Steven E Nissen

Metropolitan Heart and Vascular Institute, Minneapolis, Minnesota, United States

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Publications (270)2525.34 Total impact

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    ABSTRACT: AimBariatric surgery improves glycemic control, but not all patients achieve type 2 diabetes (T2D) remission. Thus, we aimed to identify metabolic determinants of T2D non-remission status following bariatric surgery at 12 and 24 months (m).Methods Forty adults (BMI: 36±3kg/m2, Age: 48±9y, HbA1c: 9.7±2%) undergoing bariatric surgery (i.e. RYGB or SG) were enrolled in STAMPEDE. T2D remission was defined as HbA1c <6.5% and fasting glucose <126 mg/dl without anti-diabetic medication. Indices of insulin secretion and sensitivity were calculated from plasma glucose, insulin and C-peptide during a 120 min MMTT. Body fat (DXA), incretins (GLP-1, GIP, ghrelin), and adipokines (adiponectin, leptin, TNF-α, hs-CRP) were also assessed.ResultsAt 24m, 37 subjects had follow-up data (n = 18 RYGB and n = 19 SG). Bariatric surgery-induced 40% and 27% T2D remission rates at 12 and 24m, respectively. Total fat/abdominal fat loss, insulin secretion, insulin sensitivity, and β-cell function (C-peptide0–120/Glucose0–120 x Matsuda index) improved more in remitters at 12 and 24m than non-remitters. Incretin levels were unrelated to T2D remission, but, compared to non-remitters, hs-CRP decreased and adiponectin increased more in remitters. Only baseline adiponectin predicted lower HbA1c at 12 and 24m, and elevated adiponectin correlated with enhanced β-cell function, lower triglycerides and fat loss.Conclusions Smaller rises in adiponectin, a mediator of insulin action and adipose mass, depict T2D non-remission up to 2 years after bariatric surgery. Adjunctive strategies promoting greater fat loss and/or raising adiponectin may be key for higher T2D remission rates after bariatric surgery.
    Diabetes Obesity and Metabolism 08/2014; · 5.18 Impact Factor
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    ABSTRACT: High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels are inversely associated with adverse cardiovascular outcomes. Associations between these HDL-C-related measurements and coronary plaque progression have not been studied. We performed a retrospective analysis of 2,566 statin-treated patients with angiographic coronary artery disease who underwent serial evaluation of atheroma burden with intravascular ultrasound. Relations between achieved levels of HDL-related measurements with clinical characteristics and changes in plaque burden were determined. A strong correlation between HDL-C and apoA-I (r = 0.80, p <0.001) was observed. HDL-C, apoA-I, and the HDL-C:apoA-I ratio demonstrated negative correlations with the change in percent atheroma volume and total atheroma volume (all p ≤0.001). Increasing levels of achieved HDL-C:apoA-I (p = 0.04), but not HDL-C (p = 0.18) or apoA-I (p = 0.67), were associated with less progression of percent atheroma volume. Similar results were seen for change in total atheroma volume, with less progression seen with increased HDL-C:apoA-I (p = 0.002) but not with increases in HDL-C (p = 0.09) or apoA-I (p = 0.19). In conclusion, increasing levels of HDL-C:apoA-I associated with less progression of coronary atherosclerosis. This suggests that interventions increasing the cholesterol content of HDL particles may be of cardiovascular benefit.
    The American journal of cardiology. 06/2014;
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    ABSTRACT: Potent statin therapy has been demonstrated to reduce cardiovascular events. Although statins have been considered to stabilize atherosclerotic plaque, this effect has not been well characterized in vivo. We investigated the relation between potent statin therapy and plaque microstructures imaged by frequency-domain optical coherence tomography. Two hundred ninety nonculprit lipid plaques in 275 patients with stable coronary artery disease receiving atorvastatin or rosuvastatin were analyzed. Patients were stratified into no statin, low-, and high-dose statin groups. Plaques in the high-dose statin group demonstrated a smaller lipid arc (p = 0.02) and a greater fibrous cap thickness (p = 0.01). In patients receiving statin therapy, high-dose statin therapy was associated with a greater fibrous cap thickness in patients with smaller (148.2 ± 30.5 vs 105.3 ± 41.1 μm, p = 0.004) but not larger lipid index (91.1 ± 32.6 vs 78.1 ± 43.3 μm, p = 0.21). In conclusion, potent statin therapy is associated with less vulnerable plaque features on frequency-domain optical coherence tomography imaging. This finding varies according to the size of plaque lipid content, being less effective in lipid-loaded plaques.
    The American journal of cardiology. 06/2014;
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    ABSTRACT: Large plaque burden, expansive vascular remodelling, and spotty calcification have been considered as important morphologies of high-risk plaques causing acute coronary events. Although non-occlusive rupture of high-risk plaques has been proposed as a mechanism for disease progression in post-mortem studies, the natural history of coronary atherosclerosis in stable patients with high-risk plaques has not been fully elucidated. We sought to evaluate coronary atheroma progression in stable patients with greyscale intravascular ultrasound (IVUS)-derived high-risk plaques. We analysed 4477 patients with stable coronary artery disease underwent serial greyscale IVUS imaging in eight clinical trials. We compared volumetric intravascular ultrasound (IVUS) data in the non-culprit segments between patients with and without high-risk plaques, defined as the combination of per cent atheroma volume (PAV) >63%, positive remodelling and spotty calcification. High-risk plaques were observed in 201 (4.5%) of patients. Patients with high-risk plaques exhibited a greater PAV (47.1 ± 8.4 vs. 37.7 ± 8.7%, P < 0.001) at baseline. On serial evaluation, however, regression of PAV (-0.26 ± 0.39 vs. 0.24 ± 0.32%, P = 0.03) was observed. In patients with high-risk plaques, the non-statin use was associated with the accelerated atheroma progression, whereas atheroma regression was observed under statin therapy (change in PAV: 1.87 ± 0.68% vs. -0.83 ± 0.53%, P = 0.01). Patients with high-risk plaques exhibit extensive atheroma burden, which is modifiable with anti-atherosclerotic therapies. These findings underscore risk modification using a statin in patients with high-risk plaques.
    European heart journal cardiovascular Imaging. 04/2014;
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    ABSTRACT: Background In short-term randomized trials (duration, 1 to 2 years), bariatric surgery has been associated with improvement in type 2 diabetes mellitus. Methods We assessed outcomes 3 years after the randomization of 150 obese patients with uncontrolled type 2 diabetes to receive either intensive medical therapy alone or intensive medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy. The primary end point was a glycated hemoglobin level of 6.0% or less. Results The mean (±SD) age of the patients at baseline was 48±8 years, 68% were women, the mean baseline glycated hemoglobin level was 9.3±1.5%, and the mean baseline body-mass index (the weight in kilograms divided by the square of the height in meters) was 36.0±3.5. A total of 91% of the patients completed 36 months of follow-up. At 3 years, the criterion for the primary end point was met by 5% of the patients in the medical-therapy group, as compared with 38% of those in the gastric-bypass group (P<0.001) and 24% of those in the sleeve-gastrectomy group (P=0.01). The use of glucose-lowering medications, including insulin, was lower in the surgical groups than in the medical-therapy group. Patients in the surgical groups had greater mean percentage reductions in weight from baseline, with reductions of 24.5±9.1% in the gastric-bypass group and 21.1±8.9% in the sleeve-gastrectomy group, as compared with a reduction of 4.2±8.3% in the medical-therapy group (P<0.001 for both comparisons). Quality-of-life measures were significantly better in the two surgical groups than in the medical-therapy group. There were no major late surgical complications. Conclusions Among obese patients with uncontrolled type 2 diabetes, 3 years of intensive medical therapy plus bariatric surgery resulted in glycemic control in significantly more patients than did medical therapy alone. Analyses of secondary end points, including body weight, use of glucose-lowering medications, and quality of life, also showed favorable results at 3 years in the surgical groups, as compared with the group receiving medical therapy alone. (Funded by Ethicon and others; STAMPEDE number, NCT00432809 .).
    New England Journal of Medicine 03/2014; · 54.42 Impact Factor
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    ABSTRACT: Eprotirome is a liver-selective thyroid hormone receptor agonist that has been shown to lower plasma LDL cholesterol concentrations in previous phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the long-term safety and efficacy of 50 μg and 100 μg eprotirome in patients with familial hypercholesterolaemia. For this randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients were eligible for enrolment if they were aged 18 years or older, diagnosed with heterozygous familial hypercholesterolaemia, and had not reached target LDL cholesterol concentrations after at least 8 weeks of statin therapy with or without ezetimibe. We used a computer-generated randomisation sequence to allocate patients to one of three groups: 50 μg eprotirome, 100 μg eprotirome, or placebo. This trial was planned for 52-76 weeks, with primary efficacy analysis at 12 weeks, but it was prematurely terminated when another study found that eprotirome causes cartilage damage in dogs. Although it was impossible to meet the predefined study outcomes, we analysed changes in the concentrations of LDL cholesterol and other lipids, liver parameters, thyroid hormone concentrations, and adverse effects of treatment with eprotirome versus placebo at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks of treatment. This study is registered with, number NCT01410383. We enrolled 236 patients, randomly allocating 80 to receive placebo, 79 to receive 50 μg eprotirome, and 77 to receive 100 μg eprotirome. 69 patients reached the 6 week timepoint (23 given placebo, 24 given 50 μg eprotirome, and 22 given 100 μg eprotirome). Mean LDL cholesterol concentrations increased by 9% (95% CI -2 to 20) in the placebo group, decreased by 12% (-28 to 4%; p=0·0677 vs placebo) in the 50 μg eprotirome group, and decreased by 22% (-32 to -13%; p=0·0045 vs placebo) in the 100 μg eprotirome group. We noted statistically significant increases between both eprotirome groups and placebo in aspartate aminotransferase (AST; p<0·0001), alanine aminotransferase (ALT; p<0·0001), conjugated bilirubin (p=0·0006), and gamma-glutamyltranspeptidase (p<0·0001). Four patients had to discontinue or interrupt study treatment before trial termination due to AST increases between the upper limit of normal (ULN) and six times ULN, and ALT concentrations between three and seven times ULN. Although we detected no changes in serum concentrations of thyroid-stimulating hormone or free tri-iodothyronine, free tetra-iodothyronine decreased by 19% (23 to 16) in the 50 μg eprotirome group and 27% (30 to 23) in the 100 μg eprotirome group (p<0·0001 vs placebo for both groups). Our findings show that eprotirome can lower LDL cholesterol concentrations in patients with familial hypercholesterolaemia when added to conventional statin treatment with or without ezetimibe, but that it has the potential to induce liver injury. These findings, along with findings of cartilage damage in dogs, raise serious doubts about selective thyroid hormone mimetics as a therapeutic approach to lower LDL cholesterol concentrations. Karo Bio AB.
    The lancet. Diabetes & endocrinology. 02/2014;
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    ABSTRACT: To evaluate the effect of long-term maximally intensive statin therapy on indices of coronary atheroma composition in a randomized trial, and how these changes relate to modifications of serum lipoproteins and systemic inflammation. The Study of coronary Atheroma by inTravascular Ultrasound: the effect of Rosuvastatin vs. atorvastatiN (SATURN) employed serial intravascular ultrasound (IVUS) measures of coronary atheroma in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg daily for 24 months. Seventy-one patients underwent serial assessment of indices of plaque composition by spectral analysis of the radiofrequency IVUS signal. Changes in low-density lipoprotein cholesterol [LDL-C; -52 (-72, -33) mg/dL, P < 0.001], C-reactive protein [CRP -0.2 (-1, 0.1) mg/L, P = 0.01], and high-density lipoprotein cholesterol [HDL-C; +2.8 (-0.3, 7.8) mg/dL, P < 0.001] were associated with regression of percent atheroma volume (PAV: -1.6 ± 3.6%, P < 0.001). A reduction in estimated fibro-fatty tissue volume accompanied atheroma regression (P < 0.001), while dense calcium tissue volume increased (P = 0.002). There were no changes in fibrous or necrotic core tissue volumes. Volumetric changes in necrotic core tissue correlated with on-treatment HDL-C (r = -0.27, P = 0.03) and CRP (r = 0.25, P = 0.03) levels. A per-lesion analysis showed a reduction in the number of pathological intimal thickening lesions (defined by ≥3 consecutive IVUS frames containing PAV of ≥40%, predominantly fibro-fatty plaque, with <10% confluent necrotic core and <10% confluent dense calcium) at follow-up (67 vs. 38, P = 0.001). Fibroatheromas and fibrotic lesions remained static in number. Changes in indices of atheroma composition accompany regression of coronary atheroma with maximally intensive statin therapy, and associate with anti-inflammatory effects of statins. NCT000620542.
    European heart journal cardiovascular Imaging. 01/2014;
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    ABSTRACT: IMPORTANCE Secretory phospholipase A2 (sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2 inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE To determine the effects of sPLA2 inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES The primary efficacy measure was a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95% CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95% CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2 inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION Identifier: NCT01130246.
    JAMA The Journal of the American Medical Association 11/2013; · 29.98 Impact Factor
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    ABSTRACT: Diabetes is a multisystem disorder associated with a nearly twofold excess risk for a broad range of adverse cardiovascular outcomes including coronary heart disease, stroke, and cardiovascular death. Liraglutide is a human glucagon-like peptide receptor analog approved for use in patients with type 2 diabetes mellitus (T2DM). To formally assess the cardiovascular safety of liraglutide, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial was commenced in 2010. LEADER is a phase 3B, multicenter, international, randomized, double-blind, placebo-controlled clinical trial with long-term follow-up. Patients with T2DM at high risk for cardiovascular disease (CVD) who were either drug naive or treated with oral antihyperglycemic agents or selected insulin regimens (human NPH, long-acting analog, or premixed) alone or in combination with oral antihyperglycemics were eligible for inclusion. Randomized patients are being followed for up to 5 years. The primary end point is the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. LEADER commenced in September 2010, and enrollment concluded in April 2012. There were 9,340 patients enrolled at 410 sites in 32 countries. The mean age of patients was 64.3 ± 7.2 years, 64.3% were men, and mean body mass index was 32.5 ± 6.3 kg/m(2). There were 7,592 (81.3%) patients with prior CVD and 1,748 (18.7%) who were high risk but without prior CVD. It is expected that LEADER will provide conclusive data regarding the cardiovascular safety of liraglutide relative to the current standard of usual care for a global population of patients with T2DM.
    American heart journal 11/2013; 166(5):823-830.e5. · 4.65 Impact Factor
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    ABSTRACT: Objective:Roux-en-Y gastric bypass (RYGB) produces more durable glycemic control than sleeve gastrectomy (SG) or intensive medical therapy (IMT). However, the contribution of acylated ghrelin (AG), a gluco-regulatory/appetite hormone, to improve glucose metabolism and body composition in patients with type 2 diabetes (T2D) following RYGB is unknown.Design:STAMPEDE was a prospective, randomized controlled trial.Subjects:Fifty-three (BMI: 36±3 kg/m(2), Age: 49±9y) poorly controlled patients with T2D (HbA1c: 9.7±2%) were randomized to IMT, IMT+RYGB, or IMT+SG, and underwent a mixed-meal tolerance test at baseline, 12, and 24 months (m), for evaluation of AG suppression (post-prandial minus fasting) and beta-cell function (oral disposition index; glucose-stimulated insulin secretion x Matsuda index). Total/android body fat (DXA) was also assessed.Results:RYGB and SG reduced body fat comparably (15-23 kg) at 12 and 24 m, while IMT had no effect. Beta-cell function increased 5.8-fold in RYGB and was greater than IMT at 24 m (P<0.001). However, there was no difference in insulin secretion between SG vs. IMT at 24 m (P=0.32). Fasting AG was reduced 4-fold following SG (P<0.01) and did not change with RYGB or IMT at 24 m. AG suppression improved more following RYGB than SG or IMT at 24 m (P=0.01 vs SG, P=0.07 vs IMT). At 24 m, AG suppression was associated with increased post-prandial GLP-1 (r=-0.32, P<0.02) and decreased android fat (r=0.38; P<0.006).Conclusions:Enhanced AG suppression persists for up to 2 years after RYGB and this effect is associated with decreased android obesity and improved insulin secretion. Together, these findings suggest that AG suppression is partly responsible for the improved glucose control after RYGB surgery.International Journal of Obesity accepted article preview online, 29 October 2013; doi:10.1038/ijo.2013.196.
    International journal of obesity (2005) 10/2013; · 5.22 Impact Factor
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    ABSTRACT: Baseline C-reactive protein (CRP) levels predict major adverse cardiovascular events [MACE; death, myocardial infarction, stroke, coronary revascularization and hospitalization for unstable angina]. The association between changes in CRP levels with plaque progression and MACE in the setting of maximally intensive statin therapy is unknown. SATURN employed serial intravascular ultrasound (IVUS) measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The treatment groups did not differ significantly in the change from baseline of percent atheroma volume (PAV) on IVUS, CRP-modulating effects or MACE rates, thus allowing for a (prespecified) post-hoc analysis to test associations between changes in CRP levels with coronary disease progression and MACE. Patients with non-increasing CRP levels (n=621) had higher baseline [2.3 (1.1, 4.7) vs. 1.1 (0.5, 1.8) mg/L, p<0.001] and lower follow-up CRP levels [0.8 (0.5, 1.7) vs. 1.6 (0.7, 4.1) mg/L, p<0.001] versus those with increasing CRP levels (n=364). Multivariable analysis revealed a non-increasing CRP level to independently associate with greater PAV regression (p=0.01). While the (log) change in CRP did not associate with MACE [HR 1.18 (95% CI 0.93, 1.50), p=0.17], the (log) on-treatment CRP associated significantly with MACE [HR 1.28 (95% CI 1.04, 1.56, p=0.02). On-treatment LDL-C levels did not correlate with MACE [HR 1.09 (95% CI 0.88, 1.35, p=0.45). Following 24 months of potent statin therapy, on-treatment CRP levels associated with MACE. Inflammation may be an important driver of residual cardiovascular risk in patients with coronary artery disease despite aggressive statin therapy. Identifier: NCT000620542.
    Circulation 09/2013; · 15.20 Impact Factor
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    ABSTRACT: IMPORTANCE Blood pressure reduction and renin-angiotensin-aldosterone system inhibition are targets for treatment of atherosclerosis. The effect of renin inhibition on coronary disease progression has not been investigated. OBJECTIVE To determine the effects of renin inhibition with aliskiren on progression of coronary atherosclerosis. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, multicenter trial (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) comparing aliskiren with placebo in 613 participants with coronary artery disease, systolic blood pressure between 125 and 139 mm Hg (prehypertension range), and 2 additional cardiovascular risk factors conducted at 103 academic and community hospitals in Europe, Australia, and North and South America (enrollment from March 2009 to February 2011; end of follow-up: January 31, 2013). INTERVENTIONS Participants underwent coronary intravascular ultrasound (IVUS) imaging and were randomized to receive 300 mg of aliskiren (n = 305) or placebo (n = 308) taken orally daily for 104 weeks. Disease progression was measured by repeat IVUS examination after at least 72 weeks of treatment. MAIN OUTCOMES AND MEASURES The primary efficacy parameter was the change in percent atheroma volume (PAV) from baseline to study completion. Secondary efficacy parameters included the change in normalized total atheroma volume (TAV) and the percentage of participants with atheroma regression. Safety and tolerability were also assessed. RESULTS Evaluable imaging data were available at baseline and follow-up for 458 participants (74.7%). The primary IVUS efficacy parameter, PAV, did not differ between participants treated with aliskiren (-0.33%; 95% CI, -0.68% to 0.02%) and placebo (0.11%; 95% CI, -0.24% to 0.45%) (between-group difference, -0.43% [95% CI, -0.92% to 0.05%]; P = .08). The secondary IVUS efficacy parameter, TAV, did not differ between participants treated with aliskiren (-4.1 mm3; 95% CI, -6.27 to -1.94 mm3) and placebo (-2.1 mm3; 95% CI, -4.21 to 0.07 mm3) (between-group difference, -2.04 mm3 [95% CI, -5.03 to 0.95 mm3]; P = .18). There were no significant differences in the proportion of participants who demonstrated regression of PAV (56.9% vs 48.9%; P = .08) and TAV (64.4% vs 57.5%; P = .13) in the aliskiren and placebo groups, respectively. CONCLUSIONS AND RELEVANCE Among participants with prehypertension and coronary artery disease, the use of aliskiren compared with placebo did not result in improvement or slowing of progression of coronary atherosclerosis. These findings do not support the use of aliskiren for regression or prevention of progression of coronary atherosclerosis. TRIAL REGISTRATION Identifier: NCT00853827.
    JAMA The Journal of the American Medical Association 09/2013; · 29.98 Impact Factor
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    ABSTRACT: Background To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. Methods We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. Conclusions Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE number, NCT00968708 .).
    New England Journal of Medicine 09/2013; · 54.42 Impact Factor
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    ABSTRACT: African-Americans with coronary artery disease (CAD) demonstrate worse clinical outcomes than Caucasians. While this is partly due to a lack of accessibility to established therapies, the mechanisms underlying this difference remain to be elucidated. We aimed to characterize the progression of coronary atherosclerosis in African-Americans with CAD. 3,479 patients with CAD underwent serial intravascular ultrasound (IVUS) imaging to evaluate atheroma progression in 7 clinical trials of anti-atherosclerotic therapies. Risk factor control and atheroma progression were compared between African-Americans (n=170) and Caucasians (n=3,309). African-Americans were more likely to be female (51.8% vs. 28.1%, P<0.001), have a higher body mass index (32.8±6.0 vs. 31.3±5.8 kg/m(2), P=0.002) and greater history of hypertension (85.9% vs. 78.8%, P=0.02), diabetes (41.8% vs. 30.6%, P=0.002) and stroke (12.9% vs. 3.0%, P<0.001). Despite a high use of anti-atherosclerotic medications (93% statin, 89% aspirin, 79% β-blocker, 52% ACE inhibitor), African-Americans demonstrated higher levels of LDL-C (2.4±0.7 vs. 2.2±0.7 mmol/L, P=0.006), CRP (2.9 vs. 2.0 mg/dL, P<0.001) and systolic blood pressure (133±15 vs. 129±13 mmHg, P<0.001) at follow-up. There was no significant difference in atheroma volume at baseline (189.0±82.2 vs. 191.6±83.3 mm(3), P=0.82) between two groups. Serial evaluation demonstrated a greater increase in atheroma volume in African-Americans (0.51±2.1 vs. -3.1±1.7 mm(3), P=0.01). This difference persisted with propensity matching accounting for differences in risk factor control (0.1±2.1 vs. -3.7±1.7 mm(3), P=0.02). African-Americans with CAD achieve less optimal risk factor control and greater atheroma progression. These findings support the need for more intensive risk factor modification in African-Americans.
    Cardiovascular diagnosis and therapy. 09/2013; 3(3):161-169.
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    ABSTRACT: The impact of baseline coronary plaque burden on the clinical outcome in patients receiving aggressive low-density lipoprotein cholesterol (LDL-C) lowering therapy to levels <70 mg/dL is unknown. We assessed the prognostic significance of baseline coronary plaque burden following high-intensity statin therapy. SATURN used serial intravascular ultrasound (IVUS) to measure coronary atheroma volume in 1039 patients before and after 24 months of treatment with rosuvastatin 40 mg or atorvastatin 80 mg. This post hoc analysis compared the relationship between baseline percent atheroma volume (PAV) and major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina) in patients with baseline PAV less than (n = 519) or greater than (n = 520) the median. Patients with a higher baseline PAV had a similar LDL-C compared with those with a lower baseline PAV at baseline (119.0 ± 29 vs. 121.0 ± 27 mg/dL, P = 0.09) and at follow-up (65.3 ± 23 vs. 65.8 ± 22 mg/dL, P = 0.47). In multivariable analysis, each standard deviation increase in baseline PAV was associated with a 28% increase in MACE [HR 1.28 (1.05, 1.57), P = 0.01]. Those with the highest quartile of baseline PAV (>41.8%) had a 2-year cumulative MACE rate of 12%, which was significantly higher (log-rank P = 0.001) than MACE rates of all lower PAV quartiles (MACE: quartile 3, 2, and 1 were 5.7, 7.9, and 5.1%, respectively). LDL-C levels at baseline [HR 0.96 (0.79, 1.18), P = 0.73] and on-treatment [HR 1.19 (0.83, 1.73), P = 0.35] were not associated with MACE. Following 2 years of high-intensity statin therapy, a baseline coronary atheroma volume predicted MACE, despite the achievement of very low on-treatment LDL-C levels.
    European Heart Journal 07/2013; · 14.72 Impact Factor
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    ABSTRACT: -Epicardial plaque burden and endothelial function are recognized predictors of coronary events. We aimed to investigate mechanistic relationships between atheroma volume and endothelial function in patients with non ST-segment elevation myocardial infarction (NSTEMI) utilizing intravascular ultrasound (IVUS). -In coronary vessels of patients with near normal or minimal angiographic disease (n=23) and NSTEMI (n=24), IVUS-derived measures [percent atheroma volume (PAV)], arterial remodeling index (RI) and segmental lumen volumes (SLV) were performed in contiguous 5-mm epicardial segments. Repeat IVUS imaging was performed following consecutive 5-minute intracoronary (IC) infusions (vehicle solution, 0.30 µg/min and 0.60 µg/min IC salbutamol) to measure changes in SLV (endothelium-dependent function). Male gender, diabetes, smoking, higher triglycerides and lower HDL-C were more prevalent in the NSTEMI group. Patients with NSTEMI demonstrated greater segmental PAV (40.4±12 vs 27.5±14%, p<0.001), RI [1.2 (1.0, 1.5) vs 1.0 (0.9, 1.0), p<0.001] and displayed less endothelium-dependent vasomotion (%change SLV: 2.1±0.89 vs 5.1±0.89%, p=0.02) compared to patients with minimal angiographic disease. No significant difference in endothelial function between both groups was observed when controlling for plaque burden. Multivariate analysis for change in SLV identified PAV (β= -0.18, p=0.0004), high sensitivity C-reactive protein >2mg/L (β= -3.1, p=0.03), diabetes (β= -6.9, p<0.0001), LDL-C levels (β= -0.04, p=0.01) and smoking (β= -3.2, p=0.01) as independent associates. -Although coronary endothelial vasoreactivity is blunted in the setting of NSTEMI, this is a reflection of the greater volume of atherosclerosis and cardiovascular risk factors. Thus the relationship between coronary endothelium-dependent vasomotor reactivity and atheroma volume remains constant irrespective of the nature of the clinical presentation.
    Circulation Cardiovascular Imaging 06/2013; · 5.80 Impact Factor
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    ABSTRACT: AIMS: Statins can inhibit the progression of coronary atherosclerosis. We aimed to characterize clinical factors that associate with differing measures of coronary atheroma volume following potent statin therapy. METHODS AND RESULTS: SATURN employed serial intravascular ultrasound (IVUS) to monitor changes in measures of coronary atheroma burden [total atheroma volume (TAV) and per cent atheroma volume (PAV)] in 1039 patients with coronary artery disease, treated with rosuvastatin (40 mg) or atorvastatin (80 mg) daily for 24 months. Rosuvastatin-treated patients demonstrated greater reductions in low-density lipoprotein cholesterol (LDL-C, 47 vs. 40%, P < 0.001) and greater increases in high-density lipoprotein cholesterol (HDL-C, 13 vs. 10%, P = 0.02). These alterations in the lipid profile associated with greater TAV (-6.4 vs. -4.4 mm(3), P = 0.01), but not PAV (-1.22 vs. -0.99%, P = 0.17) regression. Greater TAV reductions with rosuvastatin vs. atorvastatin occurred in patients with diabetes (P = 0.01, treatment by diabetic status interaction P-value 0.05). Greater PAV reductions with rosuvastatin were evident in females (P = 0.01, treatment by sex interaction P-value 0.03) and in those with greater than or equal to median baseline LDL-C (P = 0.02, treatment by LDL-C group interaction P-value 0.03) or HDL-C levels (P = 0.02, treatment by HDL-C group interaction P-value 0.04). On multivariable analysis assessing change in TAV and PAV, both higher baseline TAV and PAV independently associated with TAV and PAV regression, respectively (standardized estimates: TAV -0.25, P < 0.001; PAV -0.23, P < 0.001). CONCLUSION: Higher-risk patients, particularly those with greater baseline coronary atheroma volume, are more likely to experience less disease progression with potent statin therapy.
    European Heart Journal 05/2013; · 14.72 Impact Factor
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    ABSTRACT: Coronary angiography has been widely used for five decades to evaluate a range of vascular pathologies and triage patients to therapeutic interventions. The inability to directly visualize the artery wall with conventional angiographic techniques has stimulated development of a number of intravascular imaging modalities. These approaches have the potential to provide a more comprehensive characterization of the burden, composition and functionality of atherosclerotic plaque, neointimal hyperplasia and allograft vasculopathy that develop within coronary arteries. The ability to use these modalities in vivo and in a serial fashion has provided a greater insight into the factors that underlie the disease process and guide therapeutic interventions.
    International journal of cardiology 04/2013; · 6.18 Impact Factor
  • Journal of the American College of Cardiology 03/2013; 61(10_S). · 14.09 Impact Factor
  • Journal of the American College of Cardiology 03/2013; 61(10_S). · 14.09 Impact Factor

Publication Stats

12k Citations
2,525.34 Total Impact Points


  • 2010–2014
    • Metropolitan Heart and Vascular Institute
      Minneapolis, Minnesota, United States
  • 2013
    • University of Adelaide
      • South Australian Research and Development Institute (SARDI)
      Tarndarnya, South Australia, Australia
    • South Australian Health and Medical Research Institute
      Adelaide Hills, South Australia, Australia
  • 2010–2013
    • Naval Medical Center San Diego
      • Division of Cardiology
      San Diego, California, United States
  • 2012
    • University of California, San Diego
      • Division of Cardiology
      San Diego, CA, United States
    • Case Western Reserve University School of Medicine
      Cleveland, Ohio, United States
  • 1995–2012
    • Cleveland Clinic
      • • Department of Cardiology
      • • Department of Cardiovascular Medicine
      Cleveland, Ohio, United States
  • 2008
    • Baylor College of Medicine
      • Section of Atherosclerosis and Vascular Medicine
      Houston, TX, United States
    • Boston Health Economics, Inc.
      Boston, Massachusetts, United States
    • Sungkyunkwan University
      • School of Medicine
      Seoul, Seoul, South Korea
  • 1995–2007
    • American College of Cardiology
      Washington, Washington, D.C., United States
  • 2004
    • Brigham and Women's Hospital
      • Division of Renal Medicine
      Boston, MA, United States
  • 2003
    • Lerner Research Institute
      Cleveland, Ohio, United States
  • 2002
    • Barnes Jewish Hospital
      San Luis, Missouri, United States
  • 1998
    • Cleveland Clinic Laboratories
      Cleveland, Ohio, United States