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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\u003EA dual agonist of peroxisome proliferator-activated receptors (PPARs) did not reduce adverse cardiovascular outcomes in patients with type 2 diabetes mellitus. Findings from the Phase 3, multinational, AleCardio study [Lincoff AM et al. \u003Cem\u003EJAMA\u003C\/em\u003E 2014] are discussed in this article.\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\u003ELipid Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\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\u003ECardiology \u0026amp; Cardiovascular Medicine\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ELipid Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EA dual agonist of peroxisome proliferator-activated receptors (PPARs) did not reduce adverse cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus (T2DM) Findings from the Phase 3, multinational, AleCardio study [Lincoff AM et al. \u003Cem\u003EJAMA\u003C\/em\u003E 2014] were announced by A. Michael Lincoff, MD, Cleveland Clinic, Cleveland, Ohio, USA.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EAleglitazar is a PPAR agonist with balanced affinity for the PPAR-\u03b1 and PPAR-\u03b3 subtypes. The primary effect of agonists of PPAR-\u03b1 is to improve the plasma lipid profile, and the primary effect of agonists of PPAR-\u03b3 is to improve insulin sensitivity. A dual PPAR agonist, therefore, was hypothesized to combine favorable actions on lipoproteins with insulin-sensitizing and glucose-lowering affects that might translate into a reduction in adverse CV outcomes, explained Dr. Lincoff.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EIn a Phase 2 trial, aleglitazar was associated with greater reductions in HbA1C and blood levels of triglycerides, and a greater increase in high-density lipoprotein cholesterol (HDL-C) than either placebo or the PPAR-\u03b3 agonist pioglitazone [Henry RR et al. \u003Cem\u003ELancet\u003C\/em\u003E 2009].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EIn AleCardio, 7226 patients with T2DM who were hospitalized with a recent acute coronary syndrome were randomly assigned in a double-blind fashion to aleglitazar 150 \u03bcg\/day, or placebo in addition to standard care. The trial was conducted at 720 sites in 26 countries. Patients could be randomized up to 12 weeks after discharge to allow clinical stabilization or completion of planned revascularization. The primary endpoint of the study was the composite of time to CV death, nonfatal myocardial infarction, and nonfatal stroke. The anticipated follow-up duration to achieve 950 primary endpoints was \u223c2.5 years.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EAt baseline, patients were a mean age of 61 years. About two thirds were taking metformin, one third were on a sulfonylurea, and \u223c30% were being treated with insulin. More than 90% were on aspirin and a statin.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe Data Safety Monitoring Board recommended early termination of the trial due to a higher incidence of heart failure in the aleglitazar arm. The trial was terminated after a median follow-up of 104 weeks.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EThe primary composite endpoint occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo arm (\u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E), for an HR of 0.96 that was not significant (p=0.57).\u003C\/p\u003E\u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/15822\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/15822\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15822\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-9\u0022 class=\u0022first-child\u0022\u003ECardiovascular Efficacy Endpoints\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-11\u0022\u003EHeart failure occurred more frequently in the aleglitazar arm compared with the placebo arm (4.7% vs 3.8%; HR, 1.24; p=0.06). Peripheral edema also developed significantly more often in the aleglitazar arm (14.0% vs 6.6%; p\u0026lt;0.001). By Month 24, mean serum creatinine increased by 0.11 mg\/dL in the aleglitazar arm and by 0.01 mg\/dL in the placebo arm (p\u0026lt;0.001), a difference that was reversible by 4 weeks after discontinuation of aleglitazar. Gastrointestinal hemorrhage was also significantly more common in the aleglitazar group (HR, 1.44; p=0.03).\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EHbA1C was significantly lower among patients assigned to aleglitazar compared with placebo, with the mean change from baseline being \u22120.99% in the aleglitazar arm and \u22120.36% in the placebo arm. At 3 months, HDL-C levels increased from baseline by 26.9% in the aleglitazar arm and 8.4% in the placebo arm. Triglyceride levels increased in the placebo arm and decreased by 23.9% in the aleglitazar arm. The level of low-density lipoprotein cholesterol increased in both groups, but more so in the aleglitazar arm.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EThe adverse effects associated with aleglitazar highlight the difficulties in developing PPAR-activating drugs where gene modulation can result in complex metabolic effects and unpredictable therapeutic profiles, concluded Dr. Lincoff.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 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\/14\/4\/18.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?nzpbq2\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_tables.js?nzpbq2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}