Summary Background In view of evidence that statin therapy increases risk of diabetes, the balance of benefit and risk of these drugs in primary prevention has become controversial. We undertook an ...analysis of participants from the JUPITER trial to address the balance of vascular benefits and diabetes hazard of statin use. Methods In the randomised, double-blind JUPITER trial, 17 603 men and women without previous cardiovascular disease or diabetes were randomly assigned to rosuvastatin 20 mg or placebo and followed up for up to 5 years for the primary endpoint (myocardial infarction, stroke, admission to hospital for unstable angina, arterial revascularisation, or cardiovascular death) and the protocol-prespecified secondary endpoints of venous thromboembolism, all-cause mortality, and incident physician-reported diabetes. In this analysis, participants were stratified on the basis of having none or at least one of four major risk factors for developing diabetes: metabolic syndrome, impaired fasting glucose, body-mass index 30 kg/m2 or higher, or glycated haemoglobin A 1c greater than 6%. The trial is registered at ClinicalTrials.gov , NCT00239681. Findings Trial participants with one or more major diabetes risk factor (n=11 508) were at higher risk of developing diabetes than were those without a major risk factor (n=6095). In individuals with one or more risk factors, statin allocation was associated with a 39% reduction in the primary endpoint (hazard ratio HR 0·61, 95% CI 0·47–0·79, p=0·0001), a 36% reduction in venous thromboembolism (0·64, 0·39–1·06, p=0·08), a 17% reduction in total mortality (0·83, 0·64–1·07, p=0·15), and a 28% increase in diabetes (1·28, 1·07–1·54, p=0·01). Thus, for those with diabetes risk factors, a total of 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. For trial participants with no major diabetes risk factors, statin allocation was associated with a 52% reduction in the primary endpoint (HR 0·48, 95% CI 0·33–0·68, p=0·0001), a 53% reduction in venous thromboembolism (0·47, 0·21–1·03, p=0·05), a 22% reduction in total mortality (0·78, 0·59–1·03, p=0·08), and no increase in diabetes (0·99, 0·45–2·21, p=0·99). For such individuals, a total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed. In analysis limited to the 486 participants who developed diabetes during follow-up (270 on rosuvastatin vs 216 on placebo; HR 1·25, 95% CI 1·05–1·49, p=0·01), the point estimate of cardiovascular risk reduction associated with statin therapy (HR 0·63, 95% CI 0·25–1·60) was consistent with that for the trial as a whole (0·56, 0·46–0·69). By comparison with placebo, statins accelerated the average time to diagnosis of diabetes by 5·4 weeks (84·3 SD 47·8 weeks on rosuvastatin vs 89·7 50·4 weeks on placebo). Interpretation In the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including in participants at high risk of developing diabetes. Funding AstraZeneca.
Summary Background Statins lower high-sensitivity C-reactive protein (hsCRP) and cholesterol concentrations, and hypothesis generating analyses suggest that clinical outcomes improve in patients ...given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1·8 mmol/L (<70 mg/dL). However, the benefit of lowering both LDL cholesterol and hsCRP after the start of statin therapy is controversial. We prospectively tested this hypothesis. Methods In an analysis of 15 548 initially healthy men and women participating in the JUPITER trial (87% of full cohort), we prospectively assessed the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial revascularisation, or cardiovascular death (prespecified endpoints) during a maximum follow-up of 5 years (median 1·9 years), according to on-treatment concentrations of LDL cholesterol (≥1·8 mmol/L or <1·8 mmol/L) and hsCRP (≥2 mg/L or <2 mg/L). We included all events occurring after randomisation. This trial is registered with ClinicalTrials.gov , number NCT00239681. Findings Compared with placebo, participants allocated to rosuvastatin who achieved LDL cholesterol less than 1·8 mmol/L had a 55% reduction in vascular events (event rate 1·11 vs 0·51 per 100 person-years; hazard ratio HR 0·45, 95% CI 0·34–0·60, p<0·0001), and those achieving hsCRP less than 2 mg/L a 62% reduction (event rate 0·42 per 100 person-years; HR 0·38, 95% CI 0·26–0·56, p<0·0001). Although LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients ( r values <0·15), we recorded a 65% reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1·8 mmol/L and hsCRP less than 2 mg/L (event rate 0·38 per 100 person-years; adjusted HR 0·35, 95% CI 0·23–0·54), versus a 33% reduction in those who achieved one or neither target (event rate 0·74 per 100 person-years; HR 0·67, 95% CI 0·52–0·87) (p across treatment groups <0·0001). In participants who achieved LDL cholesterol less than 1·8 mmol/L and hsCRP less than 1 mg/L, we noted a 79% reduction (event rate 0·24 per 100 person-years; HR 0·21, 95% CI 0·09–0·52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein AI ratio. Interpretation For people choosing to start pharmacological prophylaxis, reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with rosuvastatin. Funding AstraZeneca.
Summary Background HDL-cholesterol concentrations are inversely associated with occurrence of cardiovascular events. We addressed, using the JUPITER trial cohort, whether this association remains ...when LDL-cholesterol concentrations are reduced to the very low ranges with high-dose statin treatment. Methods Participants in the randomised placebo-controlled JUPITER trial were adults without diabetes or previous cardiovascular disease, and had baseline concentrations of LDL cholesterol of less than 3·37 mmol/L and high-sensitivity C-reactive protein of 2 mg/L or more. Participants were randomly allocated by a computer-generated sequence to receive rosuvastatin 20 mg per day or placebo, with participants and adjudicators masked to treatment assignment. In the present analysis, we divided the participants into quartiles of HDL-cholesterol or apolipoprotein A1 and sought evidence of association between these quartiles and the JUPITER primary endpoint of first non-fatal myocardial infarction or stroke, hospitalisation for unstable angina, arterial revascularisation, or cardiovascular death. This trial is registered with ClinicalTrials.gov , number NCT00239681. Findings For 17 802 patients in the JUPITER trial, rosuvastatin 20 mg per day reduced the incidence of the primary endpoint by 44% (p<0·0001). In 8901 (50%) patients given placebo (who had a median on-treatment LDL-cholesterol concentration of 2·80 mmol/L IQR 2·43–3·24), HDL-cholesterol concentrations were inversely related to vascular risk both at baseline (top quartile vs bottom quartile hazard ratio HR 0·54, 95% CI 0·35–0·83, p=0·0039) and on-treatment (0·55, 0·35–0·87, p=0·0047). By contrast, among the 8900 (50%) patients given rosuvastatin 20 mg (who had a median on-treatment LDL-cholesterol concentration of 1·42 mmol/L IQR 1·14–1·86), no significant relationships were noted between quartiles of HDL-cholesterol concentration and vascular risk either at baseline (1·12, 0·62–2·03, p=0·82) or on-treatment (1·03, 0·57–1·87, p=0·97). Our analyses for apolipoprotein A1 showed an equivalent strong relation to frequency of primary outcomes in the placebo group but little association in the rosuvastatin group. Interpretation Although measurement of HDL-cholesterol concentration is useful as part of initial cardiovascular risk assessment, HDL-cholesterol concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who attain very low concentrations of LDL cholesterol. Funding AstraZeneca.
Background Carriers of the rs4363657C and rs4149056C alleles in SLCO1B1 have increased myopathic complaints when taking simvastatin. Whether rosuvastatin has a similar effect is uncertain. This study ...assesses whether SLCO1B1 polymorphisms relate to clinical myalgia after rosuvastatin therapy. Methods In the JUPITER trial, participants without prior cardiovascular disease or diabetes who had low-density lipoprotein cholesterol <130 mg/dL and C-reactive protein ≥2 mg/L were randomly allocated to rosuvastatin 20 mg or placebo and followed for the first cardiovascular disease events and adverse effects. We evaluated the effect of rs4363657 and rs4149056 in SLCO1B1 , which encodes organic anion–transporting polypeptide OATP1B1, a regulator of hepatic statin uptake, on clinically reported myalgia. Results Among 4,404 participants allocated to rosuvastatin, clinical myalgia occurred with a rate of 4.1 events per 100 person-years as compared with 3.7 events per 100 person-years among 4,378 participants allocated to placebo (hazard ratio HR 1.13, 95% CI 0.98-1.30). Among those on rosuvastatin, there were no differences in the rate of myalgia among those with the rs4363657C (HR 0.95, 95% CI 0.79-1.14 per allele) or the rs4149056C allele (HR 0.95, 95% CI 0.79-1.15 per allele) compared with those without the C allele. Similar null data were observed when the myalgia definition was broadened to include muscle weakness, stiffness, or pain. None of the 3 participants on rosuvastatin or the 3 participants on placebo with frank myopathy had the minor allele at either polymorphism. Conclusion There appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C or the rs4149056C allele in SLCO1B1.
Objectives The purpose of this study was to assess the impact on cardiovascular and adverse events of attaining low-density lipoprotein cholesterol (LDL-C) levels <50 mg/dl with rosuvastatin in ...apparently healthy adults in the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial. Background The safety and magnitude of cardiovascular risk reduction conferred by treatment to LDL-C levels below current recommended targets remain uncertain. Methods A cohort of 17,802 apparently healthy men and women with high-sensitivity C-reactive protein ≥2 mg/l and LDL-C <130 mg/dl were randomly allocated to rosuvastatin 20 mg daily or placebo, and followed up for all-cause mortality, major cardiovascular events, and adverse events. In a post-hoc analysis, participants allocated to rosuvastatin were categorized as to whether or not they had a follow-up LDL-C level <50 mg/dl. Results During a median follow-up of 2 years (range up to 5 years), rates of the primary trial endpoint were 1.18, 0.86, and 0.44 per 100 person-years in the placebo group (n = 8,150) and rosuvastatin groups without LDL-C <50 mg/dl (n = 4,000) or with LDL-C <50 mg/dl (n = 4,154), respectively (fully-adjusted hazard ratio: 0.76; 95% confidence interval: 0.57 to 1.00 for subjects with no LDL-C <50 mg/dl vs. placebo and 0.35, 95% confidence interval: 0.25 to 0.49 for subjects attaining LDL-C <50 mg/dl; p for trend <0.0001). For all-cause mortality, corresponding event rates were 0.67, 0.65, and 0.39 (p for trend = 0.004). Rates of myalgia, muscle weakness, neuropsychiatric conditions, cancer, and diabetes mellitus were not significantly different among rosuvastatin-allocated participants with and without LDL-C <50 mg/dl. Conclusions Among adults with LDL-C <130 mg/dl and high-sensitivity C-reactive protein ≥2 mg/l, rosuvastatin-allocated participants attaining LDL-C <50 mg/dl had a lower risk of cardiovascular events without a systematic increase in reported adverse events.
Objectives The aim of this study was to evaluate the effect of statin treatment in primary prevention of cardiovascular events in different race/ethnic groups. Background Clinical trial evidence ...about the efficacy of statins in the primary prevention of cardiovascular events among nonwhites is uncertain. Methods JUPITER trial, a randomized, double-blind, placebo-controlled evaluation of rosuvastatin 20 mg in the primary prevention of myocardial infarction (MI), stroke, arterial revascularization, hospitalization for unstable angina, and cardiovascular death included 12,683 whites and 5,117 nonwhites with low-density lipoprotein levels <130 mg/dL and high-sensitivity C-reactive protein levels ≥2.0 mg/L. Results Random allocation to rosuvastatin resulted in a 45% reduction in the primary end point among whites (hazard ratio HR 0.55, 95% CI 0.43-0.69) and a 37% reduction among nonwhites (HR 0.63, 95% CI 0.41-0.99). Blacks (HR 0.65, 95% CI 0.35-1.22) and Hispanics (HR 0.58, 95% CI 0.25-1.39) had similar risk reductions. Among nonwhites in the placebo group, the stroke rate exceeded the MI rate (0.44 vs 0.20 per 100 person-years); an opposite pattern was observed among whites (0.31 vs 0.42 per 100 person-years). Nonwhites had higher death rates than whites (2.25 vs 0.93 per 100 person-years); however, all-cause mortality was similar at 20% with rosuvastatin treatment in both participant groups. Conclusions When used in primary prevention among individuals with low-density lipoprotein <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L, rosuvastatin significantly reduced first MI, stroke, arterial revascularization, hospitalization for unstable angina, and cardiovascular death among whites and nonwhites.
To test whether long-term multivitamin supplementation affects the incidence of cataract or age-related macular degeneration (AMD) in a large cohort of men.
Randomized, double-blind, ...placebo-controlled trial.
A total of 14,641 US male physicians aged ≥ 50 years.
Daily multivitamin or placebo.
Incident cataract and visually significant AMD responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-reports confirmed by medical record review.
During an average of 11.2 years of treatment and follow-up, a total of 1817 cases of cataract and 281 cases of visually significant AMD were confirmed. There were 872 cataracts in the multivitamin group and 945 cataracts in the placebo group (hazard ratio HR, 0.91; 95% confidence interval CI, 0.83-0.99; P = 0.04). For visually significant AMD, there were 152 cases in the multivitamin group and 129 cases in the placebo group (HR, 1.19; 95% CI, 0.94-1.50; P = 0.15).
These randomized trial data from a large cohort of middle-aged and older US male physicians indicate that long-term daily multivitamin use modestly and significantly decreased the risk of cataract but had no significant effect on visually significant AMD.
To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of the diagnosis of age-related macular degeneration (AMD) in a large-scale randomized trial of ...male physicians.
Randomized, double-masked, placebo-controlled trial.
We included 14 236 apparently healthy United States male physicians aged ≥50 years who did not report a diagnosis of AMD at baseline.
Participants were randomly assigned to receive 400 international units (IU) of vitamin E or placebo on alternate days, and 500 mg of vitamin C or placebo daily. Participants reported new diagnoses of AMD on annual questionnaires and medical record data were collected to confirm the reports.
Incident diagnosis of AMD responsible for a reduction in best-corrected visual acuity to ≤20/30.
After 8 years of treatment and follow-up, a total of 193 incident cases of visually significant AMD were documented. There were 96 cases in the vitamin E group and 97 in the placebo group (hazard ratio HR, 1.03; 95% confidence interval CI, 0.78-1.37). For vitamin C, there were 97 cases in the active group and 96 in the placebo group (HR, 0.99; 95% CI, 0.75-1.31).
In a large-scale, randomized trial of United States male physicians, alternate-day use of 400 IU of vitamin E and/or daily use of 500 mg of vitamin C for 8 years had no appreciable beneficial or harmful effect on risk of incident diagnosis of AMD.
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