Mohamed B. Elshazly

Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications.

OBJECTIVESnThe aim of this study was to compare Friedewald-estimated and directly measured low-density lipoprotein cholesterol (LDL-C) values.nnnBACKGROUNDnLDL-C is routinely estimated by the Friedewald equation to guide treatment; however, compatibility with direct measurement has received relatively little scrutiny, especially at levels <70 mg/dl now targeted in high-risk patients.nnnMETHODSnWe examined 1,340,614 U.S. adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011. Following standard practice, Friedewald LDL-C was not estimated if triglyceride levels were ≥ 400 mg/dl (n = 30,174), yielding 1,310,440 total patients and 191,333 patients with Friedewald LDL-C <70 mg/dl.nnnRESULTSnPatients were 59 ± 15 years of age and 52% were women. Lipid distributions closely matched those in the National Health and Nutrition Examination Survey. A greater difference in the Friedewald-estimated versus directly measured LDL-C occurred at lower LDL-C and higher triglyceride levels. If the Friedewald-estimated LDL-C was <70 mg/dl, the median directly measured LDL-C was 9.0 mg/dl higher (5th to 95th percentiles, 1.8 to 15.4 mg/dl) when triglyceride levels were 150 to 199 mg/dl and 18.4 mg/dl higher (5th to 95th percentiles, 6.6 to 36.0 mg/dl) when triglyceride levels were 200 to 399 mg/dl. Of patients with a Friedewald-estimated LDL-C <70 mg/dl, 23% had a directly measured LDL-C ≥ 70 mg/dl (39% if triglyceride levels were concurrently 150 to 199 mg/dl; 59% if triglyceride levels were concurrently 200 to 399 mg/dl).nnnCONCLUSIONSnThe Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially if triglyceride levels are ≥ 150 mg/dl, Friedewald estimation commonly classifies LDL-C as <70 mg/dl despite directly measured levels ≥ 70 mg/dl, and therefore additional evaluation is warranted in high-risk patients.

Comparison of a Novel Method vs the Friedewald Equation for Estimating Low-Density Lipoprotein Cholesterol Levels From the Standard Lipid Profile

IMPORTANCEnIn clinical and research settings worldwide, low-density lipoprotein cholesterol (LDL-C) is typically estimated using the Friedewald equation. This equation assumes a fixed factor of 5 for the ratio of triglycerides to very low-density lipoprotein cholesterol (TG:VLDL-C); however, the actual TG:VLDL-C ratio varies significantly across the range of triglyceride and cholesterol levels.nnnOBJECTIVEnTo derive and validate a more accurate method for LDL-C estimation from the standard lipid profile using an adjustable factor for the TG:VLDL-C ratio.nnnDESIGN, SETTING, AND PARTICIPANTSnWe used a convenience sample of consecutive clinical lipid profiles obtained from 2009 through 2011 from 1,350,908 children, adolescents, and adults in the United States. Cholesterol concentrations were directly measured after vertical spin density-gradient ultracentrifugation, and triglycerides were directly measured. Lipid distributions closely matched the population-based National Health and Nutrition Examination Survey (NHANES). Samples were randomly assigned to derivation (nu2009=u2009900,605) and validation (nu2009=u2009450,303) data sets.nnnMAIN OUTCOMES AND MEASURESnIndividual patient-level concordance in clinical practice guideline LDL-C risk classification using estimated vs directly measured LDL-C (LDL-CD).nnnRESULTSnIn the derivation data set, the median TG:VLDL-C was 5.2 (IQR, 4.5-6.0). The triglyceride and non-high-density lipoprotein cholesterol (HDL-C) levels explained 65% of the variance in the TG:VLDL-C ratio. Based on strata of triglyceride and non-HDL-C values, a 180-cell table of median TG:VLDL-C values was derived and applied in the validation data set to estimate the novel LDL-C (LDL-CN). For patients with triglycerides lower than 400 mg/dL, overall concordance in guideline risk classification with LDL-CD was 91.7% (95% CI, 91.6%-91.8%) for LDL-CN vs 85.4% (95% CI, 85.3%-85.5%) for Friedewald LDL-C (LDL-CF) (Pu2009<u2009.001). The greatest improvement in concordance occurred in classifying LDL-C lower than 70 mg/dL, especially in patients with high triglyceride levels. In patients with an estimated LDL-C lower than 70 mg/dL, LDL-CD was also lower than 70 mg/dL in 94.3% (95% CI, 93.9%-94.7%) for LDL-CN vs 79.9% (95% CI, 79.3%-80.4%) for LDL-CF in samples with triglyceride levels of 100 to 149 mg/dL; 92.4% (95% CI, 91.7%-93.1%) for LDL-CN vs 61.3% (95% CI, 60.3%-62.3%) for LDL-CF in samples with triglyceride levels of 150 to 199 mg/dL; and 84.0% (95% CI, 82.9%-85.1%) for LDL-CN vs 40.3% (95% CI, 39.4%-41.3%) for LDL-CF in samples with triglyceride levels of 200 to 399 mg/dL (Pu2009<u2009.001 for each comparison).nnnCONCLUSIONS AND RELEVANCEnA novel method to estimate LDL-C using an adjustable factor for the TG:VLDL-C ratio provided more accurate guideline risk classification than the Friedewald equation. These findings require external validation, as well as assessment of their clinical importance. The implementation of these findings into clinical practice would be straightforward and at virtually no cost.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT01698489.

Non-high-density lipoprotein cholesterol, guideline targets, and population percentiles for secondary prevention in 1.3 million adults: The VLDL-2 study (very large database of lipids)

OBJECTIVESnThis study sought to examine patient-level discordance between population percentiles of non-high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).nnnBACKGROUNDnNon-HDL-C is an alternative to LDL-C for risk stratification and lipid-lowering therapy. The justification for the present guideline-based non-HDL-C cutpoints of 30 mg/dl higher than the LDL-C cutpoints remains largely untested.nnnMETHODSnWe assigned population percentiles to non-HDL-C and Friedewald-estimated LDL-C values of 1,310,440 U.S. adults with triglyceride levels <400 mg/dl who underwent lipid testing by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011.nnnRESULTSnLDL-C cutpoints of 70, 100, 130, 160, and 190 mg/dl were in the same population percentiles as non-HDL-C values of 93, 125, 157, 190, and 223 mg/dl, respectively. Non-HDL-C values reclassified a significant proportion of patients within or to a higher treatment category compared with Friedewald LDL-C values, especially at LDL-C levels in the treatment range of high-risk patients and at triglyceride levels ≥150 mg/dl. Of patients with LDL-C levels <70 mg/dl, 15% had a non-HDL-C level ≥ 100 mg/dl (guideline-based cutpoint) and 25% had a non-HDL-C level ≥ 93 mg/dl (percentile-based cutpoint); if triglyceride levels were 150 to 199 mg/dl concurrently, these values were 22% and 50%, respectively.nnnCONCLUSIONSnThere is significant patient-level discordance between non-HDL-C and LDL-C percentiles at lower LDL-C and higher triglyceride levels, which has implications for the treatment of high-risk patients. Current non-HDL-C cutpoints for high-risk patients may need to be lowered to match percentiles of LDL-C cutpoints. Relatively small absolute reductions in non-HDL-C cutpoints result in substantial reclassification of patients to higher treatment categories with potential implications for risk assessment and treatment.

Non-HDL Cholesterol and Triglycerides: Implications for Coronary Atheroma Progression and Clinical Events.

Objectives—Non–high-density lipoprotein cholesterol (non-HDLC) levels reflect the full burden of cholesterol transported in atherogenic lipoproteins. Genetic studies suggest a causal association between elevated triglycerides (TGs)-rich lipoproteins and atherosclerosis. We evaluated associations between achieved non-HDLC and TG levels on changes in coronary atheroma volume. Approach and Results—Data were analyzed from 9 clinical trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography to assess changes in percent atheroma volume (&Dgr;PAV) and were evaluated against on-treatment non-HDLC and TG levels. The effects of lower (<100 mg/dL) versus higher (≥100 mg/dL) achieved non-HDLC levels and lower (<200 mg/dL) versus higher (≥200 mg/dL) achieved TG levels were evaluated in populations with variable on-treatment low-density lipoprotein cholesterol (LDLC) 0) was associated with achieved TG levels >200 mg/dL, respectively. Lower on-treatment non-HDLC and TG levels associated with significant PAV regression compared with higher non-HDLC and TG levels across all levels of LDLC and C-reactive protein and irrespective of diabetic status (P<0.001 across all comparisons). &Dgr;PAV were more strongly influenced by changes in non-HDLC (&bgr;=0.62; P<0.001) compared with changes in LDLC (&bgr;=0.51; P<0.001). Kaplan–Meier sensitivity analyses demonstrated significantly greater major adverse cardiovascular event rates in those with higher versus lower non-HDLC and TG levels, with an earlier separation of the non-HDLC compared with the LDLC curve. Conclusions—Achieved non-HDLC levels seem more closely associated with coronary atheroma progression than LDLC. Plaque progression associates with achieved TGs, but only above levels of 200 mg/dL. These observations support a more prominent role for non-HDLC (and possibly TG) lowering in combating residual cardiovascular risk.

Very large database of lipids: Rationale and design

Blood lipids have major cardiovascular and public health implications. Lipid‐lowering drugs are prescribed based in part on categorization of patients into normal or abnormal lipid metabolism, yet relatively little emphasis has been placed on: (1) the accuracy of current lipid measures used in clinical practice, (2) the reliability of current categorizations of dyslipidemia states, and (3) the relationship of advanced lipid characterization to other cardiovascular disease biomarkers. To these ends, we developed the Very Large Database of Lipids (NCT01698489), an ongoing database protocol that harnesses deidentified data from the daily operations of a commercial lipid laboratory. The database includes individuals who were referred for clinical purposes for a Vertical Auto Profile (Atherotech Inc., Birmingham, AL), which directly measures cholesterol concentrations of low‐density lipoprotein, very low‐density lipoprotein, intermediate‐density lipoprotein, high‐density lipoprotein, their subclasses, and lipoprotein(a). Individual Very Large Database of Lipids studies, ranging from studies of measurement accuracy, to dyslipidemia categorization, to biomarker associations, to characterization of rare lipid disorders, are investigator‐initiated and utilize peer‐reviewed statistical analysis plans to address a priori hypotheses/aims. In the first database harvest (Very Large Database of Lipids 1.0) from 2009 to 2011, there were 1u2009340u2009614 adult and 10u2009294 pediatric patients; the adult sample had a median age of 59 years (interquartile range, 49–70 years) with even representation by sex. Lipid distributions closely matched those from the population‐representative National Health and Nutrition Examination Survey. The second harvest of the database (Very Large Database of Lipids 2.0) is underway. Overall, the Very Large Database of Lipids database provides an opportunity for collaboration and new knowledge generation through careful examination of granular lipid data on a large scale.

Non-HDL Cholesterol and Triglycerides

Objectives—Non–high-density lipoprotein cholesterol (non-HDLC) levels reflect the full burden of cholesterol transported in atherogenic lipoproteins. Genetic studies suggest a causal association between elevated triglycerides (TGs)-rich lipoproteins and atherosclerosis. We evaluated associations between achieved non-HDLC and TG levels on changes in coronary atheroma volume. Approach and Results—Data were analyzed from 9 clinical trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography to assess changes in percent atheroma volume (&Dgr;PAV) and were evaluated against on-treatment non-HDLC and TG levels. The effects of lower (<100 mg/dL) versus higher (≥100 mg/dL) achieved non-HDLC levels and lower (<200 mg/dL) versus higher (≥200 mg/dL) achieved TG levels were evaluated in populations with variable on-treatment low-density lipoprotein cholesterol (LDLC) 0) was associated with achieved TG levels >200 mg/dL, respectively. Lower on-treatment non-HDLC and TG levels associated with significant PAV regression compared with higher non-HDLC and TG levels across all levels of LDLC and C-reactive protein and irrespective of diabetic status (P<0.001 across all comparisons). &Dgr;PAV were more strongly influenced by changes in non-HDLC (&bgr;=0.62; P<0.001) compared with changes in LDLC (&bgr;=0.51; P<0.001). Kaplan–Meier sensitivity analyses demonstrated significantly greater major adverse cardiovascular event rates in those with higher versus lower non-HDLC and TG levels, with an earlier separation of the non-HDLC compared with the LDLC curve. Conclusions—Achieved non-HDLC levels seem more closely associated with coronary atheroma progression than LDLC. Plaque progression associates with achieved TGs, but only above levels of 200 mg/dL. These observations support a more prominent role for non-HDLC (and possibly TG) lowering in combating residual cardiovascular risk.

Patient-Level Discordance in Population Percentiles of the Total Cholesterol to High-Density Lipoprotein Cholesterol Ratio in Comparison With Low-Density Lipoprotein Cholesterol and Non–High-Density Lipoprotein Cholesterol

Background —The total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, estimated low-density lipoprotein cholesterol (LDL-C), and non-HDL-C are routinely available from the standard lipid profile. We aimed to assess the extent of patient-level discordance of TC/HDL-C with LDL-C and non-HDL-C because discordance suggests the possibility of additional information. nnMethods and Results —We compared population percentiles of TC/HDL-C, Friedewald-estimated LDL-C, and non-HDL-C in 1,310,432 U.S. adults from the Very Large Database of Lipids. Lipid testing was performed by ultracentrifugation (VAP, Atherotech, AL). One in three patients had ≥25 percentile units discordance between TC/HDL-C and LDL-C while one in four had ≥25 percentile units discordance between TC/HDL-C and non-HDL-C. The proportion of patients with TC/HDL-C > LDL-C by ≥25 percentile units increased from 3% at triglycerides non-HDL-C discordance by ≥25 percentile units increased from 6% to 21%. In those with 86% of the variance in percentile discordance between TC/HDL-C vs. LDL-C and non-HDL-C. nnConclusions —In this contemporary, cross-sectional, big data analysis of U.S. adults who underwent advanced lipid testing, the extent of patient-level discordance suggests that TC/HDL-C may offer potential additional information to LDL-C and non-HDL-C. Future studies are required to determine the clinical implications of this observation. nnClinical Trial Registration Information —www.clinicaltrials.gov. Identifier: [NCT01698489][1].nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01698489&atom=%2Fcirculationaha%2Fearly%2F2015%2F07%2F02%2FCIRCULATIONAHA.115.016163.atomBackground— The total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, estimated low-density lipoprotein cholesterol (LDL-C), and non–HDL-C are routinely available from the standard lipid profile. We aimed to assess the extent of patient-level discordance of TC/HDL-C with LDL-C and non–HDL-C, because discordance suggests the possibility of additional information. Methods and Results— We compared population percentiles of TC/HDL-C, Friedewald-estimated LDL-C, and non–HDL-C in 1 310 432 US adults from the Very Large Database of Lipids. Lipid testing was performed by ultracentrifugation (Vertical Auto Profile, Atherotech, AL). One in 3 patients had ≥25 percentile units discordance between TC/HDL-C and LDL-C, whereas 1 in 4 had ≥25 percentile units discordance between TC/HDL-C and non–HDL-C. The proportion of patients with TC/HDL-C > LDL-C by ≥25 percentile units increased from 3% at triglycerides <100 mg/dL to 51% at triglycerides 200 to 399 mg/dL. On a smaller scale, TC/HDL-C > non–HDL-C discordance by ≥25 percentile units increased from 6% to 21%. In those with <15th percentile levels of LDL-C (<70 mg/dL) or non–HDL-C (<93 mg/dL), a respective 58% and 46% were above the percentile-equivalent TC/HDL-C of 2.6. Age, sex, and directly measured components of the standard lipid profile explained >86% of the variance in percentile discordance between TC/HDL-C versus LDL-C and non–HDL-C. Conclusions— In this contemporary, cross-sectional, big data analysis of US adults who underwent advanced lipid testing, the extent of patient-level discordance suggests that TC/HDL-C may offer potential additional information to LDL-C and non–HDL-C. Future studies are required to determine the clinical implications of this observation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01698489.

Ratio of Dense to Buoyant LDL Subclass is Associated with LDL Density Phenotype (VLDL-5)

Background: Dense LDL phenotypes are associated with increased atherogenicity, and are commonly evaluated for the purposes of atherosclerosis research and cardiovascular risk discrimination. Objective: To examine the ability of LDL subclasses, expressed as a ratio of dense-to-buoyant subclass, to predict LDL density phenotype. Methods: LDL subclasses and density phenotypes were measured with vertical auto profile ultracentrifugation in 1,339,898 consecutive lipid profiles between 2009 and 2011 from a clinical sample of US adults. Logarithmic LDL density ratio (LLDR) was calculated as ratio of dense-to-buoyant LDL subclasses, ln((LDL3-C + LDL4-C) / (LDL1-C +LDL2-C)); normally distributed after log-transformation. LLDR was compared to density phenotype using ROC C- statistic with optimum sensitivity and specificity cutpoints determined. Results: There was a strong, highly significant, monotonic increase in LLDR across progressively higher density phenotypes (p 0.905, sensitivity 81%, specificity 86%. There was also a positive correlation between LLDR and LDL Max Time (R 2 =0.802). Conclusion: LLDR is a convenient, easily calculated, and continuous variable that is strongly associated with LDL density phenotype and LDL Max Time. Further research is needed to investigate the relationship between lipoprotein density and size, and whether LLDR provides more cardiovascular risk discrimination than LDL density phenotype.

Patient-Level Discordance in Population Percentiles of the Total Cholesterol to High-Density Lipoprotein Cholesterol Ratio in Comparison With Low-Density Lipoprotein Cholesterol and Non–High-Density Lipoprotein Cholesterol The Very Large Database of Lipids Study (VLDL-2B)

Background —The total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, estimated low-density lipoprotein cholesterol (LDL-C), and non-HDL-C are routinely available from the standard lipid profile. We aimed to assess the extent of patient-level discordance of TC/HDL-C with LDL-C and non-HDL-C because discordance suggests the possibility of additional information. nnMethods and Results —We compared population percentiles of TC/HDL-C, Friedewald-estimated LDL-C, and non-HDL-C in 1,310,432 U.S. adults from the Very Large Database of Lipids. Lipid testing was performed by ultracentrifugation (VAP, Atherotech, AL). One in three patients had ≥25 percentile units discordance between TC/HDL-C and LDL-C while one in four had ≥25 percentile units discordance between TC/HDL-C and non-HDL-C. The proportion of patients with TC/HDL-C > LDL-C by ≥25 percentile units increased from 3% at triglycerides non-HDL-C discordance by ≥25 percentile units increased from 6% to 21%. In those with 86% of the variance in percentile discordance between TC/HDL-C vs. LDL-C and non-HDL-C. nnConclusions —In this contemporary, cross-sectional, big data analysis of U.S. adults who underwent advanced lipid testing, the extent of patient-level discordance suggests that TC/HDL-C may offer potential additional information to LDL-C and non-HDL-C. Future studies are required to determine the clinical implications of this observation. nnClinical Trial Registration Information —www.clinicaltrials.gov. Identifier: [NCT01698489][1].nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01698489&atom=%2Fcirculationaha%2Fearly%2F2015%2F07%2F02%2FCIRCULATIONAHA.115.016163.atomBackground— The total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, estimated low-density lipoprotein cholesterol (LDL-C), and non–HDL-C are routinely available from the standard lipid profile. We aimed to assess the extent of patient-level discordance of TC/HDL-C with LDL-C and non–HDL-C, because discordance suggests the possibility of additional information. Methods and Results— We compared population percentiles of TC/HDL-C, Friedewald-estimated LDL-C, and non–HDL-C in 1 310 432 US adults from the Very Large Database of Lipids. Lipid testing was performed by ultracentrifugation (Vertical Auto Profile, Atherotech, AL). One in 3 patients had ≥25 percentile units discordance between TC/HDL-C and LDL-C, whereas 1 in 4 had ≥25 percentile units discordance between TC/HDL-C and non–HDL-C. The proportion of patients with TC/HDL-C > LDL-C by ≥25 percentile units increased from 3% at triglycerides <100 mg/dL to 51% at triglycerides 200 to 399 mg/dL. On a smaller scale, TC/HDL-C > non–HDL-C discordance by ≥25 percentile units increased from 6% to 21%. In those with <15th percentile levels of LDL-C (<70 mg/dL) or non–HDL-C (<93 mg/dL), a respective 58% and 46% were above the percentile-equivalent TC/HDL-C of 2.6. Age, sex, and directly measured components of the standard lipid profile explained >86% of the variance in percentile discordance between TC/HDL-C versus LDL-C and non–HDL-C. Conclusions— In this contemporary, cross-sectional, big data analysis of US adults who underwent advanced lipid testing, the extent of patient-level discordance suggests that TC/HDL-C may offer potential additional information to LDL-C and non–HDL-C. Future studies are required to determine the clinical implications of this observation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01698489.

Accuracy of low-density lipoprotein cholesterol estimation at very low levels

BackgroundAs the approach to low-density lipoprotein cholesterol (LDL-C) lowering becomes increasingly intensive, accurate assessment of LDL-C at very low levels warrants closer attention in individualized clinical efficacy and safety evaluation. We aimed to assess the accuracy of LDL-C estimation at very low levels by the Friedewald equation, the de facto clinical standard, and compare its accuracy with a novel, big data-derived LDL-C estimate.MethodsIn 191,333 individuals with Friedewald LDL-Cu2009<u200970xa0mg/dL, we compared the accuracy of Friedewald and novel LDL-C values in relation to direct measurements by Vertical Auto Profile ultracentrifugation. We examined differences (estimate minus ultracentrifugation) and classification according to levels initiating additional safety precautions per clinical practice guidelines.ResultsFriedewald values were less than ultracentrifugation measurement, with a median difference (25th to 75th percentile) of –2.4 (–7.4 to 0.6) at 50–69xa0mg/dL, –7.0 (–16.2 to –1.2) at 25–39xa0mg/dL, and –29.0 (–37.4 to –19.6) atu2009<u200915xa0mg/dL. The respective values by novel estimation were –0.1 (–1.5 to 1.3), –1.1 (–2.5 to 0.3), and –2.7 (–4.9 to 0.0) mg/dL. Among those with Friedewald LDL–Cu2009<u200915, 15 tou2009<u200925, and 25 tou2009<u200940xa0mg/dL, the classification was discordantly low in 94.9%, 82.6%, and 59.9% of individuals as compared with 48.3%, 42.4%, and 22.4% by novel estimation.ConclusionsEstimation of even lower LDL-C values (by Friedewald and novel methods) is even more inaccurate. More often than not, a Friedewald valueu2009<u200940xa0mg/dL is underestimated, which translates into unnecessary safety alarms that could be reduced in half by estimation using our novel method.