scholarly journals Series: Cardiovascular outcome trials for diabetes drugs Empagliflozin and EMPA-REG OUTCOME

2020 ◽  
Vol 20 (2) ◽  
pp. 138-141
Author(s):  
Miles Fisher
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Cardiovascular Events ◽  
Sglt2 Inhibitor ◽  
Cardiovascular Outcome ◽  
Secondary Outcome ◽  
Major Adverse Cardiovascular Events ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cardiovascular Outcome Trial

EMPA-REG OUTCOME was an FDA-mandated cardiovascular outcome trial with empagliflozin and was the first completed trial with a sodium-glucose co-transporter-2 (SGLT2) inhibitor. EMPA-REG OUTCOME compared empagliflozin and placebo in 7,020 subjects with type 2 diabetes and established atherosclerotic cardiovascular disease. The results were astounding as EMPA-REG OUTCOME demonstrated superiority for major cardiovascular events (cardiovascular death, myocardial infarction, stroke) and cardiovascular deaths were significantly reduced, as was all-cause mortality. Hospitalisation for heart failure, which was a secondary outcome, was also significantly reduced. Later trials with SGLT2 inhibitors have demonstrated reductions in major adverse cardiovascular events (MACE) and hospitalisation for heart failure, and trials with glucagon-like peptide 1 receptor agonists have demonstrated reductions in MACE. Collectively, these trials could transform the management of people with type 2 diabetes.

scholarly journals Series: Cardiovascular outcome trials for diabetes drugs Liraglutide and LEADER

2020 ◽  
Vol 20 (2) ◽  
pp. 142-144
Author(s):  
Miles Fisher
Keyword(s):  
Heart Failure ◽  
Cardiovascular Events ◽  
Cardiovascular Death ◽  
Cardiovascular Outcome ◽  
Secondary Outcome ◽  
Major Adverse Cardiovascular Events ◽  
Cardiovascular Outcome Trials ◽  
Major Cardiovascular Events ◽  
Cardiovascular Outcome Trial ◽  
Outcome Trial

LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) was an FDA-mandated cardiovascular outcome trial with liraglutide and was the first trial with a glucagon-like peptide-1 (GLP-1) receptor agonist to demonstrate a significant reduction in cardiovascular events. It compared liraglutide and placebo in 9,340 people with type 2 diabetes and either existing cardiovascular disease or age >60 years with at least one cardiovascular risk factor. LEADER demonstrated superiority for major cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), and cardiovascular deaths were significantly reduced, as was all-cause mortality. Hospitalisation for heart failure, which was a secondary outcome, was not significantly reduced. Compared with the EMPA-REG OUTCOME trial, the curves for major adverse cardiovascular events in LEADER separated later, and the absence of a clear effect on hospitalisation for heart failure or on estimated glomerular filtration rate suggests that the mechanism of cardiovascular benefit for liraglutide was different from that for empagliflozin

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.

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 Series: Cardiovascular outcome trials for diabetes drugs Canagliflozin and the CANVAS Program, dapagliflozin and DECLARE-TIMI 58, ertugliflozin and VERTIS CV

2021 ◽  
Author(s):  
Miles Fisher
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Cardiovascular Death ◽  
Cardiovascular Outcome ◽  
Integrated Analysis ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cardiovascular Outcome Trials ◽  
Significant Difference

EMPA-REG OUTCOME was a landmark trial with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin, which demonstrated significant reductions in major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) driven by reductions in cardiovascular deaths and accompanied by an early reduction in hospitalisation for heart failure. This was followed by cardiovascular outcome trials with canagliflozin, dapagliflozin and ertugliflozin. The CANVAS Program was an integrated analysis of the CANVAS and CANVAS-R trials with canagliflozin. It demonstrated a significant reduction in MACE, but not in any of the components, and there was an unexpected increase in amputations and fractures with canagliflozin. The DECLARE-TIMI 58 trial with dapagliflozin had two co-primary endpoints. A composite endpoint of cardiovascular death or hospitalisation for heart failure was significantly reduced, but there was no significant difference in MACE comparing dapagliflozin with placebo. Analysis of patients with a prior myocardial infarction, however, demonstrated significant reductions in MACE. The VERTIS CV trial with ertugliflozin was disappointing as there was no difference in MACE comparing ertugliflozin and placebo. In all four trials a reduction in hospitalisation for heart failure was observed in patients with type 2 diabetes, regardless of whether they had existing atherosclerotic cardiovascular disease or increased cardiovascular risk. Pre-specified renal outcomes were reduced with empagliflozin, canagliflozin and dapagliflozin, and these drugs are now commonly used in the management of people with type 2 diabetes. It is hard to envisage an ongoing role for ertugliflozin in routine clinical management as the evidence for its cardiovascular benefit is not convincing.

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.

Association of Baseline HbA1c With Cardiovascular and Renal Outcomes: Analyses From DECLARE-TIMI 58

2022 ◽  
Author(s):  
Avivit Cahn ◽  
Stephen D. Wiviott ◽  
Ofri Mosenzon ◽  
Sabina A. Murphy ◽  
Erica L. Goodrich ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Events ◽  
Cox Regression ◽  
Major Adverse Cardiovascular Events ◽  
Atherosclerotic Cardiovascular Disease ◽  
Baseline Hba1c ◽  
Renal Outcomes ◽  
Increased Risk ◽  
Hba1c Levels

<b>Objective:</b> Current guidelines recommend prescribing SGLT-2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c. <p><b>Methods:</b> In the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 trial 17,160 patients with type 2 diabetes were randomized to dapagliflozin or placebo for a median follow up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population, and with dapagliflozin vs. placebo in HbA1c subgroups were studied by Cox regression models.</p> <p><b>Results:</b> In the overall population, increasing HbA1c was associated with higher risk of cardiovascular death or hospitalization for heart failure (CVD/HHF), major adverse cardiovascular events (MACE; CVD, myocardial infarction, ischemic stroke) and of the cardiorenal outcome (adjusted HR [95% CI] 1.12 [1.06-1.19], 1.08 [1.04-1.13] and 1.17 [1.11-1.24] per 1% increase respectively). Elevated HbA1c was associated with an increased risk for MACE and for the cardiorenal outcome significantly more in patients with multiple risk factors (MRF), vs. patients with established ASCVD (P-interaction 0.0064 and 0.0093 respectively). Dapagliflozin led to a decrease in the risk of CVD/HHF, HHF and the cardiorenal outcome vs. placebo with no heterogeneity by baseline HbA1c (P-interaction >0.05).</p> <p><b>Conclusions</b>: High HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c<7%.</p>

scholarly journals Series: Cardiovascular outcome trials for diabetes drugs Lixisenatide and ELIXA

2020 ◽  
Vol 20 (1) ◽  
pp. 52-54
Author(s):  
Miles Fisher
Keyword(s):  
Myocardial Infarction ◽  
Unstable Angina ◽  
Cardiovascular Events ◽  
Cardiovascular Outcome ◽  
Secondary Outcome ◽  
Major Adverse Cardiovascular Events ◽  
Cardiovascular Outcome Trials ◽  
Receptor Agonists ◽  
Coronary Syndrome ◽  
Cardiovascular Outcome Trial

ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) was an FDA mandated cardiovascular outcome trial with lixisenatide. In contrast to later cardiovascular outcome trials with glucagon-like peptide-1 (GLP-1) receptor agonists, it was performed in subjects with a recent myocardial infarction or hospitalisation for unstable angina within the previous 180 days. ELIXA compared lixisenatide and placebo in 6,068 subjects with type 2 diabetes and demonstrated non-inferiority for major cardiovascular events plus unstable angina (cardiovascular death, myocardial infarction, stroke, unstable angina) but not superiority. Similarly, there was no difference in hospitalisation for heart failure which was a secondary outcome. A subsequent exploratory analysis showed that lixisenatide reduced progression of the urinary albumin to creatinine ratio in patients with macroalbuminuria, and was associated with a lower risk of new-onset macroalbuminuria. No clear clinical benefit has been established for lixisenatide, and there are alternative GLP-1 receptor agonists such as liraglutide, semaglutide and dulaglutide that are associated with a reduction in major adverse cardiovascular events.

scholarly journals Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes

2019 ◽  
Vol 16 (2) ◽  
pp. 133-143 ◽  
Author(s):  
Ralph A DeFronzo ◽  
Silvio Inzucchi ◽  
Muhammad Abdul-Ghani ◽  
Steven E Nissen
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Events ◽  
Cell Function ◽  
Cost Effective ◽  
Cardiovascular Outcome ◽  
Major Adverse Cardiovascular Events ◽  
Insulin Sensitizer ◽  
Nonalcoholic Fatty Liver ◽  
Cardiovascular Outcome Trials

Type 2 diabetes individuals are at high risk for macrovascular complications: myocardial infarction, stroke and cardiovascular mortality. Recent cardiovascular outcome trials have demonstrated that agents in two antidiabetic classes (SGLT2 inhibitors and GLP-1 receptor agonists) reduce major adverse cardiovascular events. However, there is strong evidence that an older and now generically available medication, the thiazolidinedione, pioglitazone, can retard the atherosclerotic process (PERISCOPE and Chicago) and reduce cardiovascular events in large randomized prospective cardiovascular outcome trials (IRIS and PROactive). Pioglitazone is a potent insulin sensitizer, preserves beta-cell function, causes durable reduction in HbA1c, corrects multiple components of metabolic syndrome and improves nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Adverse effects (weight gain, fluid retention, fractures) must be considered, but are diminished with lower doses and are arguably outweighed by these multiple benefits. With healthcare expenses attributable to diabetes increasing rapidly, this cost-effective drug requires reconsideration in the therapeutic armamentarium for the disease.

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.

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