According to the 2018 American Heart Association (AHA)/American College of Cardiology (ACC) Guideline on the Management of Blood Cholesterol, healthy lifestyle practices and statins are the cornerstone of treatment for adults with atherosclerotic cardiovascular disease (ASCVD) or high cholesterol (low density lipoprotein cholesterol [LDL-C] ≥190 mg/ dL), including blacks.1
The amount statins can benefit an individual depends on the extent to which the cholesterol levels decline in response to statins.2 A reduction of about 40 mg/dL in LDL-C is associated with a 20% to 25% drop in heart and blood vessel related events, such as myocardial infarction (MI), coronary deaths, strokes, and coronary revascularizations, for each year statins are taken. This is true even in people with lower levels of cholesterol to start with. The clinical trial data used to estimate the effectiveness of statins, however, was derived from disproportionately white populations.3
In general, blacks respond well to statins, but not always to the same degree as other ethnicities.3–6 The reasons for the differences are not well understood. Blacks have not been included in sufficient numbers in statin efficacy studies to determine the cause of the variation, but several factors may be involved.
Lipid profiles in large cohorts of black populations that have been studied differ from those in non-blacks. Blacks have higher levels of high-density lipoprotein cholesterol (HDL-C) and lower levels of triglycerides than non-Hispanic whites or Mexicans which could impact on statin efficacy.7–9
There is some evidence that individuals with variance in the HMG-CoA reductase gene may be less sensitive to treatment with certain statins, and that these effects are more evident in blacks, but more research is needed.10,11 Studies are being conducted to evaluate the effect of other genotypes on statin response.12,13
Albert et al. compared data from white and non-white moderately hypercholesterolemic participants in a randomized double-blind placebo-controlled study of rosuvastatin for the primary prevention of ASCVD.3 Statin use reduced ASCVD (MI, stroke, arterial revascularization, hospitalization for unstable angina, and cardiovascular death) by 45% for whites (hazard ratio [HR] 0.55, 95% confidence interval [CI] [0.43 – 0.69]) and only by 37% for nonwhites (HR 0.63, 95% CI [0.41 – 0.99]). Risk reduction among nonwhite Hispanics and blacks were similar, but they were grouped together for analysis because the relative sample sizes of blacks and Hispanics were too small to use for reliable comparison (confidence intervals crossed one). In this study it was not clear if this difference between racial groups was a result of differences in drug adherence, genetic differences in pharmacologic response to statins, or other factors.
Margolis et al. analyzed data from the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT) which was a randomized controlled trial of hypercholesterolemic and hypertensive patients that compared the effects of open-label pravastatin use versus usual care among black and non-black participants.14 Earlier analyses of the Lipid-Lowering Trial component of the ALLHAT data found that blacks taking pravastatin had a significantly lower risk of developing coronary heart disease compared to those randomized to usual care, while non-black participants did not.15 After adjusting for age, gender, baseline risk factors, blood pressure, and lipid levels, Margolis’ results confirmed the difference in treatment effects in blacks and non-blacks when compared to usual care. Some authors have suggested that the difference in treatment effects between blacks and non-blacks may reflect a difference in intensity in usual care in blacks compared to whites rather than in treatment effects of statins.3 Still, Margolis et al. conclude that statins are effective for prevention of CHD in blacks.14
Black patients in the US who take statins may be less likely to achieve the goal level of LDL-C, according to an analysis by Yood et al.6 Medical encounter and laboratory data of 16,052 new statin users (32.5% blacks) was analyzed. After adjusting for age, sex, baseline and target LDL-C, statin dose, and factors that might influence drug adherence, black Americans were less likely to achieve the LDL-C targets than whites (HR 0.60, 95% CI [0.57 – 0.63]). LDL-C targets were determined by the Adult Treatment Panel guidelines of the National Cholesterol Education Program. The authors felt that differences in adherence to treatment and the frequency of monitoring cholesterol levels did not explain the racial disparity, and that black Americans with high cholesterol might require different statin dosing to achieve comparable results. Other studies have found similar disparity in achieving LDL-C treatment goals by race.5
The 2018 AHA/ACC guideline also recommends statins for people with LDL-C <190 mg/dL based on an assessment of their risk for future ASCVD events.1 Because the variables that best predict risk vary somewhat by race, a race-specific tool called the Pooled Cohort Equation (PCE) has been validated for use in blacks which should be used to improve clinical decisions regarding statin use in blacks.1,16 It uses a new risk algorithm developed with data pooled from cohorts that included larger numbers of black Americans than previous tools.7 Muntner et al. assessed the accuracy of the PCE in adults age 45 to 79 years without ASCVD and with LDL-C levels below 190 mg/dL with data from the Reasons for Geographic and Racial Differences in Stroke study that included 7,705 blacks (41.6%).16 In non-diabetics not taking statins, a population likely to use the PCE, the differences between the observed incidence versus PCE-predicted risk were small, including among the black participants (see Table).
Using the Pooled Cohort ACC/AHA risk calculator,17 a 60-year-old black male with no history of heart disease, a total cholesterol of 250 mg/dL, and no other risks factors, has an 8.3% risk of having a heart attack over the next 10 years. The same man taking high dose statins and achieving more optimal LDL-C levels lowers the 10-year risk of a heart attack to 6%. A 60-year-old black man with multiple risks, such as extremely high cholesterol (LDL-C 320 mg/dL), hypertension (systolic BP 200), smoking, low HDL (20 mg/dL), and diabetes has a 61.9% 10-year risk of having a heart attack. It is estimated that lowering cholesterol to optimal levels in this man would lower his risk to 45.2%.
In addition, a measurement of coronary artery calcium (CAC) may be used to predict the likelihood of future coronary events to assist in clinical decision-making with respect to statin use.1,18 A CAC of zero indicates a low risk of ASCVD events for the subsequent 10 years. The prevalence of CAC differs by ethnic group, according to results from the Multi-Ethnic Study of Atherosclerosis.19,20 CAC scores were highest in white and Hispanic men, with significantly lower prevalence and severity of CAC in blacks. Despite these differences CAC accurately predicted future cardiovascular events in all ethnic groups studied.18
The fact that blacks in general have lower CAC scores when compared to whites is difficult to explain given the higher rates of coronary heart disease among blacks.7,20 Manolio et al. studied the relationship between CAC and carotid atherosclerosis (by ultrasound) in 6,814 individuals of white, black, Hispanic, and Chinese ethnicity.21 Carotid intima media thickness is considered one measure of atherosclerosis burden. Although the relationship between coronary artery calcium and common carotid intima thickness was strong in all ethnic groups, it was less strong in blacks, particularly black women. The authors suggest that CAC may not predict risk information as well in risk groups other than whites, in whom the measurement has been studied more thoroughly.
Sung et al. studied the effectiveness of CAC measurement as a screening tool for cardiovascular risk compared to the Framingham Risk Score (FRS) among blacks in the Jackson Heart Study, a population-based longitudinal study based in Jackson, Mississippi.22 Although the addition of CAC measurement improved the predictive value of the FRS in the Jackson Heart Study population by 4%, this improvement was considerably lower than seen in non-Hispanic whites that have been studied. The authors caution that minorities have been under-represented in early evaluation of CAC effectiveness in predicting future ASCVD risk and further study is needed to affirm the efficacy of CAC measurement to estimate risk on blacks.
Safety of statins has been studied in relatively small numbers of blacks.23–25 Although the safety profile is generally favorable, some early studies noted a relatively high incidence of elevated creatinine kinase (CK) levels among blacks taking statins and those taking placebo. Since these studies, CK levels have been shown to be significantly higher in blacks.26 This fact is of some concern because CK levels are used to assess muscle damage, a side effect of statin use that sometimes results in drug discontinuation. An elevated CK in black patients taking statins and experiencing muscle pain, may represent a false positive. The 2018 guidelines recommend use of the 95th percentile race/ethnicity-specific serum CK normal levels for assessing CK changes in patients taking statins.1
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol2018.
- Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet2016; 388 (10059): 2532-2561.
- Albert MA, Glynn RJ, Fonseca FAH, et al. Race, ethnicity, and the efficacy of rosuvastatin in primary prevention: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER ) trial. Am Heart J2011; 162 (1): 106-114.e2.
- Nanna MG, Navar AM, Zakroysky P, et al. Association of patient perceptions of cardiovascular risk and beliefs on statin drugs with racial differences in statin use. JAMA Cardiol2018; 3 (8): 739-748.
- Turner BJ, Hollenbeak CS, Weiner M, Tang SSK. A retrospective cohort study of the potency of lipid-lowering therapy and race-gender differences in LDL cholesterol control. BMC Cardiovasc Disord2011; 11 (1): 58.
- Yood MU, Mccarthy BD, Kempf J. Racial differences in reaching target low-density lipoprotein goal among individuals treated with prescription statin therapy. Am Hear J2006; 152 : 777-784.
- Carnethon M, Pu J, Howard G, Albert M, Anderson C, Bertoni A. Cardiovascular health in African Americans. Circulation2017; 136: 393-423.
- Frank ATH, Zhao B, Jose PO, Azar KMJ, Fortmann SP, Palaniappan LP. Racial/ethnic differences in dyslipidemia patterns. Circulation2014; 129 (5): 570-579.
- Pu J, Romanelli R, Zhao B, et al. Dyslipidemia in special ethnic populations. Cardiol Clin2015; 33 (2): 325-333.
- Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VPJ, Ridker PM. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA2004; 291 (23): 2821-2827.
- Krauss RM, Mangravite LM, Smith JD, et al. Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Circulation2008; 117 (12): 1537-1544.
- Barber MJ, Mangravite LM, Hyde CL, et al. Genome-wide association of lipid-lowering response to statins in combined study populations. PLoS One2010; 5 (3): e9763.
- Ho RH, Choi L, Lee W, et al. Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Pharmacogenet Genomics2007; 17 (8): 647-656.
- Margolis KL, Dunn K, Simpson LM, et al. Coronary heart disease in moderately hypercholesterolemic, hypertensive black and non-black patients randomized to pravastatin vs. usual care: The Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT-LLT). Am Hear J2009; 158 (6): 948-955.
- The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care. JAMA2002; 288 (23): 2998–3007.
- Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations. JAMA - J Am Med Assoc2014; 311 (14): 1406-1415.
- Pooled Cohort Risk Assessment Equations. https://clincalc.com/pooledcohort.aspx. Accessed 2/3/2019.
- Greenland P, Blaha M, Budoff M, Erbel R, Watson K. Coronary calcium score and cardiovascular risk. J Am Coll Cardiol2018; 72 (4).
- Bild DE, Detrano R, Peterson D, et al. Ethnic differences in coronary calcification The Multi-Ethnic Study of Atherosclerosis (MESA). Circulation2005; 111: 1313-1320.
- Alluri K, McEvoy J, Dardari Z, et al. Distribution and burden of newly detected coronary artery calcium (CAC): results from the Multi-Ethnic Study of Athersclerosis (MESA). J Cardiovasc Comput Tomogr2015; 9 (4): 337-344.
- Manolio T, Arnold A, Post W, et al. Ethnic differences in the relationship of carotid atherosclerosis to coronary calcification: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis2008; 197 (1): 132-138.
- Sung JH, Yeboah J, Lee JE, et al. Diagnostic value of coronary artery calcium score for cardiovascular disease in African Americans: the Jackson Heart Study. Br J Med Med Res2016; 11 (2).
- Jacobson TA, Chin MM, Curry CL, et al. Efficacy and safety of pravastatin in African Americans with primary hypercholesterolemia. Arch Intern Med1995; 155 (17): 1900-1906.
- Prisant LM, Downton M, Watkins LO, et al. Efficacy and tolerability of lovastatin in 459 African-Americans with hypercholesterolemia. Am J Cardiol1996; 78 (4): 420-424.
- Flack JM, Victor R, Watson K, et al. Improved attainment of blood pressure and cholesterol goals using single-pill amlodipine/atorvastatin in African Americans: the CAPABLE trial. Mayo Clin Proc2008; 83 (1): 35-45.
- George MD, Mcgill N, Baker JF. Creatine kinase in the U.S. population. Medicine 2016; 95 (33).