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In patients who have, or are at risk for, coronary artery disease, niacin added to statin therapy resulted in regression of the carotid intima–media thickness. In contrast, ezetimibe added to statin therapy paradoxically resulted in progression of the carotid intima–media thickness. Treatment with 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors reduces low-density lipoprotein (LDL) cholesterol levels and results in clinically significant reductions in the relative risk of major cardiovascular events. 1 However, because of the residual cardiovascular risk seen with statin monotherapy, treatment may be intensified with the use of combination therapy, aimed at either further reducing the LDL cholesterol level or at altering levels of other lipids, such as high-density lipoprotein (HDL) cholesterol. Progressive lowering of the LDL cholesterol level through intensification of statin therapy leads to a 16% reduction in the odds of cardiovascular events and death from cardiovascular causes. 2 This approach has . . .

Patients with mixed dyslipidaemia have raised triglycerides, low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol. Augmentation of HDL cholesterol by inhibition of the cholesteryl ester transfer protein (CETP) could benefit these patients. We aimed to investigate the effect of the CETP inhibitor, torcetrapib, on carotid atherosclerosis progression in patients with mixed dyslipidaemia. We did a randomised double-blind trial at 64 centres in North America and Europe. 752 eligible participants completed an atorvastatin-only run-in period for dose titration, after which they all continued to receive atorvastatin at the titrated dose. 377 of these patients were randomly assigned to receive 60 mg of torcetrapib per day and 375 to placebo. We made carotid ultrasound images at baseline and at 6-month intervals for 24 months. The primary endpoint was the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Analysis was restricted to 683 patients who had at least one dose of treatment and had at least one follow-up carotid intima-media measurement; they were analysed as randomised. Mean follow-up for these patients was 22 (SD 4·8) months. This trial is registered with ClinicalTrials.gov, number NCT00134238. The change in maximum carotid intima-media thickness was 0·025 (SD 0·005) mm per year in patients given torcetrapib with atorvastatin and 0·030 (0·005) mm per year in those given atorvastatin alone (difference −0·005 mm per year, 95% CI −0·018 to 0·008, p=0·46). Patients in the combined-treatment group had a 63·4% relative increase in HDL cholesterol (p<0·0001) and an 17·7% relative decrease in LDL cholesterol (p<0·0001), compared with controls. Systolic blood pressure increased by 6·6 mm Hg in the combined-treatment group and 1·5 mm Hg in the atorvastatin-only group (difference 5·4 mm Hg, 95% CI 4·3–6·4, p<0·0001). Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.

Proton pump inhibitors (PPIs) are frequently prescribed in combination with clopidogrel, but conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use and clinical outcomes for patients treated with percutaneous coronary intervention (PCI) and dual-antiplatelet therapy (DAPT) with clopidogrel plus aspirin. In the PRODIGY trial, 1,970 patients were randomized to 6- or 24-month DAPT at 30 days from index procedure. Among them, 738 patients (37.5%) received PPI (mainly lansoprazole; 90.1%) at the time of randomization. Proton pump inhibitor users were older, were most likely to be woman, had a lower creatinine clearance, presented more frequently with acute coronary syndrome, and had a higher CRUSADE bleeding score. After adjustment, the primary efficacy end point (composite of all-cause death, myocardial infarction, and cerebrovascular accident) was similar between no PPI and PPI users (9.2% vs 11.5%, adjusted hazard ratio [HR] 1.051, 95% CI 0.788-1.400, P = .736). Bleeding rates did not differ between the 2 groups (Bleeding Academic Research Consortium type 2, 3, or 5: adjusted HR 0.996, 95% CI 0.672-1.474, P = .980). Net clinical adverse events were also similar in no PPI and PPI patients (12.9% vs 14.9%, adjusted HR 0.99, 95% CI 0.772-1.268, P = .93). Results remained consistent at sensitivity analysis when focusing on the 548 patients who remained on PPI for the whole study duration. The current findings suggest that the concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel is not associated with adverse clinical outcome.

ObjectiveThe aim of this trial was to determine whether obese patients benefit from treatment with rimonabant in terms of progression of carotid atherosclerosis. Rimonabant, a selective cannabinoid-1 receptor blocker, reduces body weight and improves cardiometabolic risk factors in patients who are obese.Design, setting, patients, interventions and resultsA prospective, double-blind, placebo-controlled trial (Atherosclerosis Underlying Development assessed by Intima–media Thickness in patients On Rimonabant (AUDITOR)) randomised 661 patients with abdominal obesity and metabolic syndrome to rimonabant or placebo for 30 months of treatment. The absolute change in the average value for six segments of far wall carotid intima–media thickness from baseline to month 30 was 0.010±0.095 mm in the rimonabant group and 0.012±0.091 mm in the placebo group (p=0.67). The annualised change was an increase of 0.005±0.042 mm for the rimonabant-treated group and 0.007±0.043 mm for the placebo-treated group (p=0.45).ConclusionsThere was no difference in atherosclerosis progression between patients receiving rimonabant for 30 months and those receiving placebo for the primary efficacy measure (absolute change in carotid intima–media thickness). These findings are consistent with a similar study using coronary intravascular ultrasound and another study evaluating the occurrence of cardiovascular events. Our findings suggest that a 5% loss of body weight over a 30-month period with rimonabant is insufficient to modify atherosclerosis progression in the carotid artery in obese patients with metabolic syndrome.Clinical trial registration informationclinicaltrials.gov Identifier: NCT00228176.

Sitagliptin has been widely used for the treatment of diabetes and shown recently to have beneficial pleiotropic outcomes on cardiovascular systems in experimental studies. However, little is known about the influence of sitagliptin on atherosclerosis-related cardiovascular diseases in a clinical setting. This study examined the effect of sitagliptin on carotid intima-media thickness (IMT). A total of 76 patients with clinically stable and documented coronary artery disease, who were newly diagnosed with impaired glucose tolerance or mild type 2 diabetes mellitus, were allocated, randomly, to receive either sitagliptin 100 mg/day or the placebo control. Common carotid IMT, glucose profiles, glycosylated hemoglobin (HbA1c), and lipid profiles were measured at baseline and repeated at 12 months. Sitagliptin-treated patients showed less IMT progression than the control group (p = 0.02). In addition, the sitagliptin group showed greater reductions in body weight (2.2%), 2-hour glucose levels on the 75-g oral glucose tolerance test (17.3%), HbA1c (4.7%), and low-density lipoprotein cholesterol levels (7.9%) from that at baseline. In conclusion, treatment with sitagliptin for 12 months was associated with a beneficial effect in the prevention of carotid IMT progression, compared with the diet control.

High LDL-cholesterol is a risk factor for atherosclerosis. We aimed to determine whether aggressive cholesterol lowering with statins was more effective than conventional statin treatment in this disease. We investigated the effect of high-dose atorvastatin on carotid atherosclerosis progression. We did a randomised, double-blind clinical trial in 325 patients with familial hypercholesterolaemia. Patients were given either atorvastatin 80 mg (n=160) or simvastatin 40 mg (n=165) daily, on an intent-to-treat basis. The primary endpoint was the change of carotid intima media thickness (IMT), as measured by quantitative B-mode ultrasound, over 2 years. The overall baseline IMT, combining the measurements of the common and internal carotid artery and the carotid bifurcation on both sides, was 0.93 mm (SD 0.22) and 0.92 mm (0.21) in the atorvastatin and simvastatin groups, respectively. After treatment with atorvastatin for 2 years, IMT decreased (-0.031 mm [95% CI -0.007 to -0.055]; p=0.0017), whereas in the simvastatin group it increased (0.036 [0.014-0.058]; p=0.0005). The change in thickness differed significantly between the two groups (p=0.0001). Atorvastatin showed greater reductions in cholesterol concentrations than did simvastatin. HDL-cholesterol concentrations increased in both groups. Both drugs were equally well tolerated. Our results show that aggressive LDL-cholesterol reduction by atorvastatin was accompanied by regression of carotid intima media thickness in patients with familial hypercholesterolaemia, whereas conventional LDL lowering was not.

OBJECTIVE: To evaluate whether the administration of metformin exerts any effects on serum homocysteine (Hcy) levels in patients with polycystic ovary syndrome (PCOS) and whether supplementation with folate enhances the positive effects of metformin on the structure and function of the vascular endothelium. RESEARCH DESIGN AND METHODS: A total of 50 patients affected by PCOS, without additional metabolic or cardiovascular diseases, were enrolled in a prospective nonrandomized placebo-controlled double-blind clinical study. They were grouped into two treatment arms that were matched for age and BMI. Patients were treated with a 6-month course of metformin (1,700 mg daily) plus folic acid (400 μg daily; experimental group, n = 25) or placebo (control group, n = 25). Complete hormonal and metabolic patterns, serum Hcy, folate, vitamin B12, endothelin-1 levels, brachial artery diameter at the baseline (BAD-B) and after reactive hyperemia (BAD-RH), flow-mediated dilation, and intima-media thickness in both common carotid arteries were evaluated. RESULTS: After treatment, a significant increase in serum Hcy levels was observed in the control group compared with the baseline values and the experimental group. A beneficial effect was observed in the concentrations of BAD-B, BAD-RH, flow-mediated dilation, intima-media thickness, and serum endothelin-1 in both groups. However, the results were improved more significantly in the experimental group than in the control subjects. CONCLUSIONS: Metformin exerts a slight but significant deleterious effect on serum Hcy levels in patients with PCOS, and supplementation with folate is useful to increase the beneficial effect of metformin on the vascular endothelium.

BackgroundThe risk of cardiovascular disease in human immunodeficiency virus (HIV)–infected patients is an increasing concern. We studied the changes in vascular properties after the initiation of combination antiretroviral therapy (cART) as well as the contribution of different drug classes MethodscART-naive men were randomized to receive either lopinavir/ritonavir (LPV/r) plus zidovudine/lamivudine (ZDV/3TC) (n=19) or LPV/r plus nevirapine (NVP) (n=18). Carotid artery intima-media thickness (C-IMT), arterial stiffness (distensibility coefficients [DCs] and compliance coefficients [CCs] of the carotid, femoral, and brachial arteries; carotid elastic modulus; and augmentation index), and markers of endothelial function (soluble vascular cell adhesion molecule [sVCAM]–1, intercellular adhesion molecule [sICAM]–1, plasma von Willebrand factor (vWF) antigen, and plasminogen activator inhibitor–1 antigen) and inflammation (high-sensitivity C-reactive protein) were measured before the initiation of cART and after 3, 12, and 24 months of cART ResultsC-IMT increased by 0.061±0.016 mm (P<.001) in the ZDV/3TC/LPV/r arm and by 0.044±0.018 mm (P=.012) in the NVP/LPV/r arm (data are estimated means ± SEs). Femoral artery DC (-1.66±0.78×10-3/kPa [P=.035]) and CC (-0.11±0.053 mm2/kPa [P=.043]) decreased in the ZDV/3TC/LPV/r arm and femoral DC decreased in the NVP/LPV/r arm (-1.72±0.85×10-3/kPa [P=.046]), with no significant difference in C-IMT or arterial stiffness between arms. sVCAM-1, sICAM-1, and vWF levels decreased significantly in both groups ConclusionC-IMT and femoral artery stiffness increased after the initiation of cART, whereas several markers of endothelial function improved, regardless of the composition of cART Trial registrationClinicalTrials.gov identifier: NCT00122226

Background The atherosclerotic process progresses more dynamically in hemodialysis (HD) patients than in the general population. In HD patients, lower magnesium levels were reported to be associated with increased atherosclerosis of the common carotid artery. We tested the hypotheses that magnesium supplementation helps to improve carotid intima media thickness (IMT) in HD patients. Materials and methods A total of 47 patients on HD were included in the study. Patients were randomly divided into two groups: group A (Mg group), in which patients were given magnesium citrate orally at a dosage of 610 mg every other day for 2 months and group B (control group), in which patients received only calcium acetate therapy as a phosphate binder. At baseline and 2 months later, all patients underwent a carotid artery ultrasound scan to measure carotid IMT. Results At the end of 2 months, mean serum calcium, phosphorus, and calcium × phosphorus product were not changed in both groups. As expected, mean serum Mg level significantly increased in the Mg group at the end of 2 months. In addition, serum parathyroid hormone (PTH) level significantly decreased in the Mg group at the end of 2 months ( P  = 0.003). Baseline carotid IMT was similar between the groups. Bilateral carotid IMT was significantly improved in patients treated with magnesium citrate compared to initial values ( P  = 0.001 for left, P  = 0.002 for right). Conclusion Based on the present data, magnesium may play an important protective role in the progression of atherosclerosis in patients on dialysis. Further studies are needed to assess more accurately the role of magnesium in atherosclerotic regression in dialysis patients.

Metformin and rosiglitazone both improve glycemic control in type 2 diabetes mellitus, however may possess different anti-inflammatory and anti-atherosclerotic properties. We investigated the effects of these medications on high-sensitivity C-reactive protein (hsCRP) and carotid artery intima-media thickness (CIMT) to determine their relative potential to reduce cardiovascular risk independent of their antihyperglycemic actions. Ninety-two subjects with suboptimally controlled diabetes mellitus (hemoglobin A 1c [HbA 1c] >7.0%) were assigned to therapy with either rosiglitazone 4 mg once daily or metformin 850 mg twice daily for 24 weeks. The primary end point was the change in hsCRP after 24 weeks. The change in CIMT was prespecified as a secondary end point. Metformin and rosiglitazone treatment led to similar significant improvements in glycemic control (HbA 1c −1.08% in the rosiglitazone group and −1.18% in the metformin group, P = nonsignificant). High-sensitivity C-reactive protein levels decreased by an average of 68% in the rosiglitazone group (5.99 ± 0.88 to 1.91 ± 0.28 mg/L, P < .001), compared with a nonsignificant 4% reduction in hsCRP with metformin (5.69 ± 0.83 to 5.46 ± 0.92 mg/L; P = nonsignificant). Maximal CIMT progressed in the metformin group (+0.084 ± 0.038 mm), whereas regression of maximal CIMT was observed in the rosiglitazone group (−0.037 ± 0.031 mm; P = .02 for the between group comparison). Similar changes were observed for mean CIMT. The change in hsCRP and maximal CIMT were related in a multivariable model controlling for changes in HbA 1c and lipid parameters ( r = .31; P = .01). Rosiglitazone, compared to metformin, induced a prompt and profound reduction in hsCRP levels independent of its effect on glycemia. This change was associated with regression of CIMT after 24 weeks.