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Articles by J Genest
Total Records ( 4 ) for J Genest
  S Mora , R. J Glynn , J Hsia , J. G MacFadyen , J Genest and P. M Ridker

Background— Statin therapy in women without cardiovascular disease (CVD) is controversial, given the insufficient evidence of benefit. We analyzed sex-specific outcomes in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and synthesized the results with prior trials.

Methods and Results— JUPITER participants included 6801 women ≥60 years of age and 11 001 men ≥50 years of age with high-sensitivity C-reactive protein ≥2 mg/L and low-density lipoprotein cholesterol <130 mg/dL randomized to rosuvastatin versus placebo. Meta-analysis studies were randomized placebo-controlled statin trials with predominantly or exclusively primary prevention in women and sex-specific outcomes (20 147 women; >276 CVD events; mean age, 63 to 69 years). Absolute CVD rates (per 100 person-years) in JUPITER women for rosuvastatin and placebo (0.57 and 1.04, respectively) were lower than for men (0.88 and 1.54, respectively), with similar relative risk reduction in women (hazard ratio, 0.54; 95% confidence interval, 0.37 to 0.80; P=0.002) and men (hazard ratio, 0.58; 95% confidence interval, 0.45 to 0.73; P<0.001). In women, there was significant reduction in revascularization/unstable angina and nonsignificant reductions in other components of the primary end point. Meta-analysis of 13 154 women (240 CVD events; 216 total deaths) from exclusively primary prevention trials found a significant reduction in primary CVD events with statins by a third (relative risk, 0.63; 95% confidence interval, 0.49 to 0.82; P<0.001; P for heterogeneity=0.56) with a smaller nonsignificant effect on total mortality (relative risk, 0.78; 95% confidence interval, 0.53 to 1.15; P=0.21; P for heterogeneity=0.20). Similar results were obtained for trials that were predominantly but not exclusively primary prevention.

Conclusion— JUPITER demonstrated that in primary prevention rosuvastatin reduced CVD events in women with a relative risk reduction similar to that in men, a finding supported by meta-analysis of primary prevention statin trials.

Clinical Trial Registration— URL: Unique identifier: NCT00239681.

  N Bousette , P D'Orleans Juste , R. S Kiss , Z You , J Genest , W Al Ramli , S. T Qureshi , A Gramolini , D Behm , E. H Ohlstein , S. M Harrison , S. A Douglas and A. Giaid

Rationale: Expression of the vasoactive peptide Urotensin II (UII) is elevated in a number of cardiovascular diseases.

Objective: Here, we sought to determine the effect of UII receptor (UT) gene deletion in a mouse model of atherosclerosis.

Methods and Results: UT knockout (KO) mice were crossed with ApoE KO mice to generate UT/ApoE double knockout (DKO) mice. Mice were placed on a high-fat Western-type diet for 12 weeks. We evaluated the degree of atherosclerosis and hepatic steatosis by histology. In addition, serum glucose, insulin, and lipids were determined. DKO mice exhibited significantly increased atherosclerosis compared to ApoE KO mice (P<0.05). This was associated with a significant increase in serum insulin and lipids (P<0.001) but a decrease in hepatic steatosis (P<0.001). UT gene deletion led to a significant increase in systolic pressure and pulse pressure. RT-PCR and immunoblot analyses showed significant reductions in hepatic scavenger receptors, nuclear receptors, and acyl-CoA:cholesterol acyltransferase (ACAT1) expression in DKO mice. UII induced a significant increase in intracellular cholesteryl ester formation in primary mouse hepatocytes, which was blocked by the MEK inhibitor, PD98059. Hepatocytes of UTKO mice showed a significant reduction in lipoprotein uptake compared to wild-type mice.

Conclusions: We propose that UT gene deletion in an ApoE-deficient background promotes downregulation of ACAT1, which in turn attenuates hepatic lipoprotein receptor-mediated uptake and lipid transporter expression. As the liver is the main organ for uptake of lipoprotein-derived lipids, DKO leads to an increase in hyperlipidemia, with a concomitant decrease in hepatic steatosis, and consequently increased atherosclerotic lesion formation. Furthermore, the hypertension associated with UT gene deletion is likely to contribute to the increased atherosclerotic burden.

  P. M Ridker , F. A.H Fonseca , J Genest , A. M Gotto , J. J.P Kastelein , W Koenig , P Libby , A. J Lorenzatti , B. G Nordestgaard , J Shepherd , J. T Willerson , R. J Glynn and for the JUPITER Study Group

Background— As recently demonstrated, random allocation to rosuvastatin results in large relative risk reductions for first cardiovascular events among apparently healthy men and women with low levels of low-density lipoprotein cholesterol but elevated levels of high-sensitivity C-reactive protein. However, whether the absolute risk reduction among such individuals justifies wide application of statin therapy in primary prevention is a controversial issue with broad policy and public health implications.

Methods and Results— Absolute risk reductions and consequent number needed to treat (NNT) values were calculated across a range of end points, timeframes, and subgroups using data from Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), a randomized evaluation of rosuvastatin 20 mg versus placebo conducted among 17 802 apparently healthy men and women with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L. Sensitivity analyses were also performed to address the potential impact that alternative statin regimens might have on a similar primary prevention population. For the end point of myocardial infarction, stroke, revascularization, or death, the 5-year NNT within JUPITER was 20 (95% CI, 14 to 34). All subgroups had 5-year NNT values for this end point below 50; as examples, 5-year NNT values were 17 for men and 31 for women, 21 for whites and 19 for nonwhites, 18 for those with body mass index ≤25 kg/m2 and 21 for those with body mass index greater than 25 kg/m2, 9 and 26 for those with and without a family history of coronary disease, 19 and 22 for those with and without metabolic syndrome, and 14 and 37 for those with estimated Framingham risks greater or less than 10%. For the net vascular benefit end point that additionally included venous thromboembolism, the 5-year NNT was 18 (95% CI, 13 to 29). For the restricted "hard" end point of myocardial infarction, stroke, or death, the 5-year NNT was 29 (95% CI, 19 to 56). In sensitivity analyses addressing the theoretical utility of alternative agents, 5-year NNT values of 38 and 57 were estimated for statin regimens that deliver 75% and 50% of the relative benefit observed in JUPITER, respectively. All of these calculations compare favorably to 5-year NNT values previously reported in primary prevention for the use of statins among hyperlipidemic men (5-year NNT, 40 to 70), for antihypertensive therapy (5-year NNT, 80 to 160), or for aspirin (5-year NNT, >300).

Conclusions— Absolute risk reductions and consequent NNT values associated with statin therapy among those with elevated high-sensitivity C-reactive protein and low low-density lipoprotein cholesterol are comparable if not superior to published NNT values for several widely accepted interventions for primary cardiovascular prevention, including the use of statin therapy among those with overt hyperlipidemia.

Clinical Trial Registration— Identifier NCT00239681.

  P. M Ridker , J. G MacFadyen , B. G Nordestgaard , W Koenig , J. J. P Kastelein , J Genest and R. J. Glynn

Recent primary prevention guidelines issued in Canada endorse the use of statin therapy among individuals at "intermediate risk" who have elevated levels of high-sensitivity C-reactive protein (hsCRP). However, trial data directly addressing whether this recommendation defines a patient population in which statin therapy is effective have not previously been published.

Methods and Results—

In the Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which demonstrated a 44% reduction in first vascular events when rosuvastatin 20 mg was compared with placebo among 17 802 primary prevention patients with LDL cholesterol <130 mg/dL and hsCRP ≥2 mg/L, 6091 participants (2525 women, 3566 men) had baseline estimated 10-year Framingham risks of 5% to 10% and 7340 participants (1404 women, 5936 men) had baseline estimated Framingham risk of 11% to 20%. In these 2 "intermediate risk" subgroups, relative risk reductions consistent with the overall trial treatment effect were observed (hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.84; 5-year number needed to treat=40, P=0.005 for those with 5% to 10% risk; hazard ratio, 0.51; 95% confidence interval, 0.39 to 0.68, 5-year number needed to treat=18, P<0.0001 for those with 11% to 20% risk). Use of the Reynolds Risk Score to stratify the study population gave similar results but reclassified large numbers of individuals into lower- or higher-risk groups. The majority of women with elevated hsCRP who benefited from rosuvastatin were at 5% to 10% 10-year risk at study entry using either global risk scoring system.


Consistent with recent evidence-based Canadian Cardiovascular Society guidelines for primary prevention, the JUPITER trial demonstrates that rosuvastatin 20 mg significantly reduces major cardiovascular events among men and women with elevated hsCRP and "intermediate risk" defined either as 5% to 10% or 10% to 20% 10-year risk.

Clinical Trial Registration—

URL: Unique identifier: NCT00239681.

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