• Cardiology Clinical Trials
• Myocardial Infarction
• Diabetes Mellitus
• Hyperglycemia/Hypoglycemia

• Cardiology Clinical Trials
• Myocardial Infarction
• Diabetes Mellitus
• Hyperglycemia/Hypoglycemia

Antihyperglycemic therapies have been shown to reduce microvascular events (ie, blindness, amputation, and kidney failure); however, their impact on macrovascular events (ie, cardiovascular [CV] death, myocardial infarction [MI], and stroke) has not been well established. In addition, concerns of increased risk of CV events with some antihyperglycemic therapies prompted the United States Food and Drug Administration and European Medicines Agency to require demonstration of CV safety for all new diabetes therapies [Food and Drug Administration. Guidance for Industry. 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf]. As a result, well-powered trials of CV outcomes in high-risk patients with type 2 diabetes mellitus (T2DM) are being conducted to establish CV safety with new antihyperglycemic drugs.

Saxagliptin and alogliptin, both selective dipeptidyl peptidase 4 (DPP-4) inhibitors, are incretin-based antihyperglycemic therapies that improve glycemic control in T2DM. A meta-analysis of the Phase 2–3 clinical development trials of saxagliptin suggested it may reduce the risk of major adverse cardiac events (MACE) in T2DM but these overall findings were based on few outcomes [Frederich R et al. Postgrad Med 2010].

The purpose of the SAVOR-TIMI 53 and EXAMINE trials was to determine if treatment with saxagliptin or alogliptin, respectively, would be noninferior to placebo for MACE in patients with T2DM at heightened risk of CV events [Scirica BM et al. Am Heart J 2011; White WB et al. N Engl J Med 2013].

Saxagliptin treatment in patients with T2DM and stable atherosclerotic vascular disease or risk factors does not increase the risk of MACE. Deepak L. Bhatt, MD, MPH, Brigham and Women's Hospital, Boston, Massachusetts, USA, presented data from the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus TIMI 53 trial [SAVOR-TIMI 53; Scirica BM et al. N Engl J Med 2013].

In the international, Phase 4 SAVOR-TIMI 53 trial, 16,492 patients with T2DM and a history of or at risk for CV events were randomized to receive saxagliptin 5 mg daily (2.5 mg in patients with an estimated GFR of ≤50 mL/minute) or placebo for a median follow-up of 2.1 years [Scirica BM et al. N Engl J Med 2013]. Eligible patients with established CV disease had to be aged ≥40 years, with documented coronary, cerebrovascular, or peripheral artery atherosclerosis. Patients with risk factors were eligible if they were aged ≥55 (males) or ≥60 (females) years, and had a history of dyslipidemia, hypertension, or active tobacco use. Patients were ineligible if already treated with incretin-based therapy within the last 6 months, or had a history of end-stage renal disease, long-term dialysis, renal transplantation, or serum creatinine levels of ≥6.0 mg/dL (530 μmol/L).

The primary endpoint was a composite of CV death, nonfatal MI, or nonfatal ischemic stroke. Secondary endpoints included the primary endpoint plus hospitalization due to heart failure (HF), coronary revascularization, or unstable angina, and each component of the composite CV endpoints.

The occurrence of the primary endpoint at 2 years was similar in both study arms (7.3% saxagliptin vs 7.2% placebo; HR, 1.00; 95% CI, 0.89 to 1.12; superiority p=0.99; noninferiority p<0.001). The broader secondary endpoint was also similar (12.8% with saxagliptin vs 12.4% with placebo; HR, 1.02; 95% CI, 0.94 to 1.11; superiority p=0.66; noninferiority p<0.001).

Individual CV outcomes were consistently similar between both treatment arms with the exception of hospitalization for HF, which occurred more frequently in the saxagliptin arm (3.5%) compared with the placebo arm (2.8%; HR, 1.27; 95% CI, 1.07 to 1.51; p=0.007). Major hypoglycemic events (defined when the event required a third party to intervene actively) occurred more frequently with saxagliptin (2.1% vs 1.7%; p=0.047); however, hospitalization for hypoglycemia was similar in both arms (p=0.33). Cases of acute and chronic pancreatitis (p=0.77), and pancreatic cancer (p=0.095), were infrequent and similar between both arms.

In the EXAMINE trial, alogliptin therapy in patients with T2DM with recent acute coronary syndrome (ACS) similarly did not increase the risk of MACE. William B. White, MD, University of Connecticut School of Medicine, Farmington, Connecticut, USA, presented data from the Cardiovascular Outcomes Study of Alogliptin in Subjects With Type 2 Diabetes and Acute Coronary Syndrome [EXAMINE; White WB et al. N Engl J Med 2013].

In the international, double-blind EXAMINE trial, 5380 patients with T2DM and recent ACS (acute MI or hospitalization for unstable angina within 15 to 90 days) were randomized to receive alogliptin QD (n=2701) or placebo QD (n=2679) and followed for a median of 18 months. All patients were currently on antidiabetic treatment with an agent other than a DPP-4 inhibitor or glucagon-like peptide-1 analog (ie, incretin-based therapy). Exclusion criteria included type 1 diabetes, unstable cardiac disorders such as HF, refractory angina, uncontrolled arrhythmias, severe valvular heart disease, uncontrolled hypertension, and recent dialysis.

The primary endpoint of the EXAMINE trial was a composite of CV death, nonfatal MI, and nonfatal stroke. The secondary endpoint included the primary endpoint plus urgent revascularization due to unstable angina within 24 hours after hospitalization.

The primary endpoint was similar between groups (11.3% with alogliptin vs 11.8% with placebo; HR, 0.96; upper boundary of one-sided repeated CI, 1.16; superiority p=0.32; noninferiority p<0.001). The incidence of the secondary endpoint was also similar (12.7% vs 13.4%; HR, 0.95; upper boundary of one-sided repeated CI, 1.14; superiority p=0.26). In addition, there was no significant difference between alogliptin and placebo for CV death (p=0.21), nonfatal MI (p=0.47), nonfatal stroke (p=0.71), or all-cause death (p=0.23). Hospitalization for HF was not part of the primary endpoint.

The incidence of hypoglycemia was similar (∼6.6%) between study arms, as was the incidence of acute (∼0.4%) and chronic (∼0.2%) pancreatitis. There were no reports of pancreatic cancer occurring during the trial.

Dr. Bhatt concluded that SAVOR-TIMI 53 demonstrated noninferiority of saxagliptin for major ischemic events in patients with T2DM with heightened CV risk. Similarly, Dr. White noted that the EXAMINE trial found that MACE rates were not increased with alogliptin compared with placebo in patients with T2DM and recent ACS. In both trials, the rates of pancreatitis and pancreatic cancer were reassuring. Dr. Bhatt also pointed out that further study to elucidate the mechanism behind the unexpected increased incidence of hospitalization for HF in the saxagliptin arm observed in the SAVOR-TIMI 53 study is needed.

Science Advisor's Note: Hospitalization for HF was not reported in the primary EXAMINE publication but was recorded as an exploratory CV endpoint [White WB et al. Am Heart J 2011;162:2634–53 (Appendix A)] Given the results of SAVOR-TIMI 53, further description of this endpoint in EXAMINE will be important in determining whether this is a class effect and clarifying the underlying mechanism.

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