Renato Quispe

Relationship of the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio to the remainder of the lipid profile: The Very Large Database of Lipids-4 (VLDL-4) study

BACKGROUND High levels of the triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio are associated with obesity, metabolic syndrome, and insulin resistance. OBJECTIVES We evaluated variability in the remaining lipid profile, especially remnant lipoprotein particle cholesterol (RLP-C) and its components (very low-density lipoprotein cholesterol subfraction 3 and intermediate-density lipoprotein cholesterol), with variability in the TG/HDL-C ratio in a very large study cohort representative of the general U.S. METHODS We examined data from 1,350,908 US individuals who were clinically referred for lipoprotein cholesterol ultracentrifugation (Atherotech, Birmingham, AL) from 2009 to 2011. Demographic information other than age and sex was not available. Changes to the remaining lipid profile across percentiles of the TG/HDL-C ratio were quantified, as well as by three TG/HDL-C cut-off points previously proposed in the literature: 2.5 (male) and 2 (female), 3.75 (male) and 3 (female), and 3.5 (male and female). RESULTS The mean age of our study population was 58.7 years, and 48% were men. The median TG/HDL-C ratio was 2.2. Across increasing TG/HDL-C ratios, we found steadily increasing levels of RLP-C, non-HDL-C and LDL density. Among the lipid parameters studied, RLP-C and LDL density had the highest relative increase when comparing individuals with elevated TG/HDL-C levels to those with lower TG/HDL-C levels using established cut-off points. Approximately 47% of TG/HDL-C ratio variance was attributable to RLP-C. CONCLUSIONS In the present analysis, a higher TG/HDL-C ratio was associated with an increasingly atherogenic lipid phenotype, characterized by higher RLP-C along with higher non-HDL-C and LDL density.

Triglycerides to high-density lipoprotein-cholesterol ratio, glycemic control and cardiovascular risk in obese patients with type 2 diabetes.

Purpose of reviewThis article provides an update on the role of the triglyceride to high-density lipoprotein-cholesterol (triglyceride/HDL-C) ratio in the setting of obesity-related insulin resistance and type 2 diabetes mellitus. Recent findingsInsulin resistance and type 2 diabetes mellitus are well-established risk factors for cardiovascular diseases, and are commonly associated with metabolic abnormalities such as hypertriglyceridemia, low HDL-C and presence of small, dense low-dense lipoprotein (LDL) particles. Mounting evidence suggests that the triglyceride/HDL-C ratio is a marker of insulin resistance, although this relationship might vary as a function of ethnicity and sex. The triglyceride/HDL-C ratio has also been shown to correlate with other atherogenic lipid measurements, such as triglyceride-rich lipoproteins, remnant cholesterol and small dense LDL particles. Recent epidemiologic studies have shown that the triglyceride/HDL-C ratio associates with cardiovascular risk, mainly because of its association with insulin resistance. Finally, triglyceride/HDL-C can also be a marker of glycemic control, especially in obese patients with type 2 diabetes mellitus. SummaryThe triglyceride/HDL-C integrates information on triglyceride-rich lipoproteins, insulin resistance and glycemic control. Future studies may better define its specific clinical role.

Fasting Versus Nonfasting and Low-Density Lipoprotein Cholesterol Accuracy

Background: Recent recommendations favoring nonfasting lipid assessment may affect low-density lipoprotein cholesterol (LDL-C) estimation. The novel method of LDL-C estimation (LDL-CN) uses a flexible approach to derive patient-specific ratios of triglycerides to very low-density lipoprotein cholesterol. This adaptability may confer an accuracy advantage in nonfasting patients over the fixed approach of the classic Friedewald method (LDL-CF). Methods: We used a US cross-sectional sample of 1 545  634 patients (959 153 fasting ≥10–12 hours; 586 481 nonfasting) from the second harvest of the Very Large Database of Lipids study to assess for the first time the impact of fasting status on novel LDL-C accuracy. Rapid ultracentrifugation was used to directly measure LDL-C content (LDL-CD). Accuracy was defined as the percentage of LDL-CD falling within an estimated LDL-C (LDL-CN or LDL-CF) category by clinical cut points. For low estimated LDL-C (<70 mg/dL), we evaluated accuracy by triglyceride levels. The magnitude of absolute and percent differences between LDL-CD and estimated LDL-C (LDL-CN or LDL-CF) was stratified by LDL-C and triglyceride categories. Results: In both fasting and nonfasting samples, accuracy was higher with the novel method across all clinical LDL-C categories (range, 87%–94%) compared with the Friedewald estimation (range, 71%–93%; P⩽0.001). With LDL-C <70 mg/dL, nonfasting LDL-CN accuracy (92%) was superior to LDL-CF accuracy (71%; P<0.001). In this LDL-C range, 19% of fasting and 30% of nonfasting patients had differences ≥10 mg/dL between LDL-CF and LDL-CD, whereas only 2% and 3% of patients, respectively, had similar differences with novel estimation. Accuracy of LDL-C <70 mg/dL further decreased as triglycerides increased, particularly for Friedewald estimation (range, 37%–96%) versus the novel method (range, 82%–94%). With triglycerides of 200 to 399 mg/dL in nonfasting patients, LDL-CN <70 mg/dL accuracy (82%) was superior to LDL-CF (37%; P<0.001). In this triglyceride range, 73% of fasting and 81% of nonfasting patients had ≥10 mg/dL differences between LDL-CF and LDL-CD compared with 25% and 20% of patients, respectively, with LDL-CN. Conclusions: Novel adaptable LDL-C estimation performs better in nonfasting samples than the fixed Friedewald estimation, with a particular accuracy advantage in settings of low LDL-C and high triglycerides. In addition to stimulating further study, these results may have immediate relevance for guideline committees, laboratory leadership, clinicians, and patients. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01698489.

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. Methods 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. Conclusions —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. Clinical Trial Registration Information —www.clinicaltrials.gov. Identifier: [NCT01698489][1]. [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.

Vitamin D deficiency and non-lipid biomarkers of cardiovascular risk

Introduction Deficient 25-hydroxyvitamin D (25(OH)D) levels have been associated with dyslipidemia and cardiovascular diseases, though the underlying mechanism of these associations is uncertain. We analyzed associations between vitamin D and other non-lipid biomarkers of cardiovascular risk to better elucidate possible relationships between deficient 25(OH)D and cardiovascular disease. Material and methods We performed a cross-sectional analysis of 4,591 adults included in a clinical laboratory database from 2009 to 2011 with available measurements for 25(OH)D and the following biomarkers: homocysteine (Hcy), high-sensitivity C-reactive protein (hs-CRP), cystatin-C, creatinine, γ-glutamyltransferase (GGT), uric acid, and hemoglobin A1c (HbA1c). We calculated odds ratios (OR) of having high levels of each biomarker associated with 25(OH)D deficiency (< 20 ng/ml) compared to optimal levels (≥ 30 ng/ml) using logistic regression adjusted for age, sex, and lipids. Results The mean ± SD age was 60 ±14 years and 46% of patients were women. In multivariable-adjusted models, adults with deficient 25(OH)D compared to those with optimal levels had increased odds of elevated biomarkers as follows: Hcy (OR = 2.53, 95% CI: 1.92–3.34), hs-CRP (1.62, 1.36–1.93), cystatin-C (2.02, 1.52–2.68), creatinine (2.06, 1.35–3.14), GGT (1.39, 1.07–1.80), uric acid (1.60, 1.31–1.95), and HbA1c (2.47, 1.95–3.13). In analyses evaluating women and men separately, 25(OH)D deficient women but not men had increased odds of elevated levels of all biomarkers studied. There were significant interactions based on sex between 25(OH)D and Hcy (p = 0.003), creatinine (p = 0.004), uric acid (p = 0.040), and HbA1c (p = 0.037). Conclusions Deficient 25(OH)D is associated with elevated levels of many biomarkers of cardiovascular risk, particularly among women, in a United States population.

Patient-Level Discordance in Population Percentiles of the TC/HDL-C Ratio Compared with LDL-C and Non-HDL-C: 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. Methods 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. Conclusions —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. Clinical Trial Registration Information —www.clinicaltrials.gov. Identifier: [NCT01698489][1]. [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.

Impact of Novel Low-Density Lipoprotein-Cholesterol Assessment on the Utility of Secondary Non-High-Density Lipoprotein-C and Apolipoprotein B Targets in Selected Worldwide Dyslipidemia Guidelines

Background: Selected dyslipidemia guidelines recommend non-high-density lipoprotein-cholesterol (non-HDL-C) and apolipoprotein B (apoB) as secondary targets to the primary target of low-density lipoprotein-cholesterol (LDL-C). After considering 2 LDL-C estimates that differ in accuracy, we examined: (1) how frequently non-HDL-C guideline targets could change management; and (2) the utility of apoB targets after meeting LDL-C and non-HDL-C targets. Methods: We analyzed 2518 adults representative of the US population from the 2011 to 2012 National Health and Nutrition Examination Survey and 126 092 patients from the Very Large Database of Lipids study with apoB. We identified all individuals as well as those with high-risk clinical features, including coronary artery disease, diabetes mellitus, and metabolic syndrome who met very high- and high-risk guideline targets of LDL-C <70 and <100 mg/dL using Friedewald estimation (LDL-CF) and a novel, more accurate method (LDL-CN). Next, we examined those not meeting non-HDL-C (<100, <130 mg/dL) and apoB (<80, <100 mg/dL) guideline targets. In those meeting dual LDL-C and non-HDL-C targets (<70 and <100 mg/dL, respectively, or <100 and <130 mg/dL, respectively), we determined the proportion of individuals who did not meet guideline apoB targets (<80 or <100 mg/dL). Results: A total of 7% to 9% and 31% to 36% of individuals had LDL-C <70 and <100 mg/dL, respectively. Among those with LDL-CF<70 mg/dL, 14% to 15% had non-HDL-C ≥100 mg/dL, and 7% to 8% had apoB ≥80 mg/dL. Among those with LDL-CF<100 mg/dL, 8% to 10% had non-HDL-C ≥130 mg/dL and 2% to 3% had apoB ≥100 mg/dL. In comparison, among those with LDL-CN<70 or 100 mg/dL, only ≈2% and ≈1% of individuals, respectively, had non-HDL-C and apoB values above guideline targets. Similar trends were upheld among those with high-risk clinical features: ≈0% to 3% of individuals with LDL-CN<70 mg/dL had non-HDL-C ≥100 mg/dL or apoB ≥80 mg/dL compared with 13% to 38% and 9% to 25%, respectively, in those with LDL-CF<70 mg/dL. With LDL-CF or LDL-CN<70 mg/dL and non-HDL-C <100 mg/dL, 0% to 1% had apoB ≥80 mg/dL. Among all dual LDL-CF or LDL-CN<100 mg/dL and non-HDL-C <130 mg/dL individuals, 0% to 0.4% had apoB ≥100 mg/dL. These findings were robust to sex, fasting status, and lipid-lowering therapy status. Conclusions: After more accurately estimating LDL-C, guideline-suggested non-HDL-C targets could alter management in only a small fraction of individuals, including those with coronary artery disease and other high-risk clinical features. Furthermore, current guideline-suggested apoB targets provide modest utility after meeting cholesterol targets. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01698489.

Coronary Artery Calcium Score: the “Mammogram” of the Heart?

Purpose of ReviewTo discuss the classic analogy of “coronary artery calcium (CAC) as a mammogram of the heart”, by evaluating the conceptual strengths, weaknesses, opportunities, and threats of a potential cardiovascular disease (CVD) screening strategy using CAC in apparently healthy adults.Recent FindingsCAC is typically used for further CVD risk assessment. CAC is also currently being used as a screening test in specific subgroups of individuals, particularly in some Asian countries. Although this has yielded valuable insights on the determinants and pathophysiology of CVD, whether this approach results in improved clinical outcomes compared to other assessment and management approaches is currently unclear.SummaryAlthough CAC and mammograms share a number of characteristics, there are also important conceptual differences. The evidence supporting CAC, which is a robust CVD risk assessment tool, for CVD screening purposes is currently very limited, and further research is needed.

Lipid phenotypes at the extremes of high-density lipoprotein cholesterol: The very large database of lipids-9

BACKGROUND Low serum levels of high-density lipoprotein cholesterol (HDL-C) are an important risk factor for atherosclerotic disease. To date, therapeutically raising HDL-C has not been shown to impact risk for cardiovascular events. OBJECTIVE We aim to characterize lipid parameters at the extremes of HDL-C. METHODS We examined cholesterol profiles from 1,350,908 US adults and children from the Very Large Database of Lipids who were clinically referred for advanced lipoprotein testing from 2009 to 2011. We categorized patients into HDL-C percentile categories (<0.1th, 0.1th-<1st, 1st-5th, 25th-75th, 95th-99th, >99th-99.9th, and >99.9th). Within these groups, we examined HDL-C subclasses, low-density lipoprotein cholesterol (LDL-C), LDL and very-low density lipoprotein densities, non-HDL-C, triglycerides (TG), very-low density lipoprotein cholesterol, and remnant lipoprotein cholesterol (RLP-C), as well as prevalence of Fredrickson-Levy dyslipidemias. RESULTS Extremely low HDL-C percentiles were associated with increased LDL density, TG, and especially RLP-C. Very high HDL-C levels (≥ 92 mg/dL) showed increasing HDL2-C/HDL3-C ratio and very low levels of RLP-C and triglyceride-rich lipoproteins. Type IV dyslipidemia had the highest prevalence among classical dyslipidemia and was the most frequent at extremely low HDL-C percentiles. CONCLUSIONS These findings demonstrate a high prevalence of elevated triglyceride-rich lipoprotein levels and increased LDL density in patients with extremely low HDL-C levels. The relative contributions of these various changes in lipid profiles of patients with low HDL-C to cardiovascular risk need to be further scrutinized to more fully establish if low HDL-C is truly an independent risk factor for coronary heart disease or simply reflects detrimental shifts in the levels of atherogenic lipoproteins.

Time to Make a Change: Assessing LDL-C Accurately in the Era of Modern Pharmacotherapeutics and Precision Medicine

Purpose of ReviewThe Friedewald equation for estimation of low-density lipoprotein cholesterol (LDL-C) was published in 1972 as an alternative to direct assessment by preparative ultracentrifugation. In this equation, very low-density lipoprotein is estimated by dividing triglycerides by a fixed factor (5 in mg/dL or 2.2 in mmol/L) and subtracting this term from non-high-density lipoprotein cholesterol (non-HDL-C). This method was derived in fasting samples from a small cohort of patients with primarily genetic dyslipidemias followed at the NIH. The method served well as the global standard for LDL-C estimation for decades, but is not well suited to modern clinical practice because it tends to underestimate LDL-C at low LDL-C and high triglyceride levels. The concern is that underestimation could lead to undertreatment in high-risk patients.Recent FindingsDerived from big data and now validated around the world, a novel LDL-C equation created at Johns Hopkins replaces the fixed factor seen in the classic equation with a patient-specific variable based on triglyceride and non-HDL-C levels.SummaryGiven its superior accuracy in fasting and non-fasting populations alike, the novel equation is now the preferred method for LDL-C estimation and is being incorporated by leading clinical laboratories.