hospitalization for heart failure (HHF), with ≈2-fold higher risk. Joint modeling showed that renal function deterioration frequently occurs even among patients who did not experience a cardiovascular event. In multistate models, patients with a medium-high cardiovascular risk (compared with those with a low cardiovascular risk) are at higher risk of HHF or cardiovascular death first (HR=4.76, 95% CI 3.63 to 6.23) than of WKF first (HR=1.37, 95% CI 1.21 to 1.56); remarkably, the risk of cardiovascular death or HHF is highest after a WKF event (HR=6.20, 95% CI 2.71 to 14.8).ConclusionsIn patients with T2D and a high cardiovascular risk, WKF occurs in more than 10% of patients and is independently associated with risk of subsequent cardiovascular events, irrespective of baseline eGFR. Preventing serious WKF and the transition from WKF to HHF or cardiovascular death is an important objective of future trials.Trial registration numberNCT00000620.


2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Basilio Pintaudi ◽  
Alessia Scatena ◽  
Gabriella Piscitelli ◽  
Vera Frison ◽  
Salvatore Corrao ◽  
...  

Abstract Background The European Society of Cardiology (ESC) recently defined cardiovascular risk classes for subjects with diabetes. Aim of this study was to explore the distribution of subjects with type 2 diabetes (T2D) by cardiovascular risk groups according to the ESC classification and to describe the quality indicators of care, with particular regard to cardiovascular risk factors. Methods The study is based on data extracted from electronic medical records of patients treated at the 258 Italian diabetes centers participating in the AMD Annals initiative. Patients with T2D were stratified by cardiovascular risk. General descriptive indicators, measures of intermediate outcomes, intensity/appropriateness of pharmacological treatment for diabetes and cardiovascular risk factors, presence of other complications and overall quality of care were evaluated. Results Overall, 473,740 subjects with type 2 diabetes (78.5% at very high cardiovascular risk, 20.9% at high risk and 0.6% at moderate risk) were evaluated. Among people with T2D at very high risk: 26.4% had retinopathy, 39.5% had albuminuria, 18.7% had a previous major cardiovascular event, 39.0% had organ damage, 89.1% had three or more risk factors. The use of DPP4-i markedly increased as cardiovascular risk increased. The prescription of secretagogues also increased and that of GLP1-RAs tended to increase. The use of SGLT2-i was still limited, and only slightly higher in subjects with very high cardiovascular risk. The overall quality of care, as summarized by the Q score, tended to be lower as the level of cardiovascular risk increased. Conclusions A large proportion of subjects with T2D is at high or very high risk. Glucose-lowering drug therapies seem not to be adequately used with respect to their potential advantages in terms of cardiovascular risk reduction. Several actions are necessary to improve the quality of care.


2020 ◽  
Author(s):  
Vlado Perkovic ◽  
Robert Toto ◽  
Mark E Cooper ◽  
Johannes FE Mann ◽  
Julio Rosenstock ◽  
...  

<b>Objective</b> <p>Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular and kidney outcomes across baseline eGFR categories (≥ 60, 45-<60, 30-<45 and < 30 ml/min/1.73 m<sup>2</sup>) in CARMELINA, a cardio-renal placebo-controlled outcome trial of the DPP-4 inhibitor linagliptin (NCT01897532).</p> <p><b>Research Design and Methods</b></p> <p>Participants with cardiovascular disease (CVD) and/or CKD were included. The primary outcome was time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3P-MACE), with a secondary outcome renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other endpoints included progression of albuminuria, change in HbA1c and adverse events (AEs) including hypoglycemia. </p> <p><b>Results</b></p> <p>6979 subjects (mean age 65.9 years, eGFR 54.6 ml/min/1.73m<sup>2</sup>, 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared to placebo did not affect the risk for 3P-MACE (HR.1.02 [95% CI, 0.89, 1.17]), or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction p-values > 0.05). Regardless of eGFR, albuminuria-progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced between groups overall and across eGFR categories. </p> <p><b>Conclusions </b></p> <p>Across all GFR categories, in participants with type 2 diabetes and CKD and/or CVD, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c, and no difference in AEs was observed.</p>


2020 ◽  
Vol 66 (9) ◽  
pp. 1283-1288
Author(s):  
Eduardo Bello Martins ◽  
Eduardo Gomes Lima ◽  
Fábio Grunspun Pitta ◽  
Leticia Neves Solon Carvalho ◽  
Thiago Dias de Queiroz ◽  
...  

SUMMARY The pharmacological therapy for type 2 diabetes mellitus has presented important advances in recent years, which has impacted the treatment of patients with established cardiovascular disease or with high cardiovascular risk. In this scenario, two drug classes have emerged and demonstrated clear clinical benefits: SGLT-2 inhibitors and GLP-1 agonists. The present review discusses the pharmacology, adverse effects, and clinical trials that have demonstrated the benefits of these medications in reducing cardiovascular risk.


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