scholarly journals Early Change in Albuminuria with Canagliflozin Predicts Kidney and Cardiovascular Outcomes: A PostHoc Analysis from the CREDENCE Trial

2020 ◽  
Vol 31 (12) ◽  
pp. 2925-2936 ◽  
Author(s):  
Megumi Oshima ◽  
Brendon L. Neuen ◽  
JingWei Li ◽  
Vlado Perkovic ◽  
David M. Charytan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Cardiovascular Events ◽  
Renin Angiotensin System ◽  
Cardiovascular Death ◽  
Cardiovascular Outcomes ◽  
Major Adverse Cardiovascular Events ◽  
Early Change ◽  
Sodium Glucose Cotransporter

BackgroundThe association between early changes in albuminuria and kidney and cardiovascular events is primarily based on trials of renin-angiotensin system blockade. It is unclear whether this association occurs with sodium-glucose cotransporter 2 inhibition.MethodsThe Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial enrolled 4401 patients with type 2 diabetes and CKD (urinary albumin-creatinine ratio [UACR] >300 mg/g). This post hoc analysis assessed canagliflozin’s effect on albuminuria and how early change in albuminuria (baseline to week 26) is associated with the primary kidney outcome (ESKD, doubling of serum creatinine, or kidney death), major adverse cardiovascular events, and hospitalization for heart failure or cardiovascular death.ResultsComplete data for early change in albuminuria and other covariates were available for 3836 (87.2%) participants in the CREDENCE trial. Compared with placebo, canagliflozin lowered UACR by 31% (95% confidence interval [95% CI], 27% to 36%) at week 26, and significantly increased the likelihood of achieving a 30% reduction in UACR (odds ratio, 2.69; 95% CI, 2.35 to 3.07). Each 30% decrease in UACR over the first 26 weeks was independently associated with a lower hazard for the primary kidney outcome (hazard ratio [HR], 0.71; 95% CI, 0.67 to 0.76; P<0.001), major adverse cardiovascular events (HR, 0.92; 95% CI, 0.88 to 0.96; P<0.001), and hospitalization for heart failure or cardiovascular death (HR, 0.86; 95% CI, 0.81 to 0.90; P<0.001). Residual albuminuria levels at week 26 remained a strong independent risk factor for kidney and cardiovascular events, overall and in each treatment arm.ConclusionsIn people with type 2 diabetes and CKD, use of canagliflozin results in early, sustained reductions in albuminuria, which were independently associated with long-term kidney and cardiovascular outcomes.

scholarly journals Treatment of Heart Failure with Sodium-Glucose Cotransporter 2 Inhibitors and Other Anti-diabetic Drugs

2019 ◽  
Vol 5 (1) ◽  
pp. 27-30 ◽  
Author(s):  
Thomas A Zelniker ◽  
Eugene Braunwald
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Renal Failure ◽  
Cardiovascular Death ◽  
Cardiovascular Outcomes ◽  
Sodium Glucose Cotransporter ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Glucagon Like Peptide 1

Patients with type 2 diabetes are at increased risk of developing heart failure, cardiovascular death and renal failure. The recent results of three large sodium-glucose cotransporter 2 inhibitor cardiovascular outcomes trials have demonstrated a reduction in heart failure hospitalisation and progressive renal failure. One trial also showed a fall in cardiovascular and total death. A broad spectrum of patients with diabetes benefit from these salutary effects in cardiac and renal function and so these trials have important implications for the management of patients with type 2 diabetes. Selected glucagon-like peptide 1 receptor agonists have also been shown to reduce adverse cardiovascular outcomes.

scholarly journals The Effects of Dapagliflozin in Patients With Heart Failure Complicated With Type 2 Diabetes: A Meta-Analysis of Placebo-Controlled Randomized Trials

2021 ◽  
Vol 2 ◽  
Author(s):  
Miaobo Zhai ◽  
Xin Du ◽  
Changmei Liu ◽  
Huipu Xu
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Meta Analysis ◽  
Cardiovascular Death ◽  
Major Adverse Cardiovascular Events ◽  
Significant Heterogeneity ◽  
Sodium Glucose Cotransporter ◽  
All Cause Mortality ◽  
Incidence Of Hospitalization

BackgroundCardiovascular disease threatens the health and quality of life of individuals, particularly those with type II diabetes. Recently, some studies have reported the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing the rates of hospitalization or urgent visits, resulting in IV therapy for heart failure in patients with type 2 diabetes mellitus (T2DM).MethodsWe did a comprehensive search in electronic databases from inception through July 2020 for randomized-controlled trials, using the keywords “sodium-glucose cotransporter-2 inhibitor”, “dapagliflozin”, “heart failure”, “cardiovascular outcomes”, “major adverse cardiovascular events”, “all-cause mortality”, and “cardiovascular death”. Random-effects summary odds ratios (OR) were constructed using M-L heterogeneity model.ResultsFive trials with 5,252 patients were ultimately included. The incidence of hospitalization for heart failure (HHF) (n=4, OR=0.74; 95% CI, 0.61 to 0.88; I2 = 0%) and all-cause mortality (ACM, n=4, OR=0.76; 95% CI, 0.66 to 0.94; I2 = 0%); was reduced by dapagliflozin, respectively, in all heart failure patients, without obvious heterogeneity. The incidence of cardiovascular death in dapagliflozin was lower than that in placebo without statistically significant (CVD, n=5, OR=0.84; 95% CI, 0.69 to 1.03; I2 = 0%). In HFrEF subgroup, dapagliflozin was associated with a reduced incidence of hospitalization for heart failure (n=4, OR=0.74; 95% CI, 0.60 to 0.91; I2 = 0%), cardiovascular death (n=4, OR=0.72; 95% CI, 0.58 to 0.91; I2 = 8%), and all-cause mortality (n=3, OR=0.70; 95% CI, 0.50 to 0.99; I2 = 43%) without significant heterogeneity. In contrast, in the HFpEF subgroup, there was no difference in the incidence of cardiovascular death (n=2, OR=1.45; 95% CI, 0.95 to 2.22; I2 = 0%) and all-cause mortality (n=2, OR=1.04; 95% CI, 0.76 to 1.43; I2 = 0%) between dapagliflozin and placebo.ConclusionIn our study, dapagliflozin performed a statistical reduction in the rate of heart failure hospitalization, cardiovascular death, and all-cause mortality in patients with HFrEF and diabetes. However, in the HFpEF subgroup, dapagliflozin did not show a significant cardiovascular protective effect.

scholarly journals Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Shih-Chieh Shao ◽  
Kai-Cheng Chang ◽  
Ming-Jui Hung ◽  
Ning-I Yang ◽  
Yuk-Ying Chan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Cohort Study ◽  
Ischemic Stroke ◽  
Cardiovascular Events ◽  
Cardiovascular Death ◽  
Sglt2 Inhibitors ◽  
Diabetes Patients

Abstract Background To compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin. Methods We conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium–glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients’ age, sex, laboratory data, co-morbidities, and concomitant medications. Results We identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73–1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14–2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49–1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80–1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49–0.95). Conclusion The risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospective studies are required to confirm the findings.

scholarly journals A higher non-severe hypoglycaemia rate is associated with an increased risk of subsequent severe hypoglycaemia and major adverse cardiovascular events in individuals with type 2 diabetes in the LEADER study

Diabetologia ◽  
2021 ◽  
Author(s):  
Simon R. Heller ◽  
Milan S. Geybels ◽  
Ahmed Iqbal ◽  
Lei Liu ◽  
Lily Wagner ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Events ◽  
Severe Hypoglycaemia ◽  
Cardiovascular Death ◽  
Cardiovascular Outcomes ◽  
Post Hoc Analysis ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Post Hoc

Abstract Aims/hypothesis Hypoglycaemia is a common side effect of insulin and some other antihyperglycaemic agents used to treat diabetes. Severe hypoglycaemia has been associated with adverse cardiovascular events in trials of intensive glycaemic control in type 2 diabetes. The relationship between non-severe hypoglycaemic episodes (NSHEs) and severe hypoglycaemia in type 2 diabetes has been documented. However, an association between more frequent NSHEs and cardiovascular events has not been verified. This post hoc analysis of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial aimed to confirm whether there is an association between NSHEs and severe hypoglycaemic episodes in individuals with type 2 diabetes. In addition, the possible association between NSHEs and major adverse cardiac events (MACE), cardiovascular death and all-cause mortality was investigated. Methods LEADER was a double-blind, multicentre, placebo-controlled trial that found that liraglutide significantly reduced the risk of MACE compared with the placebo. In this post hoc analysis, we explored, in all LEADER participants, whether the annual rate of NSHEs (defined as self-measured plasma glucose <3.1 mmol/l [56 mg/dl]) was associated with time to first severe hypoglycaemic episode (defined as an episode requiring the assistance of another person), time to first MACE, time to cardiovascular death and time to all-cause mortality. Participants with <2 NSHEs per year were used as reference for HR estimates. Cox regression with a time-varying covariate was used. Results We demonstrate that there is an association between NSHEs (2–11 NSHEs per year and ≥12 NSHEs per year) and severe hypoglycaemic episodes (unadjusted HRs 1.98 [95% CI 1.43, 2.75] and 5.01 [95% CI 2.84, 8.84], respectively), which was consistent when baseline characteristics were accounted for. Additionally, while no association was found between participants with 2–11 NSHEs per year and adverse cardiovascular outcomes, higher rates of NSHEs (≥12 episodes per year) were associated with higher risk of MACE (HR 1.50 [95% CI 1.01, 2.23]), cardiovascular death (HR 2.08 [95% CI 1.17, 3.70]) and overall death (HR 1.80 [95% CI 1.11, 2.92]). Conclusions/interpretation The analysis of data from the LEADER trial demonstrated that higher rates of NSHEs were associated with both a higher risk of severe hypoglycaemia and adverse cardiovascular outcomes in individuals with type 2 diabetes. Therefore, irrespective of the cause of this association, it is important that individuals with high rates of hypoglycaemia are identified so that the potentially increased risk of cardiovascular events can be managed and steps can be taken to reduce NSHEs. Trial registration ClinicalTrials.gov (NCT01179048). Graphical abstract

Prognostic utility of early systolic lengthening by speckle tracking echocardiography in patients with type 2 diabetes

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P Brainin ◽  
M.T Jensen ◽  
T Biering-Soerensen ◽  
R Moegelvang ◽  
T Fritz-Hansen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Cardiovascular Events ◽  
Speckle Tracking ◽  
Longitudinal Strain ◽  
Global Longitudinal Strain ◽  
Major Adverse Cardiovascular Events ◽  
Forest Plot ◽  
Systolic Strain

Abstract Background Early systolic lengthening (ESL) has recently recognized as a predictor of cardiovascular events in patients with myocardial ischemia. Our aim was to evaluate the prognostic value of ESL in patients with type 2 diabetes. Methods In this prospective study we conducted speckle tracking examinations in 743 patients with type 2 diabetes (62% male; age 63±10 years; diabetes duration 11 [5, 17] years). Patients were free from interventricular conduction disturbances, atrial fibrillation, heart failure and ischemic heart disease at study inclusion. We assessed the ESL index, defined as: (−100 x [peak positive systolic strain / global longitudinal strain (GLS)]), and duration of ESL, defined as time from onset of QRS complex on the electrocardiogram to time of peak positive systolic strain. Measurements were averaged from 18 myocardial segments. Results During the median follow-up time of 4.8 years [IQR 4, 5.3 years], 93 (13%) patients experienced major adverse cardiovascular events (MACE), a composite of incident heart failure, myocardial infarction and cardiovascular death. Because GLS modified the association with MACE (P interaction &lt;0.05), the population was stratified by the median GLS value (low &gt;−15% and high ≤−15%). In patients with low GLS, the ESL index (HR 1.47 per 1% increase [1.12 to 1.93], P=0.005) and ESL duration (HR 1.73 per 1ms increase [1.10 to 2.72], P=0.017) were associated with MACE. Both associations remained significant in multivariable models adjusted for clinical, echocardiographic and speckle tracking measurements (Figure). No associations were found in patients with high GLS (Figure). Conclusion Assessment of ESL yields novel and independent prognostic information on major adverse cardiovascular events in patients with diabetes type 2 and reduced longitudinal strain. Forest plot: ESL and risk of MACE by GLS Funding Acknowledgement Type of funding source: None

scholarly journals Effect of Apabetalone on Cardiovascular Events in Diabetes, CKD, and Recent Acute Coronary Syndrome

2021 ◽  
pp. CJN.16751020
Author(s):  
Kamyar Kalantar-Zadeh ◽  
Gregory G. Schwartz ◽  
Stephen J. Nicholls ◽  
Kevin A. Buhr ◽  
Henry N. Ginsberg ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Acute Coronary Syndrome ◽  
Adverse Events ◽  
Confidence Interval ◽  
Cardiovascular Events ◽  
Hazard Ratio ◽  
Major Adverse Cardiovascular Events ◽  
Coronary Syndrome

Background and objectivesCKD and type 2 diabetes mellitus interact to increase the risk of major adverse cardiovascular events (i.e., cardiovascular death, nonfatal myocardial infarction, or stroke) and congestive heart failure. A maladaptive epigenetic response may be a cardiovascular risk driver and amenable to modification with apabetalone, a selective modulator of the bromodomain and extraterminal domain transcription system. We examined this question in a prespecified analysis of BETonMACE, a phase 3 trial.Design, setting, participants, & measurementsBETonMACE was an event-driven, randomized, double-blind, placebo-controlled trial comparing effects of apabetalone versus placebo on major adverse cardiovascular events and heart failure hospitalizations in 2425 participants with type 2 diabetes and a recent acute coronary syndrome, including 288 participants with CKD with eGFR <60 ml/min per 1.73 m2 at baseline. The primary end point in BETonMACE was the time to the first major adverse cardiovascular event, with a secondary end point of time to hospitalization for heart failure.ResultsMedian follow-up was 27 months (interquartile range, 20–32 months). In participants with CKD, apabetalone compared with placebo was associated with fewer major adverse cardiovascular events (13 events in 124 patients [11%] versus 35 events in 164 patients [21%]; hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.96) and fewer heart failure–related hospitalizations (three hospitalizations in 124 patients [3%] versus 14 hospitalizations in 164 patients [9%]; hazard ratio, 0.48; 95% confidence interval, 0.26 to 0.86). In the non-CKD group, the corresponding hazard ratio values were 0.96 (95% confidence interval, 0.74 to 1.24) for major adverse cardiovascular events, and 0.76 (95% confidence interval, 0.46 to 1.27) for heart failure–related hospitalization. Interaction of CKD on treatment effect was P=0.03 for major adverse cardiovascular events, and P=0.12 for heart failure–related hospitalization. Participants with CKD showed similar numbers of adverse events, regardless of randomization to apabetalone or placebo (119 [73%] versus 88 [71%] patients), and there were fewer serious adverse events (29% versus 43%; P=0.02) in the apabetalone group.ConclusionsApabetalone may reduce the incidence of major adverse cardiovascular events in patients with CKD and type 2 diabetes who have a high burden of cardiovascular disease.

scholarly journals The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics

2017 ◽  
Vol 46 (6) ◽  
pp. 462-472 ◽  
Author(s):  
Meg J. Jardine ◽  
Kenneth W. Mahaffey ◽  
Bruce Neal ◽  
Rajiv Agarwal ◽  
George L. Bakris ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kidney Disease ◽  
Clinical Evaluation ◽  
Cardiovascular Events ◽  
Controlled Trial ◽  
Cardiovascular Death ◽  
Cardiovascular Outcomes ◽  
Double Blind ◽  
Urinary Glucose

Background: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. Methods: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin ­versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ∼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate ≥30 to <90 mL/min/1.73 m2, and albuminuria (urinary albumin:creatinine ratio >300 to ≤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. Conclusion: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. Trial Registration: EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791.

Dapagliflozin and cardiovascular outcomes in patients with Type 2 diabetes

2020 ◽  
Vol 16 (2) ◽  
pp. 77-88
Author(s):  
Dalal Y Al-Bazz ◽  
John PH Wilding
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Ejection Fraction ◽  
Cardiovascular Events ◽  
Major Adverse Cardiovascular Events ◽  
Glucose Lowering ◽  
Reduced Ejection Fraction ◽  
The Relationship

The relationship between cardiovascular disease, heart failure (HF) and Type-2 diabetes (T2DM) is widely recognized. Cardiovascular (CV) outcome trials are required for all new glucose-lowering agents to confirm safety with respect to CV risk. CV outcome trials with SGLT2i inhibitors have shown CV benefit, with reductions in major CV events and HF. This review focuses on the DECLARE-TIMI 58 trial with dapagliflozin in T2DM, which showed noninferiority for major adverse cardiovascular events and reduction in hospitalization for HF and associated CV mortality in a broad range of patients with T2DM. The DAPA-HF trial of dapagliflozin in people with HF with reduced ejection fraction with and without T2DM confirms benefits for those with HF.

scholarly journals A Practical Guide for Cardiologists to the Pharmacological Treatment of Patients with Type 2 Diabetes and Cardiovascular Disease

2021 ◽  
Vol 16 ◽  
Author(s):  
Tariq Ahmad ◽  
Ralph J Riello ◽  
Silvio E Inzucchi
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Clinical Trial Data ◽  
Major Adverse Cardiovascular Events ◽  
Sodium Glucose Cotransporter ◽  
High Risk Type ◽  
Glucagon Like Peptide 1 ◽  
Professional Guidelines

Patients with type 2 diabetes are at increased cardiovascular risk. Until recently, reductions in HbA1c and the use of specific glucose-lowering agents have not had a clear, reproducible benefit in reducing the incidence of cardiovascular disease. However, over the past 5 years, members of two categories of diabetes medications, sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, have been associated with improved rates of major adverse cardiovascular events when used in high-risk type 2 diabetes patients. Importantly, these effects are not necessarily linked to these agents’ effects on HbA1c. Sodium–glucose cotransporter 2 inhibitors have also been associated with reductions in heart failure hospitalization, a benefit that appears to extend to individuals without diabetes with established heart failure. Cardiovascular specialists should become familiar with these emerging data and be prepared to implement corresponding strategies in their practice to improve the cardiovascular outcomes of their patients. Recent clinical trial data and the changing landscape of corresponding professional guidelines are reviewed. Practical recommendations for safe prescribing of these anti-diabetes drugs are provided.

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