Saxagliptin for T2DM: Assessing Cardiovascular Data
Saxagliptin for T2DM: Assessing Cardiovascular Data
Within each trial and across all trials, the saxagliptin and comparator groups were generally balanced for baseline demographic and clinical characteristics, including median age (54 y vs 55 y), sex (51% vs 50% female), race (73% vs 71% white), mean BMI (30.4 kg/m vs 30.3 kg/m), mean HbA1c (8.5% vs 8.4%), and presence of at least 1 additional CV risk factor other than T2DM (81% vs 83%; including hypertension [52% vs 55%], hypercholesterolemia [44% vs 45%], and history of CV disease [12% vs 13%]).
The meta-analysis identified a total of 41 first major adverse CV events (MACE), including CV-related death, nonfatal myocardial infarction, and nonfatal stroke. These events occurred in 23 patients who received saxagliptin (0.7% of all saxagliptin-treated patients) and 18 patients who received comparators (1.4% of all comparator-treated patients) (Table 1). In addition, an independent clinical events committee performed a blinded, post-hoc, retrospective adjudication of all deaths and all events possibly representing a myocardial infarction and/or stroke from among all events coded to any of the 148 preferred terms representing possible ischemic events from 2 MedDRA standard queries: "myocardial infarction" and "central nervous system hemorrhages and cerebrovascular accidents". The results were close to the numbers of investigator-reported MACE (Table 1). From a total of 147 cases reviewed for potential MACE, 40 patients had confirmed events, including 22 saxagliptin-treated patients and 18 comparator-treated patients. Investigator reports and the independent clinical events committee identified 38 common patients with MACE; 3 patients were unique to the investigator report and 2 patients were unique to the adjudicated cases.
In the analysis of relative risk with saxagliptin, the Cox proportional hazard ratio was 0.44 (95% CI, 0.24–0.82) for investigator-based assessments and 0.43 (95% CI, 0.23–0.80) for independently adjudicated events. The numbers of patients with a CV event per 1000 patient-years of follow-up are lower with all saxagliptin regimens combined than with all comparators (Table 2). This finding suggested that saxagliptin may reduce CV risk in patients with T2DM, a hypothesis that will be evaluated in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial.
Pooled analyses of nonadjudicated events with sitagliptin and adjudicated CV-related events with vildagliptin, linagliptin, and alogliptin have been reported. The relative risk for sitagliptin versus comparators was 0.68 (95% CI, 0.41–1.12). With vildagliptin, relative risks of cardiocerebrovascular events were 0.88 (95% CI, 0.37–2.11) with vildagliptin 50 mg once daily and 0.84 (95% CI, 0.62–1.14) with vildagliptin 50 mg twice daily. Data from a prespecified, prospective meta-analysis of the linagliptin phase III studies showed a relative risk of CV-related events with linagliptin versus comparators of 0.34 (95% CI, 0.16–0.70). Meta-analysis of phase II and III studies with alogliptin versus placebo calculated a relative risk of 0.63 (95% CI, 0.21–1.91).
Saxagliptin is being evaluated in the SAVOR-TIMI 53 trial (ClinicalTrials.gov identifier NCT01107886), to demonstrate CV safety. Additionally, based on the results of the saxagliptin meta-analysis, the SAVOR-TIMI 53 trial was also powered to determine whether saxagliptin can reduce the risk of CV events. The study plans to enroll 16,500 patients with T2DM who have HbA1c ≥6.5% and a high risk for CV events (defined as established CV disease and/or multiple risk factors). Eligible patients will be randomly allocated to receive saxagliptin (5 mg for patients with normal or mildly impaired renal function or 2.5 mg for those with moderate renal impairment) or placebo once daily during the approximately 5-year study period, the projected timeframe necessary to observe 1,040 MACE. The primary outcome is a composite of CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke; completion is expected by the middle of 2015.
Sitagliptin is being evaluated in the TECOS trial (Randomized, Placebo-Controlled Clinical Trial to Evaluate Cardiovascular Outcomes After Treatment With Sitagliptin in Patients With T2DM and Inadequate Glycemic Control trial [NCT00790205]), which is designed to assess CV outcomes with sitagliptin (100 mg once daily; or 50 mg for those with moderate renal impairment) versus placebo in patients older than 50 years with preexisting CV disease and HbA1c of 6.5% to 8.0% receiving usual care including other antihyperglycemic agents. The primary outcome measure is time to first CV event (a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina requiring hospitalization). The study plans to enroll 14,000 patients who will be treated and followed up for ≤5 years, until 1300 CV events are observed; study completion is expected in December 2014.
Linagliptin, the newest DPP-4 inhibitor (approved by the FDA in May 2011), will be evaluated for CV outcomes in the CAROLINA trial (Multicentre, International, Randomised, Parallel-Group, Double-Blind Study to Evaluate Cardiovascular Safety of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk [NCT01243424]). The planned study population is 6000 patients with T2DM who have preexisting or T2DM-related CV disease, are older than 70 years, or have ≥2 specified CV risk factors. The primary endpoint is time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina pectoris; study completion is expected in 2018.
The effect of alogliptin on CV outcomes is being investigated in patients with T2DM who have acute coronary syndrome in the EXAMINE trial (Examination of Cardiovascular Outcomes: Alogliptin vs Standard-of-Care in Patients With T2DM and Acute Coronary Syndrome trial [NCT00968708]). This study plans to enroll 5400 patients (HbA1c 6.5%-11.0% on monotherapy or combination antidiabetic therapy, or 7.0%-9.0% if the regimen includes insulin) who have a diagnosis of acute coronary syndrome within 15 to 90 days before randomization. Patients will be randomly allocated to receive alogliptin or placebo once daily for up to 4.75 years, each in addition to the standard of care; the daily dose of alogliptin will be 25 mg for patients with normal or mildly impaired renal function, 12.5 mg for those with moderate renal impairment, and 6.25 mg for those with severe renal impairment or end-stage renal disease. The primary outcome is a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and urgent revascularization due to unstable angina, with study completion expected in 2014.
Results
Within each trial and across all trials, the saxagliptin and comparator groups were generally balanced for baseline demographic and clinical characteristics, including median age (54 y vs 55 y), sex (51% vs 50% female), race (73% vs 71% white), mean BMI (30.4 kg/m vs 30.3 kg/m), mean HbA1c (8.5% vs 8.4%), and presence of at least 1 additional CV risk factor other than T2DM (81% vs 83%; including hypertension [52% vs 55%], hypercholesterolemia [44% vs 45%], and history of CV disease [12% vs 13%]).
The meta-analysis identified a total of 41 first major adverse CV events (MACE), including CV-related death, nonfatal myocardial infarction, and nonfatal stroke. These events occurred in 23 patients who received saxagliptin (0.7% of all saxagliptin-treated patients) and 18 patients who received comparators (1.4% of all comparator-treated patients) (Table 1). In addition, an independent clinical events committee performed a blinded, post-hoc, retrospective adjudication of all deaths and all events possibly representing a myocardial infarction and/or stroke from among all events coded to any of the 148 preferred terms representing possible ischemic events from 2 MedDRA standard queries: "myocardial infarction" and "central nervous system hemorrhages and cerebrovascular accidents". The results were close to the numbers of investigator-reported MACE (Table 1). From a total of 147 cases reviewed for potential MACE, 40 patients had confirmed events, including 22 saxagliptin-treated patients and 18 comparator-treated patients. Investigator reports and the independent clinical events committee identified 38 common patients with MACE; 3 patients were unique to the investigator report and 2 patients were unique to the adjudicated cases.
In the analysis of relative risk with saxagliptin, the Cox proportional hazard ratio was 0.44 (95% CI, 0.24–0.82) for investigator-based assessments and 0.43 (95% CI, 0.23–0.80) for independently adjudicated events. The numbers of patients with a CV event per 1000 patient-years of follow-up are lower with all saxagliptin regimens combined than with all comparators (Table 2). This finding suggested that saxagliptin may reduce CV risk in patients with T2DM, a hypothesis that will be evaluated in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial.
Cardiovascular Risk With Other Dipeptidyl Peptidase-4 Inhibitors
Pooled analyses of nonadjudicated events with sitagliptin and adjudicated CV-related events with vildagliptin, linagliptin, and alogliptin have been reported. The relative risk for sitagliptin versus comparators was 0.68 (95% CI, 0.41–1.12). With vildagliptin, relative risks of cardiocerebrovascular events were 0.88 (95% CI, 0.37–2.11) with vildagliptin 50 mg once daily and 0.84 (95% CI, 0.62–1.14) with vildagliptin 50 mg twice daily. Data from a prespecified, prospective meta-analysis of the linagliptin phase III studies showed a relative risk of CV-related events with linagliptin versus comparators of 0.34 (95% CI, 0.16–0.70). Meta-analysis of phase II and III studies with alogliptin versus placebo calculated a relative risk of 0.63 (95% CI, 0.21–1.91).
Ongoing Cardiovascular Outcome Studies
Saxagliptin is being evaluated in the SAVOR-TIMI 53 trial (ClinicalTrials.gov identifier NCT01107886), to demonstrate CV safety. Additionally, based on the results of the saxagliptin meta-analysis, the SAVOR-TIMI 53 trial was also powered to determine whether saxagliptin can reduce the risk of CV events. The study plans to enroll 16,500 patients with T2DM who have HbA1c ≥6.5% and a high risk for CV events (defined as established CV disease and/or multiple risk factors). Eligible patients will be randomly allocated to receive saxagliptin (5 mg for patients with normal or mildly impaired renal function or 2.5 mg for those with moderate renal impairment) or placebo once daily during the approximately 5-year study period, the projected timeframe necessary to observe 1,040 MACE. The primary outcome is a composite of CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke; completion is expected by the middle of 2015.
Sitagliptin is being evaluated in the TECOS trial (Randomized, Placebo-Controlled Clinical Trial to Evaluate Cardiovascular Outcomes After Treatment With Sitagliptin in Patients With T2DM and Inadequate Glycemic Control trial [NCT00790205]), which is designed to assess CV outcomes with sitagliptin (100 mg once daily; or 50 mg for those with moderate renal impairment) versus placebo in patients older than 50 years with preexisting CV disease and HbA1c of 6.5% to 8.0% receiving usual care including other antihyperglycemic agents. The primary outcome measure is time to first CV event (a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina requiring hospitalization). The study plans to enroll 14,000 patients who will be treated and followed up for ≤5 years, until 1300 CV events are observed; study completion is expected in December 2014.
Linagliptin, the newest DPP-4 inhibitor (approved by the FDA in May 2011), will be evaluated for CV outcomes in the CAROLINA trial (Multicentre, International, Randomised, Parallel-Group, Double-Blind Study to Evaluate Cardiovascular Safety of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk [NCT01243424]). The planned study population is 6000 patients with T2DM who have preexisting or T2DM-related CV disease, are older than 70 years, or have ≥2 specified CV risk factors. The primary endpoint is time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina pectoris; study completion is expected in 2018.
The effect of alogliptin on CV outcomes is being investigated in patients with T2DM who have acute coronary syndrome in the EXAMINE trial (Examination of Cardiovascular Outcomes: Alogliptin vs Standard-of-Care in Patients With T2DM and Acute Coronary Syndrome trial [NCT00968708]). This study plans to enroll 5400 patients (HbA1c 6.5%-11.0% on monotherapy or combination antidiabetic therapy, or 7.0%-9.0% if the regimen includes insulin) who have a diagnosis of acute coronary syndrome within 15 to 90 days before randomization. Patients will be randomly allocated to receive alogliptin or placebo once daily for up to 4.75 years, each in addition to the standard of care; the daily dose of alogliptin will be 25 mg for patients with normal or mildly impaired renal function, 12.5 mg for those with moderate renal impairment, and 6.25 mg for those with severe renal impairment or end-stage renal disease. The primary outcome is a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and urgent revascularization due to unstable angina, with study completion expected in 2014.
