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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\u003EThere is no evidence of cardiovascular benefit that is associated with long-term treatment with nateglinide and valsartan in patients with impaired glucose tolerance and cardiovascular disease (CVD) or CV risk factors. However, valsartan therapy is associated with a reduction in the incidence of diabetes. This article discusses results from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research [NAVIGATOR; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00097786\u0026amp;atom=%2Fspmdc%2F10%2F2%2F12.2.atom\u0022\u003ENCT00097786\u003C\/a\u003E] Trial.\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\u003Ediabetes mellitus\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EThere is no evidence of cardiovascular (CV) benefit that is associated with long-term treatment with nateglinide and valsartan in patients with impaired glucose tolerance and cardiovascular disease (CVD) or CV risk factors. However, valsartan therapy is associated with a reduction in the incidence of diabetes. Rury R. Holman, MB, ChB, FRCP, Churchill Hospital, Oxford, United Kingdom, and Robert M. Califf, MD, Duke Translational Medicine Institute, Durham, NC, presented results from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00097786\u0026amp;atom=%2Fspmdc%2F10%2F2%2F12.2.atom\u0022\u003ENCT00097786\u003C\/a\u003E) Trial.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003ENAVIGATOR was a double-blind, randomized, multicenter, controlled trial that included 9306 patients with impaired glucose tolerance, defined as fasting plasma glucose (FPG) \u226595 mg\/dL and \u0026lt;125 mg\/dL and either known CVD if \u226550 years old or \u22651 risk factor for CVD if \u226555 years old. The use of any antidiabetic agent within the last 5 years was an exclusion. Patients were randomized in a 2\u00d72 factorial design to either valsartan (an angiotensin receptor blocker) 160 mg daily or placebo, and to either nateglinide (a short-acting secretagogue) 60 mg 3 times daily or placebo. All study subjects participated in a lifestyle modification program throughout the duration of the study.\u003C\/p\u003E\n         \u003Cp\u003EOne-quarter of participants had known CVD at baseline. The mean age was 64 years, and the median follow-up was 6.5 years for vital status and 5.0 years for incident diabetes. On average, patients in this study were obese at baseline (average BMI 30.5 kg\/m\u003Csup\u003E2\u003C\/sup\u003E). The three coprimary endpoints for both comparisons of this study were:\n\u003C\/p\u003E\u003Col class=\u0022list-ord \u0022 id=\u0022list-1\u0022\u003E\u003Cli id=\u0022list-item-1\u0022\u003E\n                  \u003Cp id=\u0022p-5\u0022\u003EThe incidence of diabetes, defined as fasting plasma glucose (FPG) \u2265126 mg\/dL (\u22657.0 mmol\/L) and\/or 2-hour plasma glucose \u2265200 mg\/dL (\u226511.1 mmol\/L), confirmed by oral glucose tolerance test within 12 weeks;\u003C\/p\u003E\n               \u003C\/li\u003E\u003Cli id=\u0022list-item-2\u0022\u003E\n                  \u003Cp id=\u0022p-6\u0022\u003EAn extended CV composite outcome of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure, revascularization or unstable angina;\u003C\/p\u003E\n               \u003C\/li\u003E\u003Cli id=\u0022list-item-3\u0022\u003E\n                  \u003Cp id=\u0022p-7\u0022\u003EThe core CV composite outcome of CV death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.\u003C\/p\u003E\n               \u003C\/li\u003E\u003C\/ol\u003E\u003Cp\u003E\n         \u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EDr. Holman discussed findings from the nateglinide arm of NAVIGATOR. There was no significant difference between nateglinide (n=4645) and placebo (n=4661) with regard to the extended CV composite outcome or the core CV composite outcome. There was a nonsignificant increase in incident diabetes with nateglinide (36% vs 34%; p=0.05). While patients who were treated with nateglinide demonstrated lower FPG levels over the course of the study (p=0.03), plasma glucose levels 2 hours post-glucose challenge were significantly higher (p\u0026lt;0.001) in the nateglinide group compared with placebo (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). \u201cThese results were unexpected, based on nateglinide\u0027s mechanism of action, and the reason for this disparity is unclear,\u201d said Dr. Holman. However, these findings may be due to a decline in drug response over time or an acute withdrawal reaction, as the study drug was withheld on the day of the oral glucose tolerance test.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/2\/12.2\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Changes in Mean Plasma Glucose Levels.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-301786099\u0022 data-figure-caption=\u0022Changes in Mean Plasma Glucose Levels.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/2\/12.2\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/2\/12.2\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/2\/12.2\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11298\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\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-9\u0022 class=\u0022first-child\u0022\u003EChanges in Mean Plasma Glucose Levels.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003ECopyright \u00a9 2010 Massachusetts Medical Society. All rights reserved.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EAdverse events did not differ between the two treatment groups, with the exception of hypoglycemic events. Nateglinide therapy was associated with an increased risk of hypoglycemia compared with placebo (19.6% vs 11.3%; p\u0026lt;0.001). Of the events in the nateglinide group, 21 were deemed severe, 214 were moderate, and 676 were mild versus 12, 104, and 411 in the placebo group, respectively.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EMean body weight and waist circumference were also higher in the nateglinide group, despite an overall trend in mean body weight reduction throughout the duration of the study. Ten percent of participants lost 5% of their baseline weight by 6 months.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EDr. Califf presented the details of the valsartan (n=4631) versus placebo (n=4675) comparison of NAVIGATOR. He began by pointing out that the difference in the use of concomitant beta-blockers, calcium channel blockers, and diuretics from baseline to last study visit was greater in the placebo arm than in the valsartan arm (p\u0026lt;0.001).\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EValsartan did not significantly reduce the incidence of the extended or core CV outcomes. However, there was a 14% relative reduction in the incidence of diabetes in the valsartan group. The cumulative incidence of diabetes was 33.1% in the valsartan group versus 36.8% in the placebo group, amounting to an absolute reduction of 3.8% (HR, 0.86; 95% CI, 0.80 to 0.92; p\u0026lt;0.001). Additional exploratory outcomes of CV death and total mortality were not significantly different.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EAs with the nateglinide arm of the trial, patients in the treatment arm demonstrated lower FPG over the course of the study. Contrary to the nateglinide results, glucose levels 2 hours post-glucose challenge were also lower in the valsartan treatment arm compared with placebo (p\u0026lt;0.001).\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003ETreatment with valsartan significantly reduced mean sitting blood pressure throughout the duration of the study (p\u0026lt;0.001 for systolic and diastolic measurements). However, hypotension-related adverse events were more common in those who received valsartan (42.4%) than in those who received placebo (35.9%; p\u0026lt;0.001). Other common adverse events were nasopharyngitis, back pain, and arthralgia.\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003ENo major safety concerns were identified during the course of the NAVIGATOR study. The rates of major CV events were comparable in all arms of this study, and neither treatment appeared to impact the incidence of CV outcomes. Nateglinide therapy was associated with a higher incidence of hypoglycemia, while valsartan therapy was associated with a higher incidence of hypotension-related adverse events. Valsartan therapy, in combination with lifestyle modification, did reduce the incidence of diabetes in patients with impaired glucose tolerance and CVD or CV risk factors.\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EDr. Califf concluded that NAVIGATOR demonstrates that the risks and benefits of therapies can not be predicted accurately based on biology and intermediate measures. Instead, they must be empirically demonstrated with proper randomized clinical trials. While lifestyle modification continues to be the key to diabetes prevention and management, it is important to investigate pharmaceutical options as well, especially in the presence of comorbidities, such as CVD.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2010 MD Conference Express\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\/10\/2\/12.2.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_figures.js?nzmt61\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_openurl.js?nzmt61\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}