saxagliptin and heart failure

INTRODUCTION: Saxagliptin, a member of the dipeptidyl peptidase-4 inhibitor (DPP-4i) class of drugs, was approved by the FDA for the treatment of type 2 diabetes (T2D) in 2009, and has been in clinical use for more than a decade. Since the drug was first launched, much real-world evidence has also been accumulated. The efficacy and safety of saxagliptin, especially its cardiovascular safety, are of particular interest. AREAS COVERED: This review provides an overview of the safety and efficacy of saxagliptin based on observational studies, pharmacovigilance, and meta-analyses...

Type 2 diabetes mellitus (T2DM) is highly prevalent in the general population and especially in patients with heart failure (HF). It is not only a risk factor for incident HF, but is also associated with worse outcomes in prevalent HF. Therefore, antihyperglycaemic management in patients at risk of or with established HF is of importance to reduce morbidity/mortality. Following revision of the drug approval process in 2008 by the Food and Drug Administration and European Medicines Agency, several cardiovascular outcome trials on antihyperglycaemic drugs have recently investigated HF endpoints...

Dipeptidyl peptidase-4 (DPP-4) inhibitors or gliptins belong to the class of incretin mimetics, one important group of antidiabetic medications. These drugs were available in the market for management of type 2 diabetes mellitus (T2DM) over a decade. Sitagliptin, linagliptin, vildagliptin, saxagliptin and alogliptin are the common drugs from gliptin family widely available globally, whilst anagliptin, gemigliptin and teneliptin are used mainly in the Asian countries. The glycemic control conferred by gliptins varies among individual molecules with an average reduction of glycated hemoglobin (HbA1c) ranging between -0...

BACKGROUND: The World Health Organization estimates that diabetes is the seventh leading cause of death. Uncontrolled diabetes may cause severe consequences such as cardiovascular (CV) events (myocardial infarction, stroke, or CV mortality), lower-extremity amputations, and end-stage renal disease. Microvascular complications include retinopathy, autonomic and peripheral neuropathy, nephropathy, and diabetic ulcers. Major CV outcomes trials that were by the Food and Drug Administration for all new antihyperglycemia medications for patients at high risk for CV events were recently completed for all 4 US-marketed dipeptidyl peptidase-4 (DPP-4) inhibitors...

PURPOSE OF REVIEW: Results from cardiovascular (CV) outcome trials have revealed important insights into the CV safety and efficacy of glucose-lowering agents, including dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). RECENT FINDINGS: Among patients with T2DM, DPP-4i have no significant effect on risk of major adverse CV events (MACE: CV death, myocardial infarction, or stroke) with mixed results regarding risk for heart failure (HF)...

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are one of the most widely used antihyperglycemic therapeutic classes in type 2 diabetes mellitus management. In April 2016 and August 2017, the US Food and Drug Administration (FDA) introduced sequential labelling requirements regarding heart failure risk related to DPP-4i. We explored longitudinal trends in prescription of DPP-4i before and after these FDA warnings in a multicenter health system. We identified all first-time prescriptions of DPP4i or their combinations across the Partners HealthCare system (Boston, MA) from October 2006 (FDA approval of first DPP-4i) to December 2018...

Treatment options for type 2 diabetes have expanded. While metformin remains the first line treatment in most cases, choices for second line treatment now extend beyond sulfonylureas and include the sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors. SGLT2 inhibitors are recommended for people with atherosclerotic cardiovascular disease, heart failure or kidney disease. Diabetic ketoacidosis is an uncommon but important side effect; its occurrence can be minimised with appropriate patient education and management, especially during perioperative periods and times of illness...

Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality. Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose-lowering medications showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical implications in HF [i.e. dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose co-transporter type 2 (SGLT-2) inhibitors]...

INTRODUCTION: Dipeptidyl peptidase 4 (DPP4) inhibitors are widely used in type 2 diabetes mellitus (T2DM) patients but the data available in existing clinical trial programmes on DPP4 inhibitors include limited number of patients from India. Hence, this study attempted to understand usage, efficacy and safety of saxagliptin as first add-on after metformin in Indians with T2DM. METHODOLOGY: It was a multicenter, prospective, non-interventional and observational study planned to enrol T2DM patients who were inadequately controlled with metformin alone and had been recently (i...

INTRODUCTION: Since 2008 United State (US) food drug administration mandate, several newer anti-diabetic drugs (ADD) have undergone a mandatory cardiovascular (CV) outcome trial (CVOT) in type diabetes (T2DM) patients with high CV risk. These includes CVOT done with dipeptidyl-peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonist (GLP-1RAs). Several double-blind, randomized, placebo-controlled CVOT have been presented and published in the last decade (2008-2018)...

PURPOSE OF REVIEW: Since the 2008 FDA guidance restructuring the design of trials for the approval of novel glucose-lowering agents, 13 medications have now been evaluated by dedicated cardiovascular outcome trials. All of the completed trials have included data (though with varying definitions) on rates of hospitalization for heart failure. This review is aimed at summarizing current heart failure outcome data available from cardiovascular safety trials for novel glucose-lowering agents in patients with type 2 diabetes mellitus...

Background: Heart failure hospitalization (hHF) with dipeptyl-dipeptidase-4 inhibitors (DPP-4Is) remains at the center stage since the publication of Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus - Thrombolysis in Myocardial Infarction (SAVOR-TIMI) in 2013 showing significant increase with saxagliptin, compared to placebo. This outcome led to additional label of hHF to both saxagliptin and alogliptin in April 2016 and eventual labelling of hHF to all the four approved DPP-4Is in United States in August 2017, by US Food Drug Administration...

Heart failure (HF) in type 2 diabetes mellitus (T2DM) poses a significant increase in mortality. Until recently, anti-diabetic drugs have not been shown to reduce hospitalization due to heart failure (hHF). While thiazolidinedione class and saxagliptin has shown a significantly increased risk, sodium-glucose linked co-transporter 2 inhibitors (SGLT-2Is) have demonstrated a significant reduction in the risk of hHF. Areas covered: We systematically searched the database of PubMed, Embase, ClinicalTrials.gov, and International conference presentation up to 25 December 2018 and retrieved all the studies that were conducted for ≥24 weeks and explicitly reported hHF outcome...

Diabetes mellitus is a major risk factor for cardiovascular (CV) disease. Conversely, CV disease is responsible for a majority of the deaths in patients with diabetes. Many drug trials have concentrated on blood glucose (hemoglobin A1c ) reduction. This strategy, while reducing microvascular outcomes like nephropathy and neuropathy, has little or no effect on reducing macrovascular events like heart attack, stroke, and heart failure. It has been postulated that hypoglycemia may counterbalance some of the beneficial effects of anti-hyperglycemic agents, but this is not proven...

The aim of this network meta-analysis (NMA) was to indirectly compare the cardiovascular (CV) safety of new antidiabetic medications in patients with type 2 diabetes mellitus (T2DM). DATA SYNTHESIS: A search of the Embase and MEDLINE databases was conducted systematically to identify cardiovascular outcome trials (CVOTs) of new antidiabetic medications (DPP-4 inhibitors, GLP-1 agonists and SGLT-2 inhibitors) in patients with T2DM. The primary outcomes were the composite endpoint of CV death, nonfatal MI, and nonfatal stroke (MACE), death from CV causes, nonfatal MI, nonfatal stroke and death from any cause...

An excess risk of heart failure (HF) persists in patients with type 2 diabetes (T2D) despite optimal control of an array of conventional risk factors, including hyperglycaemia. Twelve cardiovascular outcome trials (CVOTs) have been published to date, although none, with the exception of the DECLARE trial with dapagliflozin, has included HF as a primary endpoint. The four trials with dipeptidyl-peptidase inhibitors (DPP-4i) (SAVOR-TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin and CARMELINA with linagliptin) failed to show any significant effect on HF risk in patients with T2D, with the notable exception of saxagliptin which was associated with a 27% increased risk...

Three further cardiovascular (CV) outcome studies of glucose-lowering drugs (linagliptin, albiglutide and dapagliflozin) have recently been published, adding to the twelve earlier within-class studies. The linagliptin study (CARMELINA) recruited people with renal disease as well as prior CV events and confirms the overall CV safety (and other safety) of the dipeptidylpeptidase-4 (DPP4) inhibitors, with no heart failure risk associated with this agent. However, taken together with the findings from two previous studies of DPP4 inhibitors (sitagliptin and saxagliptin), the three DPP4 inhibitor CV outcome trials (CVOTs) have highlighted a safety signal regarding risk of pancreatitis...

OBJECTIVE: While improving glycemic control with antihyperglycemics has been demonstrated to reduce microvascular complications, the benefits of reduction in cardiovascular diseases (CVDs) have not been demonstrated with older agents. This article reviews current evidence of the CV outcomes of newer antihyperglycemics approved since 2008. DATA SOURCES: Peer-reviewed articles were identified from MEDLINE (1966 to October 31, 2018) using search terms exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide, alogliptin, linagliptin, saxagliptin, sitagliptin, canagliflozin, dapagliflozin, empagliflozin, mortality, myocardial infarction (MI), heart failure (HF), and stroke...

Some oral anti-hyperglycemic drugs, including gliptins that inhibit dipeptidyl peptidase 4 (DPP4), have been linked to the increased risk of heart failure (HF) in type-2 diabetic patients. While the cardiovascular safety trial, TECOS, revealed no link between sitagliptin and the risk of HF, a substantial 27% increase in the hospitalization for HF was observed in type-2 diabetic patients treated with saxagliptin within the SAVOR-TIMI 53 trial. A previous in vitro study revealed that saxagliptin impairs the Ca2+ /calmodulin-dependent protein kinase II (CaMKII)-phospholamban (PLB)-sarcoplasmic reticulum Ca2+ -ATPase 2a axis and protein kinase C (PKC) activity in cardiomyocytes leading to impaired cardiac contractility and electrophysiological function...

Dipeptidyl peptidase-4 inhibitors form part of the group of incretin derivatives and conse-quently have a specific mechanism of action. The incretin effect avoids the adverse ef-fects of classic drugs (sulphonylureas) and provides specific benefits for their use in as-sociation with other drugs and in special situations. Because they have a low risk of pro-ducing hypoglycaemia or weight gain, these inhibitors are useful in combination with other oral antidiabetic drugs and even with insulin, although this latter combination may increase the risk of hypoglycaemia...