The purpose of the present substudy of the Lipid Treatment Assessment Project 2 was to assess dual C-reactive protein (CRP) and low-density lipoprotein (LDL) cholesterol goal attainment across a spectrum of low-, moderate-, and high-risk patients with dyslipidemia in 8 countries in North America, Latin America, Europe, and Asia. Of the 9,518 patients studied overall, 45% were women, 64% had hypertension, 31% had diabetes, 14% were current smokers, 60% were high risk, and 79% were taking a statin. The median CRP level was 1.5 mg/L (interquartile range 0.2 to 2.8). On multivariate analysis, higher CRP levels were associated with older age, female gender, hypertension, current smoking, greater body mass index, larger waist circumference, LDL cholesterol level, and triglyceride/high-density lipoprotein cholesterol ratio. In contrast, being from Asia or taking a statin was associated with lower levels. Across all risk groups, 59% of patients attained the CRP target of <2 mg/L, and 33% had <1 mg/L. Overall, 44% of patients attained both their National Cholesterol Education Program Adult Treatment Panel III LDL cholesterol target and a CRP level of <2 mg/L, but only 26% attained their LDL cholesterol target and a CRP level of <1 mg/L. In the very high-risk group with coronary heart disease and ≥2 risk factors, only 19% attained both their LDL cholesterol goal and a CRP level of <2 mg/L and 12% their LDL cholesterol goal and a CRP level of <1 mg/L. In conclusion, with current treatment, most dyslipidemic patients do not reach the dual CRP and LDL cholesterol goals. Smoking cessation, weight reduction, and the greater use of more potent statins at higher doses might be able to improve these outcomes.
The relation of C-reactive protein (CRP) levels to low-density lipoprotein (LDL) cholesterol goals in treated patients with dyslipidemia has not been assessed in large populations, in particular from geographically diverse regions. The Lipid Treatment Assessment Project (L-TAP) 2 was a multinational survey evaluating LDL cholesterol goal attainment according to relevant national guidelines in patients receiving stable (≥3 months) lipid-lowering therapy in 9 countries (United States, Canada, Brazil, Mexico, France, Spain, The Netherlands, Korea, and Taiwan). The purpose of the present report was to describe the results of the CRP measurements in L-TAP 2, and to examine LDL cholesterol goal attainment in relation to the CRP levels. We determined the proportion of patients in each risk category who had attained both the LDL cholesterol goals and a CRP level of <2 mg/L and <1 mg/L. Furthermore, we characterized the clinical features associated with high CRP levels.
Methods
The design of L-TAP 2 has been previously described in detail. Patients were eligible if they were aged ≥20 years and had been treated with the same lipid-lowering therapy for ≥3 months. Diet and exercise were counted as permissible lipid-lowering therapies. Patients were excluded if any of the following conditions were present: major trauma; surgery requiring anesthesia or hospitalization of <12 weeks; acute infection requiring antibiotic therapy; a change in their usual diet of <1 month; pregnancy, breastfeeding, or postpartum for <6 months; myocardial infarction <12 weeks; any unstable medical condition; life expectancy <6 months; or treatment with an investigational lipid-altering drug or device within <30 days of the study visit. All patients gave written informed consent, and the study was approved by an institutional review board, where required.
The goal for enrollment was 3,000 patients in the United States; 1,000 patients each in Canada, Spain, The Netherlands, France, Taiwan, and Korea; 400 patients in Brazil; and 600 patients in Mexico. However, the patients from Mexico were excluded from the present analysis because the CRP levels were not measured in Mexico. Cluster sampling was used, with a cluster defined as each physician-investigator. Each investigator was expected to enroll approximately 20 patients. The sample size was chosen to provide a 2% margin of error for estimating the LDL cholesterol success rate in the United States and a 3% margin of error in each of the other countries.
All samples were analyzed at a central laboratory (MDS Pharma Services Central Laboratory, Mississauga, Ontario, Canada) for total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), blood glucose, and high-sensitivity CRP using a Roche Modular Analyzer. The LDL cholesterol was calculated using the Friedewald formula if the TG were ≤400 mg/dl and directly measured if the TG were >400 mg/dl. The Framingham 10-year risk of experiencing a coronary event was calculated for each patient.
The CRP subanalysis was one of several secondary objectives of the original L-TAP 2 analysis. The patients were evaluated as to whether they had attained a CRP goal of <2 mg/L or <1 mg/L. For each CRP level, they were also classified as to whether they had achieved their LDL cholesterol goal according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Goals were determined for low, moderate, and high Adult Treatment Panel III risk groups, and for very high-risk patients, for whom the optional LDL cholesterol goal of <70 mg/dl has been established.
The number and percentage of subjects meeting the goals are reported, and the p values for differences among the risk groups (low, moderate, and high) are reported according to the logistic regression analysis results.
The predictors of CRP levels were evaluated using stepwise linear regression analysis. The CRP levels were log-transformed for the analysis to satisfy normality assumptions. Candidate predictors included region (North America, Latin America, Europe, and Asia), gender, age, hypertension, log transformed body mass index (BMI), diabetes, smoking classification (nonsmoker, smoker, exsmoker), log transformed LDL cholesterol, log transformed TG/HDL cholesterol ratio, log transformed waist circumference, family history of coronary heart disease, and lipid-lowering therapy (i.e., statin therapy, nonstatin drug therapy, and nondrug therapy). The BMI, LDL cholesterol, TG/HDL cholesterol ratio, and waist circumference were log transformed to express their changes on a percentage scale. For categorical variables, the geometric mean, percentage of differences, and 95% confidence intervals for the percentage of differences are presented. For continuous predictors, the percentage of change in the CRP levels and the 95% confidence interval are presented for a given change in each predictor. The criterion for entry into the model and staying in the model was set at p = 0.05. Two-sided p values of <0.05 were considered significant. No adjustments were made for multiplicity.
Results
The clinical features of the patients are listed in Table 1 according to the CRP category. Patients with a CRP level of ≥2 mg/L tended to be women, non-Asians, and current smokers; to have a greater BMI and waist circumference; and to have diabetes and hypertension. They were less likely to be taking a statin and had greater LDL cholesterol and TG levels but lower HDL cholesterol levels.
| C-Reactive Protein Level | CRP (mg/L) | |||
|---|---|---|---|---|
| <1 (n = 3,159) | 1–<2 (n = 2,415) | ≥2 (n = 3,944) | All Patients (n = 9,518) | |
| Age (years) | 61.5 ± 11.7 | 62.5 ± 11.6 | 61.7 ± 11.7 | 61.8 ± 11.7 |
| Men | 1,860 (59%) | 1,382 (57%) | 1,993 (51%) | 5,235 (55%) |
| Women | 1,294 (41%) | 1,026 (43%) | 1,941 (49%) | 4,261 (45%) |
| Waist circumference (cm) | 92.5 ± 20.3 | 96.3 ± 15.9 | 100.9 ± 17.9 | 96.9 ± 18.6 |
| Body mass index (kg/m 2 ) | 26.2 ± 4.2 | 28.5 ± 9.6 | 30.3 ± 6.3 | 28.6 ± 7.0 |
| Diabetes mellitus | 861 (27%) | 714 (30%) | 1,379 (35%) | 2,954 (31%) |
| Hypertension | 1,893 (60%) | 1,548 (64%) | 2,608 (66%) | 6,049 (64%) |
| Current smoker | 358 (11%) | 340 (14%) | 644 (17%) | 1,342 (14%) |
| Region | ||||
| Asia | 983 (31%) | 490 (20%) | 527 (13%) | 2,000 (21%) |
| Europe | 904 (29%) | 785 (33%) | 1,345 (34%) | 3,034 (32%) |
| Latin America | 119 (3.7%) | 111 (4.5%) | 172 (4.3%) | 402 (4.2%) |
| North America | 1,153 (36%) | 1,029 (43%) | 1,900 (48%) | 4,082 (43%) |
| Coronary heart disease risk category ⁎ | ||||
| Low | 745 (24%) | 455 (19%) | 727 (18%) | 1,927 (20%) |
| Moderate | 582 (18%) | 491 (20%) | 818 (21%) | 1,891 (20%) |
| High | 1,832 (58%) | 1,469 (61%) | 2,399 (61%) | 5,700 (60%) |
| Therapy | ||||
| Statin | 2,671 (85%) | 1,946 (81%) | 2,949 (75%) | 7,566 (79%) |
| Nonstatin | 205 (6.4%) | 205 (8.4%) | 413 (10%) | 823 (8.6%) |
| No drug | 283 (8.9%) | 264 (11%) | 582 (15%) | 1,129 (12%) |
| Lipid levels | ||||
| Total cholesterol (mg/dl) | 177.5 ± 40.9 | 183.9 ± 42.0 | 187.5 ± 44.8 | 183.3 ± 43.1 |
| Low-density lipoprotein cholesterol (mg/dl) | 95.9 ± 34.6 | 100.7 ± 36.1 | 103.8 ± 37.5 | 100.4 ± 36.3 |
| High-density lipoprotein cholesterol (mg/dl) | 54.4 ± 15.3 | 52.9 ± 14.8 | 50.8 ± 14.4 | 52.5 ± 14.9 |
| Triglycerides (mg/dl) | 140.8 ± 96.7 | 155.3 ± 101.3 | 169.1 ± 115.6 | 156.2 ± 106.7 |
| Triglyceride/high-density lipoprotein cholesterol ratio | 3.0 ± 2.8 | 3.4 ± 2.1 | 3.9 ± 3.7 | 3.4 ± 3.3 |
⁎ According to National Cholesterol Education Program Adult Treatment Panel III guidelines.
The predictors of CRP level on multivariate analysis are listed in Table 2 . Quantitatively, the CRP levels were 31% greater in women, 30% greater in non-Asian regions, 38% greater in smokers, 6% greater in those with hypertension, and 18% lower in statin users. A 10-year increase in age increased the CRP level by 6%, and each 20% increment in the BMI, waist circumference, LDL cholesterol, and TG/HDL cholesterol ratio increased CRP by 31%, 4.3%, 3.6%, and 3.3%, respectively.
| Variable | CRP ⁎ (mg/L) | Difference (%) |
|---|---|---|
| Categorical | ||
| Women | 2.2 | +31% (25%, 38%) |
| Men (reference) | 1.7 | |
| Hypertension | 2.0 | +6.2% (1.4%, 11%) |
| No hypertension (reference) | 1.9 | |
| Smoker | 2.3 | +38% (29%, 47%) |
| Exsmoker | 1.9 | +13% (7.4%, 19%) |
| Nonsmoker (reference) | 1.6 | |
| Europe | 2.1 | +32% (24%, 41%) |
| Latin America | 2.1 | +32% (18%, 48%) |
| North America | 2.0 | +30% (22%, 38%) |
| Asia (reference) | 1.6 | |
| Statin therapy | 1.7 | −18% (−23%, −12%) |
| Nonstatin therapy | 2.0 | −1.8% (−11%, +7.9%) |
| No drug therapy (reference) | 2.1 | |
| Continuous | Change (%) | |
| Age (10-year increase) | +6.4% (4.4%, 8.5%) | |
| Body mass index (20% increase) | +31% (28%, 35%) | |
| Low-density lipoprotein cholesterol (20% increase) | +3.6% (2.4%, 4.7%) | |
| Triglyceride/high-density lipoprotein cholesterol ratio (20% increase) | +3.3% (2.6%, 3.9%) | |
| Waist circumference (20% increase) | +4.3% (1.7%, 6.8%) |
The distribution of CRP levels in each of the 8 countries is illustrated in Figure 1 . Little variation was seen across the United States, Canada, Brazil, France, The Netherlands, and Spain; however, the proportion of patients with CRP levels <1 mg/L was much greater in the 2 Asian countries, in particular Korea. Only 18% of Korean patients had a CRP level of ≥2 mg/L.
Overall, 71% of patients attained their LDL cholesterol goal ( Table 3 ). Across all risk groups, 59% of patients attained the CRP target of <2 mg/L and 33% had a level of <1 mg/L. Overall, 44% of patients attained both their LDL cholesterol target and a CRP level of <2 mg/L; however, only 26% attained their LDL cholesterol target and a CRP level of <1 mg/L. In the very high-risk group, only 19% attained both their LDL cholesterol goal and a CRP level of <2 mg/L and 12% their LDL cholesterol goal and a CRP level of <1 mg/L. The CRP level according to the LDL cholesterol success and risk group is listed in Table 4 .
