scholarly journals Heterogeneity amongst GLP-1 RA cardiovascular outcome trials results: can definition of established cardiovascular disease be the missing link?

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Miguel Melo ◽  
Cristina Gavina ◽  
José Silva-Nunes ◽  
Luís Andrade ◽  
Davide Carvalho
Keyword(s):  
Cardiovascular Disease ◽  
Adverse Outcomes ◽  
Cardiovascular Outcome ◽  
Incretin Mimetics ◽  
Cardiovascular Outcome Trials ◽  
Glucose Levels ◽  
Reduce Blood Glucose ◽  
Glucagon Like Peptide 1 ◽  
Definition Of ◽  
Atherosclerotic Cardiovascular Diseases

AbstractAtherosclerotic cardiovascular diseases are the leading cause of adverse outcomes in patients with type 2 diabetes, and all new anti-diabetic agents are mandated to undergo cardiovascular outcome trials (CVOTs). Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are incretin mimetics that reduce blood glucose levels with a low associated risk of hypoglycaemia. CVOTs with different GLP-1 RAs yielded different results in terms of major cardiovascular composite outcome (MACE), with some trials showing superiority in the treatment arm, whereas other simply displayed non-inferiority. More importantly, the significance of each component of MACE varied between drugs. This begs the question of whether these differences are due to dissimilarities between drugs or other factors, namely trial design, are at the root of these differences. We analyse the trial designs for all CVOTs with GLP-1 RAs and highlight important differences between them, namely in terms of definition of established cardiovascular disease, and discuss how these differences might explain the disparate results of the trials and preclude direct comparisons between them. We conclude that a fair comparison between GLP-1 RA CVOTs would involve post-hoc analysis re-grouping the patients into different cardiovascular risk categories based upon their baseline clinical parameters, in order to even out the criteria used to classify patients.

scholarly journals Emerging glucose-lowering therapies: a guide for cardiologists

Heart ◽  
2019 ◽  
Vol 106 (1) ◽  
pp. 18-23 ◽  
Author(s):  
Gaurav S Gulsin ◽  
Matthew P M Graham-Brown ◽  
Melanie J Davies ◽  
Gerry P McCann
Keyword(s):  
Cardiovascular Disease ◽  
Clinical Practice ◽  
Large Scale ◽  
Cardiovascular Outcome ◽  
Glucose Lowering ◽  
Cardiovascular Outcome Trials ◽  
Sodium Glucose Cotransporter ◽  
Emerging Treatments ◽  
Glucagon Like Peptide 1 ◽  
Safety Considerations

In recent large-scale cardiovascular outcome trials, two new classes of glucose-lowering medications—sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs)—demonstrated cardiovascular benefits in adults with type 2 diabetes mellitus (T2DM). These findings have prompted growing optimism among clinicians regarding the potential for these agents to reduce the burden of cardiovascular disease in people with T2DM. GLP-1RAs and SGLT2i are now advocated as second-line agents in European and US guidelines for management of both hyperglycaemia and for primary prevention of cardiovascular disease in people with T2DM. Given the high prevalence of T2DM in patients with cardiovascular disease, cardiologists will increasingly encounter these agents in routine clinical practice. In this review, we summarise evidence from cardiovascular outcome trials of GLP-1RAs and SGLT2i, give practical advice on prescribing and detail safety considerations associated with their use. We also highlight areas where further work is needed, giving details on active clinical trials. The review aims to familiarise cardiologists with these emerging treatments, which will be increasingly encountered in clinical practice, given the expanding representation of T2DM in patients with cardiovascular disease. Whether these drugs will be initiated by cardiologists remains to be determined.

Redefining Cardiovascular (CV) Death as a Primary Endpoint Component in Cardiovascular Outcome Trials

2020 ◽  
Vol 16 (9) ◽  
pp. 917-921 ◽  
Author(s):  
Samit Ghosal ◽  
Binayak Sinha
Keyword(s):  
Meta Analysis ◽  
Cardiovascular Outcome ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cardiovascular Outcome Trials ◽  
Sodium Glucose Cotransporter ◽  
Primary Endpoints ◽  
Glucagon Like Peptide 1 ◽  
Definition Of ◽  
Strength Of Association

Sodium-Glucose cotransporter-2 inhibitors (SGLT-2i) and Glucagon-like peptide 1 receptor agonists (GLP1-RA) have revolutionised the approach for modern management of type 2 diabetes in view of their outcome altering abilities. An objective component of the primary endpoints used in the Cardiovascular Outcome Trials (CVOT) is cardiovascular (CV) death. However, the reason behind the decrease in CV deaths (compared to the placebo arm) appear to arise from divergent underlying processes. A recent meta-analysis of SGLT-2i and GLP1-RA indicated that the reduction in CV death associated with the former is predominantly due to its impact on heart failure (HF), while the association with the latter is due to its effect on atherosclerotic cardiovascular disease (ASCVD). A Pearson’s product- moment correlation coefficient (r) analysis was performed on SGLT-2i exposed to CVOTs, exploring the strength of the association between CV death and hospitalisation for HF (hHF) and myocardial infarction (MI). The strength of association was strongest with hHF and negative with MI. In view of these findings, it has been proposed that future CVOTs should use a more objective definition of CVD, defining well in advance the anticipated impact on CVD (either as a consequence of the reduction in HF or ASCVD).

scholarly journals Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes

2019 ◽  
Vol 116 (5) ◽  
pp. 916-930 ◽  
Author(s):  
Valerie D Heuvelman ◽  
Daniël H Van Raalte ◽  
Mark M Smits
Keyword(s):  
Cardiovascular Disease ◽  
Blood Glucose ◽  
Cardiovascular Effects ◽  
Lifestyle Changes ◽  
Mechanistic Studies ◽  
Receptor Agonists ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Type 2 diabetes mellitus (T2DM) is currently one of the most prevalent diseases, with as many as 415 million patients worldwide. T2DM is characterized by elevated blood glucose levels and is often accompanied by several comorbidities, such as cardiovascular disease. Treatment of T2DM is focused on reducing glucose levels by either lifestyle changes or medical treatment. One treatment option for T2DM is based on the gut-derived hormone glucagon-like peptide 1 (GLP-1). GLP-1 reduces blood glucose levels by stimulating insulin secretion, however, it is rapidly degraded, and thereby losing its glycaemic effect. GLP-1 receptor agonists (GLP-1RAs) are immune to degradation, prolonging the glycaemic effect. Lately, GLP-1RAs have spiked the interest of researchers and clinicians due to their beneficial effects on cardiovascular disease. Preclinical and clinical data have demonstrated that GLP-1 receptors are abundantly present in the heart and that stimulation of these receptors by GLP-1 has several effects. In this review, we will discuss the effects of GLP-1RA on heart rate, blood pressure, microvascular function, lipids, and inflammation, as measured in human mechanistic studies, and suggest how these effects may translate into the improved cardiovascular outcomes as demonstrated in several trials.

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