Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure

Koyani, Chintan N.; Kolesnik, Ewald; Wölkart, Gerald; Shrestha, Niroj; Scheruebel, Susanne; Trummer, Christopher; Zorn-Pauly, Klaus; Hammer, Astrid; Lang, Petra; Reicher, Helga; Maechler, H.; Mayer, Bernd; Rainer, Peter P.; Sourij, Harald; Sattler, Wolfgang; Malle, Ernst; Pelzmann, Brigitte; Lewinski, Dirk von

doi:10.1016/j.bcp.2017.08.021

Cited by 34 publications

(45 citation statements)

References 75 publications

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“…These findings may support a possible link between saxagliptin and an increased risk of HF. 85 Whether such changes may also be observed with other DPP-4 inhibitors is unknown. Currently, the safety of saxagliptin about the risk of HF remains a matter of controversy, which justifies a warning in the FDA and European Medicines Agency (EMA) labels of the compound.…”

Section: Results Of Dedicated CV Outcome Trials With Dpp-4 Inhibitorsmentioning

confidence: 99%

Cardiovascular Effects of New Oral Glucose-Lowering Agents

Scheen

2018

Circulation Research

244

157

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Cardiovascular disease (CVD) is a major challenge in the management of type 2 diabetes mellitus. Glucose-lowering agents that reduce the risk of major cardiovascular events would be considered a major advance, as recently reported with liraglutide and semaglutide, 2 glucagon-like peptide-1 receptor agonists, and with empagliflozin and canagliflozin, 2 SGLT-2 (sodium-glucose cotransporter type 2) inhibitors, but not with DPP-4 (dipeptidyl peptidase-4) inhibitors. The present review is devoted to CV effects of new oral glucose-lowering agents. DPP-4 inhibitors (gliptins) showed some positive cardiac and vascular effects in preliminary studies, and initial data from phase 2 to 3 clinical trials suggested a reduction in major cardiovascular events. However, subsequent CV outcome trials with alogliptin, saxagliptin, and sitagliptin showed noninferiority but failed to demonstrate any superiority compared with placebo in patients with type 2 diabetes mellitus and high CV risk. An unexpected higher risk of hospitalization for heart failure was reported with saxagliptin. SGLT-2 inhibitors (gliflozins) promote glucosuria, thus reducing glucose toxicity and body weight, and enhance natriuresis, thus lowering blood pressure. Two CV outcome trials in type 2 diabetes mellitus patients mainly in secondary prevention showed remarkable positive results. Empagliflozin in EMPA-REG-OUTCOME (EMPAgliflozin Cardiovascular OUTCOME Events in Type 2 Diabetes Mellitus Patients) reduced major cardiovascular events, CV mortality, all-cause mortality, and hospitalization for heart failure. In CANVAS (Canagliflozin Cardiovascular Assessment Study), the reduction in CV mortality with canagliflozin failed to reach statistical significance despite a similar reduction in major cardiovascular events. The underlying protective mechanisms of SGLT-2 inhibitors remain unknown and both hemodynamic and metabolic explanations have been proposed. CVD-REAL studies (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors; with the limitation of an observational approach) suggested that these favorable results may be considered as a class effect shared by all SGLT-2 inhibitors (including dapagliflozin) and be extrapolated to a larger population of patients with type 2 diabetes mellitus in primary prevention. Ongoing CV outcome trials with other DPP-4 (linagliptin) and SGLT-2 (dapagliflozin, ertugliflozin) inhibitors should provide additional information about CV effects of both pharmacological classes.

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Section: Results Of Dedicated CV Outcome Trials With Dpp-4 Inhibitorsmentioning

confidence: 99%

Cardiovascular Effects of New Oral Glucose-Lowering Agents

Scheen

2018

Circulation Research

244

157

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“…This results in depleted SR Ca 2+ -content and cytosolic Ca 2+ -overload, as seen in HF, which consequently leads to impaired myocardial function. Moreover, saxagliptin induced prolonged action potential duration and consequently QTc interval via reduced protein-kinase C-mediated delayed rectifier K + current ( Koyani et al, 2017 ).…”

Section: Current Therapies: Novel Glucose-lowering Drugsmentioning

confidence: 99%

Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control

et al. 2018

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Diabetes mellitus and the associated complications represent a global burden on human health and economics. Cardiovascular diseases are the leading cause of death in diabetic patients, who have a 2–5 times higher risk of developing heart failure than age-matched non-diabetic patients, independent of other comorbidities. Diabetic cardiomyopathy is defined as the presence of abnormal cardiac structure and performance in the absence of other cardiac risk factors, such coronary artery disease, hypertension, and significant valvular disease. Hyperglycemia, hyperinsulinemia, and insulin resistance mediate the pathological remodeling of the heart, characterized by left ventricle concentric hypertrophy and perivascular and interstitial fibrosis leading to diastolic dysfunction. A change in the metabolic status, impaired calcium homeostasis and energy production, increased inflammation and oxidative stress, as well as an accumulation of advanced glycation end products are among the mechanisms implicated in the pathogenesis of diabetic cardiomyopathy. Despite a growing interest in the pathophysiology of diabetic cardiomyopathy, there are no specific guidelines for diagnosing patients or structuring a treatment strategy in clinical practice. Anti-hyperglycemic drugs are crucial in the management of diabetes by effectively reducing microvascular complications, preventing renal failure, retinopathy, and nerve damage. Interestingly, several drugs currently in use can improve cardiac health beyond their ability to control glycemia. GLP-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors have been shown to have a beneficial effect on the cardiovascular system through a direct effect on myocardium, beyond their ability to lower blood glucose levels. In recent years, great improvements have been made toward the possibility of modulating the expression of specific cardiac genes or non-coding RNAs in vivo for therapeutic purpose, opening up the possibility to regulate the expression of key players in the development/progression of diabetic cardiomyopathy. This review summarizes the pathogenesis of diabetic cardiomyopathy, with particular focus on structural and molecular abnormalities occurring during its progression, as well as both current and potential future therapies.

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“…The interaction between DPP-4 inhibitors, the cardiovascular system, and more specifically cardiomyocytes has been previously established, but the direct link or mechanism connecting DPP-4 inhibitors to its effects on cardiac contractility and general function is still not fully understood. A recently published paper reported adverse off-target effects of saxagliptin on cardiac function by increasing diastolic calcium content [ 94 ]. Further mechanistic studies are necessary to develop a better understanding of the cardiovascular implications of DPP-4 inhibitors.…”

Section: Introduction and Epidemiologymentioning

confidence: 99%

Revisiting the Diabetes-Heart Failure Connection

et al. 2018

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Purpose of the ReviewTo summarize current clinical data investigating the link between diabetes and heart failure pathophysiology, the association of glucose control with heart failure, and the impact of current antihyperglycemic drugs on heart failure.Recent FindingsAlthough heart failure is one of the most prevalent outcomes occurring in real life and cardiovascular outcome trials, insufficient attention was given to this condition in diabetes research over the last decades. With both beneficial and detrimental findings for heart failure hospitalization in the health authority–mandated outcome trials for new antihyperglycemic agents, research on heart failure and its interplay with diabetes mellitus gained momentum.SummaryDiabetes mellitus and heart failure are both prevalent and intertwined conditions. While currently available heart failure therapies have a similar degree of effectiveness in patients with and without diabetes, the choice of glucose-lowering agents can substantially affect heart failure-related outcome.

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Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure

Cited by 34 publications

References 75 publications

Cardiovascular Effects of New Oral Glucose-Lowering Agents

Cardiovascular Effects of New Oral Glucose-Lowering Agents

Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control

Revisiting the Diabetes-Heart Failure Connection

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