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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EAntihyperglycemic therapies have been shown to reduce microvascular events; however, their impact on macrovascular events has not been well established. Saxagliptin and alogliptin, both selective dipeptidyl peptidase 4 (DPP-4) inhibitors, are incretin-based antihyperglycemic therapies that improve glycemic control in type 2 diabetes mellitus (T2DM). This article discusses 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 major adverse cardiac events in patients with T2DM at heightened risk of CV events [Scirica BM et al. \u003Cem\u003EAm Heart J 2011\u003C\/em\u003E; White WB et al. \u003Cem\u003EN Engl J Med 2013\u003C\/em\u003E].\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EMyocardial Infarction\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHyperglycemia\/Hypoglycemia\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EMyocardial Infarction\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHyperglycemia\/Hypoglycemia\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EAntihyperglycemic 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. \u003Ca href=\u0022http:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/ucm071627.pdf\u0022\u003Ehttp:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/ucm071627.pdf\u003C\/a\u003E]. 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.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003ESaxagliptin 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\u20133 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. \u003Cem\u003EPostgrad Med\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe 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. \u003Cem\u003EAm Heart J\u003C\/em\u003E 2011; White WB et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003ESaxagliptin 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\u0027s 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. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EIn 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 \u226450 mL\/minute) or placebo for a median follow-up of 2.1 years [Scirica BM et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2013]. Eligible patients with established CV disease had to be aged \u226540 years, with documented coronary, cerebrovascular, or peripheral artery atherosclerosis. Patients with risk factors were eligible if they were aged \u226555 (males) or \u226560 (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 \u22656.0 mg\/dL (530 \u03bcmol\/L).\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe 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.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EThe 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\u0026lt;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\u0026lt;0.001).\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EIndividual 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). \u003Cem\u003EMajor\u003C\/em\u003E 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, \u003Cem\u003Ehospitalization\u003C\/em\u003E 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.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EIn 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. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EIn 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.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EThe 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.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EThe 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\u0026lt;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.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003EThe incidence of hypoglycemia was similar (\u223c6.6%) between study arms, as was the incidence of acute (\u223c0.4%) and chronic (\u223c0.2%) pancreatitis. There were no reports of pancreatic cancer occurring during the trial.\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003EDr. 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.\u003C\/p\u003E\u003Cdiv class=\u0022boxed-text\u0022 id=\u0022boxed-text-1\u0022\u003E\u003Cbr\/\u003E\u003Cdiv class=\u0022graphic\u0022 id=\u0022graphic-1\u0022\u003E\u003Cdiv class=\u0022graphic-inline anchor\u0022\u003E\u003Cimg class=\u0022highwire-embed\u0022 alt=\u0022Embedded Image\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/highwire\/spmdc\/13\/15\/17\/embed\/graphic-1.gif\u0022\/\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-16\u0022\u003EScience Advisor\u0027s Note: Hospitalization for HF was not reported in the primary EXAMINE publication but was recorded as an exploratory CV endpoint [White WB et al. \u003Cem\u003EAm Heart J\u003C\/em\u003E 2011;162:2634\u201353 (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.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2013 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/13\/15\/17.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nznmw1\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}