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The JUPITER Study: Biomarkers Plus Statin vs. Lifestyle Modification for Preventing Cardiovascular Events
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Context.—
Although cholesterol-reducing treatment has been shown to reduce fatal
and nonfatal coronary disease in patients with coronary heart disease (CHD),
it is unknown whether benefit from the reduction of low-density lipoprotein
cholesterol (LDL-C) in patients without CHD extends to individuals with average
serum cholesterol levels, women, and older persons.Objective.—
To compare lovastatin with placebo for prevention of the first acute
major coronary event in men and women without clinically evident atherosclerotic
cardiovascular disease with average total cholesterol (TC) and LDL-C levels
and below-average high-density lipoprotein cholesterol (HDL-C) levels.Design.—
A randomized, double-blind, placebo-controlled trial.Setting.—
Outpatient clinics in Texas.Participants.—
A total of 5608 men and 997 women with average TC and LDL-C and below-average
HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort
without cardiovascular disease from the National Health and Nutrition Examination
Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21]
mg/dL) (51st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150
[17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L
(36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th
and 16th percentiles, respectively), and median (SD) triglyceride levels were
1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile).Intervention.—
Lovastatin (20-40 mg daily) or placebo in addition to a low–saturated
fat, low-cholesterol diet.Main Outcome Measures.—
First acute major coronary event defined as fatal or nonfatal myocardial
infarction, unstable angina, or sudden cardiac death.Results.—
After an average follow-up of 5.2 years, lovastatin reduced the incidence
of first acute major coronary events (183 vs 116 first events; relative risk
[RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001),
myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI,
0.43-0.83; P=.002), unstable angina (87 vs 60 first
unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02),
coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95%
CI, 0.52-0.85; P=.001), coronary events (215 vs 163
coronary events; RR, 0.75; 95% CI, 0.61-0.92; P=.006),
and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95%
CI, 0.62-0.91; P=.003). Lovastatin (20-40 mg daily)
reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6%
to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in
safety parameters between treatment groups.Conclusions.—
Lovastatin reduces the risk for the first acute major coronary event
in men and women with average TC and LDL-C levels and below-average HDL-C
levels. These findings support the inclusion of HDL-C in risk-factor assessment,
confirm the benefit of LDL-C reduction to a target goal, and suggest the need
for reassessment of the National Cholesterol Education Program guidelines
regarding pharmacological intervention.
Figures in this Article
EPIDEMIOLOGICAL observations have demonstrated consistently a strong
positive, continuous, independent, graded relation between plasma total cholesterol
(TC) and the incidence of coronary heart disease (CHD). This relation covers
a wide range of cholesterol concentrations, including those considered normal
or mildly elevated.1- 3
In the Multiple Risk Factor Intervention Trial follow-up of screened men,
69% of deaths from CHD in the first 6 years of follow-up occurred in subjects
with TC values between 4.71 and 6.83 mmol/L (182-264 mg/dL).4
In the first 16 years of the Framingham Heart Study, 40% of participants who
developed a myocardial infarction had a TC level between 5.17 and 6.47 mmol/L
(200-250 mg/dL).5
Large end point studies have demonstrated conclusively that effective
cholesterol-lowering treatment can substantially reduce myocardial infarction
and other coronary events. In the Scandinavian Simvastatin Survival Study
the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin
reduced total mortality in patients with CHD by 30% because of a 42% reduction
in deaths from CHD.6 Subsequently, pravastatin
was shown to reduce fatal and nonfatal coronary events in patients with7 and without8 CHD. However,
it is unknown whether benefit from reduction of low-density lipoprotein cholesterol
(LDL-C) in patients without CHD (primary prevention) extends to individuals
with average serum cholesterol levels, women, and older persons.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
targeted a cohort of generally healthy middle-aged and older men and women
with average TC and LDL-C levels and with below-average high-density lipoprotein
cholesterol (HDL-C) levels. The primary end point analysis was the incidence
of first acute major coronary events, defined as fatal or nonfatal myocardial
infarction, unstable angina, or sudden cardiac death. The inclusion of unstable
angina was a unique feature of this study, and its inclusion as a primary
end point reflects the increasing frequency of unstable angina as the initial
presentation of CHD in the United States.9
Background:
Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.
Methods:
We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.
Results:
The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.
Conclusions:
In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)
Dietary patterns and lifestyle factors are associated with mortality from all causes, coronary heart disease, cardiovascular diseases, and cancer, but few studies have investigated these factors in combination.
To investigate the single and combined effect of Mediterranean diet, being physically active, moderate alcohol use, and nonsmoking on all-cause and cause-specific mortality in European elderly individuals.
The Healthy Ageing: a Longitudinal study in Europe (HALE) population, comprising individuals enrolled in the Survey in Europe on Nutrition and the Elderly: a Concerned Action (SENECA) and the Finland, Italy, the Netherlands, Elderly (FINE) studies, includes 1507 apparently healthy men and 832 women, aged 70 to 90 years in 11 European countries. This cohort study was conducted between 1988 and 2000.
Ten-year mortality from all causes, coronary heart disease, cardiovascular diseases, and cancer.
During follow-up, 935 participants died: 371 from cardiovascular diseases, 233 from cancer, and 145 from other causes; for 186, the cause of death was unknown. Adhering to a Mediterranean diet (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.68-0.88), moderate alcohol use (HR, 0.78; 95% CI, 0.67-0.91), physical activity (HR, 0.63; 95% CI, 0.55-0.72), and nonsmoking (HR, 0.65; 95% CI, 0.57-0.75) were associated with a lower risk of all-cause mortality (HRs controlled for age, sex, years of education, body mass index, study, and other factors). Similar results were observed for mortality from coronary heart disease, cardiovascular diseases, and cancer. The combination of 4 low risk factors lowered the all-cause mortality rate to 0.35 (95% CI, 0.28-0.44). In total, lack of adherence to this low-risk pattern was associated with a population attributable risk of 60% of all deaths, 64% of deaths from coronary heart disease, 61% from cardiovascular diseases, and 60% from cancer.
Among individuals aged 70 to 90 years, adherence to a Mediterranean diet and healthful lifestyle is associated with a more than 50% lower rate of all-causes and cause-specific mortality.
No change in strategy is needed despite the hype surrounding the recent JUPITER study
This week, the New England Journal of Medicine published the randomised controlled trial JUPITER,1 which compared rosuvastatin (20 mg daily) with placebo in 18 000 patients with no apparent vascular disease, low density lipoprotein cholesterol (LDL-C) of less than 3.4 mmol/l (130 mg/dl), and high sensitivity C reactive protein concentrations of 2.0 mg/l or higher. The combined primary end point was myocardial infarction, stroke, arterial revascularisation, hospital admission for unstable angina, or death from cardiovascular causes. The trial was stopped after a median of two years after a highly significant improvement in the primary end point with rosuvastatin (hazard ratio 0.56; 95% confidence interval 0.46 to 0.69; P<0.00001). It is hardly surprising that the JUPITER study is seen by many as opening the door to new avenues to prevention.
What do the results mean? Do we really have to change our ways of targeting our preventive efforts—for example, measure high sensitivity C reactive protein on a regular basis? …
Many lifestyle-related risk factors for coronary heart disease have been identified, but little is known about their effect on the risk of disease when they are considered together.
We followed 84,129 women participating in the Nurses' Health Study who were free of diagnosed cardiovascular disease, cancer, and diabetes at base line in 1980. Information on diet and lifestyle was updated periodically. During 14 years of follow-up, we documented 1128 major coronary events (296 deaths from coronary heart disease and 832 nonfatal infarctions). We defined subjects at low risk as those who were not currently smoking, had a body-mass index (the weight in kilograms divided by the square of the height in meters) under 25, consumed an average of at least half a drink of an alcoholic beverage per day, engaged in moderate-to-vigorous physical activity (which could include brisk walking) for at least half an hour per day, on average, and scored in the highest 40 percent of the cohort for consumption of a diet high in cereal fiber, marine n-3 fatty acids, and folate, with a high ratio of polyunsaturated to saturated fat, and low in trans fat and glycemic load, which reflects the extent to which diet raises blood glucose levels.
Many of the factors were correlated, but each independently and significantly predicted risk, even after further adjustment for age, family history, presence or absence of diagnosed hypertension or diagnosed high cholesterol level, and menopausal status. Women in the low-risk category (who made up 3 percent of the population) had a relative risk of coronary events of 0.17 (95 percent confidence interval, 0.07 to 0.41) as compared with all the other women. Eighty-two percent of coronary events in the study cohort (95 percent confidence interval, 58 to 93 percent) could be attributed to lack of adherence to this low-risk pattern.
Among women, adherence to lifestyle guidelines involving diet, exercise, and abstinence from smoking is associated with a very low risk of coronary heart disease.
Healthy lifestyle choices such as eating a prudent diet, exercising regularly, managing weight, and not smoking may substantially reduce coronary heart disease (CHD) risk by improving lipids, blood pressure, and other risk factors. The burden of CHD that could be avoided through adherence to these modifiable lifestyle factors has not been assessed among middle-aged and older US men, specifically men taking medications for hypertension or hypercholesterolemia.
We prospectively monitored 42 847 men in the Health Professionals Follow-up Study, 40 to 75 years of age and free of disease in 1986. Lifestyle factors were updated through self-reported questionnaires. Low risk was defined as (1) absence of smoking, (2) body mass index <25 kg/m2, (3) moderate-to-vigorous activity > or = 30 min/d, (4) moderate alcohol consumption (5 to 30 g/d), and (5) the top 40% of the distribution for a healthy diet score. Over 16 years, we documented 2183 incident cases of CHD (nonfatal myocardial infarction and fatal CHD). In multivariate-adjusted Cox proportional hazards models, men who were at low risk for 5 lifestyle factors had a lower risk of CHD (relative risk: 0.13; 95% confidence interval [CI]: 0.09, 0.19) compared with men who were at low risk for no lifestyle factors. Sixty-two percent (95% CI: 49%, 74%) of coronary events in this cohort may have been prevented with better adherence to these 5 healthy lifestyle practices. Among men taking medication for hypertension or hypercholesterolemia, 57% (95% CI: 32%, 79%) of all coronary events may have been prevented with a low-risk lifestyle. Compared with men who did not make lifestyle changes during follow-up, those who adopted > or = 2 additional low-risk lifestyle factors had a 27% (95% CI: 7%, 43%) lower risk of CHD.
A majority of CHD events among US men may be preventable through adherence to healthy lifestyle practices, even among those taking medications for hypertension or hypercholesterolemia.
To determine the frequency of adopting a healthy lifestyle (5 or more fruits and vegetables daily, regular exercise, BMI 18.5-29.9 kg/m2, no current smoking) in a middle-aged cohort, and determine the subsequent rates of cardiovascular disease (CVD) and mortality among those who adopt a healthy lifestyle.
We conducted a cohort study in a diverse sample of adults age 45-64 in the Atherosclerosis Risk in Communities survey. Outcomes are all-cause mortality and fatal or non-fatal cardiovascular disease.
Of 15,708 participants, 1344 (8.5%) had 4 healthy lifestyle habits at the first visit, and 970 (8.4%) of the remainder had newly adopted a healthy lifestyle 6 years later. Men, African Americans, individuals with lower socioeconomic status, or a history of hypertension or diabetes were less likely to newly adopt a healthy lifestyle (all P <.05). During the following 4 years, total mortality and cardiovascular disease events were lower for new adopters (2.5% vs 4.2%, chi2P <.01, and 11.7% vs 16.5%, chi2P <.01 respectively) compared to individuals who did not adopt a healthy lifestyle. After adjustment, new adopters had lower all-cause mortality (OR 0.60, 95% Confidence Interval [CI], 0.39-0.92) and fewer cardiovascular disease events (OR 0.65, 95% CI, 0.39-0.92) in the next 4 years.
People who newly adopt a healthy lifestyle in middle-age experience a prompt benefit of lower rates of cardiovascular disease and mortality. Strategies to encourage adopting healthy lifestyles should be implemented, especially among people with hypertension, diabetes, or low socioeconomic status.