Phenotypic Predictors of Response to Simvastatin Therapy Among African-Americans and Caucasians: The Cholesterol and Pharmacogenetics (CAP) Study

doi:10.1016/j.amjcard.2005.09.134

The American Journal of Cardiology

Volume 97, Issue 6, 15 March 2006, Pages 843-850

https://doi.org/10.1016/j.amjcard.2005.09.134 Get rights and content

Although statins are effective lipid-lowering agents, the phenotypic and demographic predictors of such lowering have been less well examined. We enrolled 944 African-American and white men and women who completed an open-label, 6-week pharmacogenetics trial of 40 mg of simvastatin. The phenotypic and demographic variables were examined as predictors of the change in lipids and lipoproteins using linear regression analysis. On average, treatment with simvastatin lowered low-density lipoprotein (LDL) cholesterol by 54 mg/dl and increased high-density lipoprotein (HDL) cholesterol by 2 mg/dl. Compared with African-Americans, whites had a 3-mg/dl greater LDL reduction and a 1-mg/dl higher HDL elevation, independent of other variables, including baseline lipoprotein levels (p <0.01). Multivariate analyses revealed moderate subgroup differences, with older participants having a larger decrease in LDL cholesterol and apolipoprotein B levels compared with younger participants (p <0.001), women having larger increases in HDL than men (p <0.01), nonsmokers having larger decreases in LDL and triglyceride levels compared with smokers (p <0.05), those with hypertension having smaller decreases in apolipoprotein B than those without hypertension (p <0.05), and those with a larger waist circumference having a diminished lowering of triglycerides in response to treatment with simvastatin (p <0.01). In conclusion, treatment with simvastatin produced favorable lipid and lipoprotein changes among all participants. The magnitude of the lipid and lipoprotein responses, however, differed among participants according to a number of phenotypic and demographic characteristics.

Section snippets

Study population

Between March 2002 and October 2004, we enrolled 1,007 African-American and white men and women, aged ≥30 years, with a baseline total serum cholesterol level of 160 to 400 mg/dl in the PARC Study. Using clinic-based flyers, public service advertisements, and community outreach, we recruited and enrolled participants at 2 clinical centers located at San Francisco General Hospital (San Francisco, California) and from the University of California, Los Angeles, School of Medicine (Los Angeles,

Results

The baseline characteristics of the CAP participants are presented in Table 1. On average, we enrolled middle-age African-American and white men and women who were overweight or obese and had high blood pressure (Table 1). The African-American and white participants differed in a number of demographic and medical variables. Compared with the African-Americans, the whites were more likely to be married, more educated, and leaner, and were less likely to have high blood pressure or be current

Discussion

Most studies of the effects of statins have reported that the beneficial effect of statins on clinical outcomes, such as coronary heart disease events, occurs across all subgroups. Relatively few studies have examined whether statins affect lipid and lipoprotein levels differentially when stratified by demographic and phenotypic characteristics. The Expanded Clinical Evaluation of Lovastatin (EXCEL) study reported on the differential effects of lovastatin by patient characteristics.³ In the

Acknowledgment

Simvastatin was donated by Merck and Company, Incorporated, Horsham, Pennsylvania.

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Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to statins varies among patients and can be modeled using 3 distinct pharmacological properties: 1) E₀ (baseline LDL-C), 2) ED₅₀ (potency: median dose achieving 50% reduction in LDL-C); and 3) E_max (efficacy: maximum LDL-C reduction). However, individualized dose-response and its association with ASCVD events remains unknown.
The authors analyzed the relationship between ED₅₀ and E_max with real-world cardiovascular disease outcomes.
We leveraged deidentified electronic health record data to identify individuals exposed to multiple doses of the 3 most commonly prescribed statins (atorvastatin, simvastatin, or rosuvastatin) within the context of their longitudinal health care. We derived ED₅₀ and E_max to quantify the relationship with a composite primary end point of ASCVD events (ischemic heart disease, cerebrovascular disease, peripheral vascular disease, coronary artery revascularization procedure) and all-cause mortality.
We estimated ED₅₀ and E_max for 3,033 unique individuals (atorvastatin: 1,632, simvastatin: 1,089, and rosuvastatin: 312) using a nonlinear, mixed effects dose-response model. Time-to-event analyses revealed that ED₅₀ and E_max are independently associated with the primary end point. Hazard ratios were 0.85 (P < 0.01), 0.83 (P < 0.01), and 0.87 (P = 0.10) for ED₅₀ and 1.13 (P < 0.001), 1.06 (P < 0.001), and 1.15 (P = 0.009) for E_max in the atorvastatin, simvastatin, and rosuvastatin cohorts, respectively.
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A gene–diet interaction controlling relative intake of dietary carbohydrates and fats
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Citation Excerpt :
In a preliminary study, we examined whether the use of statins may affect plasma AGRP levels in a cohort of human subjects. In 79 individuals in the Cholesterol and Pharmacogenetics (CAP) clinical trial treated with 40 mg/d simvastatin for 6 weeks [44], there was a small but significant reduction of AGRP levels (paired t-test: 66.5 vs. 63.5 pg/mL, p = 0.004). Body weights were not significantly altered by statin treatment.
Preference for dietary fat vs. carbohydrate varies markedly across free-living individuals. It is recognized that food choice is under genetic and physiological regulation, and that the central melanocortin system is involved. However, how genetic and dietary factors interact to regulate relative macronutrient intake is not well understood.
We investigated how the choice for food rich in carbohydrate vs. fat is influenced by dietary cholesterol availability and agouti-related protein (AGRP), the orexigenic component of the central melanocortin system. We assessed how macronutrient intake and different metabolic parameters correlate with plasma AGRP in a cohort of obese humans. We also examined how both dietary cholesterol levels and inhibiting de novo cholesterol synthesis affect carbohydrate and fat intake in mice, and how dietary cholesterol deficiency during the postnatal period impacts macronutrient intake patterns in adulthood.
In obese human subjects, plasma levels of AGRP correlated inversely with consumption of carbohydrates over fats. Moreover, AgRP-deficient mice preferred to consume more calories from carbohydrates than fats, more so when each diet lacked cholesterol. Intriguingly, inhibiting cholesterol biosynthesis (simvastatin) promoted carbohydrate intake at the expense of fat without altering total caloric consumption, an effect that was remarkably absent in AgRP-deficient mice. Finally, feeding lactating C57BL/6 dams and pups a cholesterol-free diet prior to weaning led the offspring to prefer fats over carbohydrates as adults, indicating that altered cholesterol metabolism early in life programs adaptive changes to macronutrient intake.
Together, our study illustrates a specific gene–diet interaction in modulating food choice.
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: CAP was supported by Grant U01-HL69757 from the National Institutes of Health, Bethesda, Maryland. Additional support was provided by Pfizer, Incorporated, New York, New York.

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Preventive cardiologyPhenotypic Predictors of Response to Simvastatin Therapy Among African-Americans and Caucasians: The Cholesterol and Pharmacogenetics (CAP) Study

Section snippets

Study population

Results

Discussion

Acknowledgment

Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge

Clin Chem

Statistical analysis system, version 8.02

Expanded Clinical Evaluation of Lovastatin (EXCEL) study resultseffect of patient characteristics on lovastatin-induced changes in plasma concentrations of lipids and lipoproteins

Circulation

Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary disease are equal to or exceed those seen in younger patientsresults from the LIPID trial

Ann Intern Med

Efficacy and tolerability of lovastatin in a six-month studyanalysis by gender, age and hypertensive status

Am J Cardiol

Preventive cardiology
Phenotypic Predictors of Response to Simvastatin Therapy Among African-Americans and Caucasians: The Cholesterol and Pharmacogenetics (CAP) Study