Cardiovascular Outcome Trial of Empagliflozin
Cardiovascular Outcome Trial of Empagliflozin
Background: Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME™ trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes.
Methods: Patients who were drug-naïve (HbA1c ≥7.0% and ≤9.0%), or on background glucose-lowering therapy (HbA1c ≥7.0% and ≤10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until ≥691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided α of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved.
Results: Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 ± 9 years, BMI 30.6 ± 5.3 kg/m, HbA1c 8.1 ± 0.8%, and eGFR 74 ± 21 ml/min/1.73 m. The study is expected to report in 2015.
Discussion: EMPA-REG OUTCOME™ will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.
Type 2 diabetes mellitus (T2DM) is frequently associated with comorbidities that exacerbate cardiovascular (CV) risk, such as obesity and hypertension. The risk of CV disease is increased approximately two to four-fold in adults with diabetes even after adjustment for conventional risk factors (age, sex, smoking status, body mass index [BMI], systolic blood pressure [BP], and lipids). Recommended strategies for reducing CV risk in patients with T2DM include glucose management, lipid lowering, BP control, smoking cessation, and weight loss. Improved glycemic control has been associated with a reduction in microvascular events and there is a clear association between microvascular complications such as albuminuria and an increased risk of CV events in patients with T2DM. However, the impact of reducing blood glucose, and the potential benefit of specific glucose-lowering agents, on CV events in patients with T2DM remains unclear and highly controversial. Moreover, treatment must likely occur over a substantial duration of time, since macrovascular outcome events are known to be late complications of a progressive multifaceted pathogenic process that spans decades. Lately, regulatory authorities have issued guidance for evaluating the long-term CV safety of new anti-diabetes agents to ensure that CV safety is demonstrated with reasonable assurance. These mandated trials provide an opportunity to potentially demonstrate CV as well as microvascular benefits of new anti-diabetes drugs.
Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetes agents that reduce hyperglycemia in patients with T2DM by reducing renal glucose reabsorption and thus increasing urinary glucose excretion (UGE). Empagliflozin is a potent and selective inhibitor of SGLT2. In placebo-controlled phase III trials in patients with T2DM, empagliflozin used as monotherapy or add-on therapy improved hemoglobin A1c (HbA1c) approximately 0.7–1.0% -point (depending on baseline HbA1c and renal function) with a low risk of hypoglycemia, reduced body weight and BP, without increases in heart rate, and had small effects on plasma lipids (increase in HDL-cholesterol, increase in LDL-cholesterol, no change in LDL/HDL cholesterol ratio). In addition, empagliflozin has been shown to improve arterial stiffness and reduce glomerular hyperfiltration in patients with type 1 diabetes mellitus (T1DM). Moreover, SGLT2 inhibitors have also been reported to reduce other CV risk markers such as visceral fat mass and proteinuria. Based on these pleiotropic effects on CV risk factors, we hypothesized that empagliflozin may reduce CV risk in patients with T2DM.
The EMPA-REG OUTCOME™ trial was designed to determine the long-term CV safety of empagliflozin in patients with T2DM and to investigate its potential cardioprotective effects, as well as impact on microvascular outcomes, in a dedicated study that complied with current regulatory requirements.
Abstract and Introduction
Abstract
Background: Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME™ trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes.
Methods: Patients who were drug-naïve (HbA1c ≥7.0% and ≤9.0%), or on background glucose-lowering therapy (HbA1c ≥7.0% and ≤10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until ≥691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided α of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved.
Results: Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 ± 9 years, BMI 30.6 ± 5.3 kg/m, HbA1c 8.1 ± 0.8%, and eGFR 74 ± 21 ml/min/1.73 m. The study is expected to report in 2015.
Discussion: EMPA-REG OUTCOME™ will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.
Introduction
Type 2 diabetes mellitus (T2DM) is frequently associated with comorbidities that exacerbate cardiovascular (CV) risk, such as obesity and hypertension. The risk of CV disease is increased approximately two to four-fold in adults with diabetes even after adjustment for conventional risk factors (age, sex, smoking status, body mass index [BMI], systolic blood pressure [BP], and lipids). Recommended strategies for reducing CV risk in patients with T2DM include glucose management, lipid lowering, BP control, smoking cessation, and weight loss. Improved glycemic control has been associated with a reduction in microvascular events and there is a clear association between microvascular complications such as albuminuria and an increased risk of CV events in patients with T2DM. However, the impact of reducing blood glucose, and the potential benefit of specific glucose-lowering agents, on CV events in patients with T2DM remains unclear and highly controversial. Moreover, treatment must likely occur over a substantial duration of time, since macrovascular outcome events are known to be late complications of a progressive multifaceted pathogenic process that spans decades. Lately, regulatory authorities have issued guidance for evaluating the long-term CV safety of new anti-diabetes agents to ensure that CV safety is demonstrated with reasonable assurance. These mandated trials provide an opportunity to potentially demonstrate CV as well as microvascular benefits of new anti-diabetes drugs.
Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetes agents that reduce hyperglycemia in patients with T2DM by reducing renal glucose reabsorption and thus increasing urinary glucose excretion (UGE). Empagliflozin is a potent and selective inhibitor of SGLT2. In placebo-controlled phase III trials in patients with T2DM, empagliflozin used as monotherapy or add-on therapy improved hemoglobin A1c (HbA1c) approximately 0.7–1.0% -point (depending on baseline HbA1c and renal function) with a low risk of hypoglycemia, reduced body weight and BP, without increases in heart rate, and had small effects on plasma lipids (increase in HDL-cholesterol, increase in LDL-cholesterol, no change in LDL/HDL cholesterol ratio). In addition, empagliflozin has been shown to improve arterial stiffness and reduce glomerular hyperfiltration in patients with type 1 diabetes mellitus (T1DM). Moreover, SGLT2 inhibitors have also been reported to reduce other CV risk markers such as visceral fat mass and proteinuria. Based on these pleiotropic effects on CV risk factors, we hypothesized that empagliflozin may reduce CV risk in patients with T2DM.
The EMPA-REG OUTCOME™ trial was designed to determine the long-term CV safety of empagliflozin in patients with T2DM and to investigate its potential cardioprotective effects, as well as impact on microvascular outcomes, in a dedicated study that complied with current regulatory requirements.