Cardiovascular Safety of Saxagliptin in Patients With T2DM
Cardiovascular Safety of Saxagliptin in Patients With T2DM
Background: It is important to establish the cardiovascular (CV) safety profile of novel antidiabetic drugs.
Methods: Pooled analyses were performed of 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy in patients with type 2 diabetes mellitus (T2DM) as well as a subset of 11 saxagliptin + metformin studies. Adjudicated major adverse CV events (MACE; CV death, myocardial infarction [MI], and stroke) and investigator-reported heart failure were assessed, and incidence rates (IRs; events/100 patient-years) and IR ratios (IRRs; saxagliptin/control) were calculated (Mantel-Haenszel method).
Results: In pooled datasets, the IR point estimates for MACE and individual components of CV death, MI, and stroke favored saxagliptin, but the 95% CI included 1. IRR (95% CI) for MACE in the 20-study pool was 0.74 (0.45, 1.25). The Cox proportional hazard ratio (95% CI) was 0.75 (0.46, 1.21), suggesting no increased risk of MACE in the 20-study pool. In the 11-study saxagliptin + metformin pool, the IRR for MACE was 0.93 (0.44, 1.99). In the 20-study pool, the IRR for heart failure was 0.55 (0.27, 1.12).
Conclusions: Analysis of pooled data from 20 clinical trials in patients with T2DM suggests that saxagliptin is not associated with an increased CV risk.
Cardiovascular (CV) disease is the leading cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). In the United States, the prevalence of self-reported CV disease in people with T2DM is estimated to be >30%, and CV events account for almost 70% of diabetes-related deaths in individuals aged ≥65 years.
Although epidemiologic studies suggest that hyperglycemia is associated with adverse CV events, the effects of intensive glycemic control on CV outcomes in interventional studies are not clear. Moreover, in some studies and with some antihyperglycemic drugs, a tendency toward an increased risk for CV events has been reported. However, follow-up of prominent clinical trials in type 1 and T2DM suggest that intensive glycemic control may reduce CV events over the long term.
Because of the uncertainty surrounding glycemic control and CV events and the association of increased CV events with some antihyperglycemic drugs, in 2008 the US Food and Drug Administration recommended that CV safety be assessed as a component of the clinical development program of new antihyperglycemic drugs.
Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. DPP-4 inhibitors are oral antihyperglycemic agents that inhibit the inactivation of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, resulting in increased glucose-dependent insulin secretion and suppression of glucagon secretion. Observational evidence suggests that GLP-1 may have protective effects on the CV system, independent of glucose control. However, DPP-4 is increased in patients with T2DM and elevated circulating DPP-4 is associated with subclinical left ventricular dysfunction in these patients. Therefore, it is of interest to assess the CV safety of DPP-4 inhibitors.
In randomized, controlled, clinical trials, saxagliptin was effective and well tolerated over 24 weeks in improving glycemic control when used as monotherapy and as add-on therapy to metformin, glyburide, or a thiazolidinedione in patients with T2DM. The advantages of DPP-4 inhibitors are their tolerability, a low rate of hypoglycemia, and weight neutrality.
Results from large outcome trials of saxagliptin in patients with prior CV disease or multiple CV risk factors (SAVOR) and alogliptin in patients after acute coronary syndrome (EXAMINE) have recently been published and have shown that saxagliptin and alogliptin do not increase or decrease major adverse CV events (MACE). In contrast to those trials in patients with T2DM and high CV risk, the current analysis evaluated MACE and its individual component events of CV death, myocardial infarction (MI) and stroke, as well as heart failure, with saxagliptin in the general population of patients with T2DM that participated in the saxagliptin clinical development program. The present analysis expands on a previous assessment of the CV safety of saxagliptin and analyzes MACE in 20 phase 2 and 3 trials of saxagliptin versus placebo or active comparator.
Abstract and Introduction
Abstract
Background: It is important to establish the cardiovascular (CV) safety profile of novel antidiabetic drugs.
Methods: Pooled analyses were performed of 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy in patients with type 2 diabetes mellitus (T2DM) as well as a subset of 11 saxagliptin + metformin studies. Adjudicated major adverse CV events (MACE; CV death, myocardial infarction [MI], and stroke) and investigator-reported heart failure were assessed, and incidence rates (IRs; events/100 patient-years) and IR ratios (IRRs; saxagliptin/control) were calculated (Mantel-Haenszel method).
Results: In pooled datasets, the IR point estimates for MACE and individual components of CV death, MI, and stroke favored saxagliptin, but the 95% CI included 1. IRR (95% CI) for MACE in the 20-study pool was 0.74 (0.45, 1.25). The Cox proportional hazard ratio (95% CI) was 0.75 (0.46, 1.21), suggesting no increased risk of MACE in the 20-study pool. In the 11-study saxagliptin + metformin pool, the IRR for MACE was 0.93 (0.44, 1.99). In the 20-study pool, the IRR for heart failure was 0.55 (0.27, 1.12).
Conclusions: Analysis of pooled data from 20 clinical trials in patients with T2DM suggests that saxagliptin is not associated with an increased CV risk.
Introduction
Cardiovascular (CV) disease is the leading cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). In the United States, the prevalence of self-reported CV disease in people with T2DM is estimated to be >30%, and CV events account for almost 70% of diabetes-related deaths in individuals aged ≥65 years.
Although epidemiologic studies suggest that hyperglycemia is associated with adverse CV events, the effects of intensive glycemic control on CV outcomes in interventional studies are not clear. Moreover, in some studies and with some antihyperglycemic drugs, a tendency toward an increased risk for CV events has been reported. However, follow-up of prominent clinical trials in type 1 and T2DM suggest that intensive glycemic control may reduce CV events over the long term.
Because of the uncertainty surrounding glycemic control and CV events and the association of increased CV events with some antihyperglycemic drugs, in 2008 the US Food and Drug Administration recommended that CV safety be assessed as a component of the clinical development program of new antihyperglycemic drugs.
Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. DPP-4 inhibitors are oral antihyperglycemic agents that inhibit the inactivation of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, resulting in increased glucose-dependent insulin secretion and suppression of glucagon secretion. Observational evidence suggests that GLP-1 may have protective effects on the CV system, independent of glucose control. However, DPP-4 is increased in patients with T2DM and elevated circulating DPP-4 is associated with subclinical left ventricular dysfunction in these patients. Therefore, it is of interest to assess the CV safety of DPP-4 inhibitors.
In randomized, controlled, clinical trials, saxagliptin was effective and well tolerated over 24 weeks in improving glycemic control when used as monotherapy and as add-on therapy to metformin, glyburide, or a thiazolidinedione in patients with T2DM. The advantages of DPP-4 inhibitors are their tolerability, a low rate of hypoglycemia, and weight neutrality.
Results from large outcome trials of saxagliptin in patients with prior CV disease or multiple CV risk factors (SAVOR) and alogliptin in patients after acute coronary syndrome (EXAMINE) have recently been published and have shown that saxagliptin and alogliptin do not increase or decrease major adverse CV events (MACE). In contrast to those trials in patients with T2DM and high CV risk, the current analysis evaluated MACE and its individual component events of CV death, myocardial infarction (MI) and stroke, as well as heart failure, with saxagliptin in the general population of patients with T2DM that participated in the saxagliptin clinical development program. The present analysis expands on a previous assessment of the CV safety of saxagliptin and analyzes MACE in 20 phase 2 and 3 trials of saxagliptin versus placebo or active comparator.
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