Journal of Clinical Lipidology

From the Editor-in-Chief

W. Virgil Brown — 2010-01-04

The disparity between the very strong performance of high-density lipoprotein (HDL) cholesterol as a risk factor and the very weak effects that have been demonstrated in large clinical trials has frustrated clinicians and clinical trialists for many years. A major factor has been the lack of interventions that specifically change HDL without having major effects on other aspects of lipoprotein metabolism. Exercise, weight loss, fibrates, niacin, and, to a lesser degree, statins and bile acid sequestrants, produce some elevation in HDL cholesterol. However, all these interventions tend to reduce low-density lipoprotein (LDL) cholesterol, and most speed the clearance of very-low-density lipoprotein and chylomicron remnants. Furthermore, the long-term changes in HDL cholesterol are usually very small with the exception of niacin. However, we do not have a large long-term study with niacin alone in which HDL was measured in all participants. Great promise for niacin has been postulated on the basis of small trials with combinations of agents. The most dramatic increase in HDL cholesterol has been achieved with drugs that suppress cholesterol ester transfer protein. However, the first of these agents, torcetrapib, failed to demonstrate clinical or anatomical benefit in two trials. Adverse clinical effects on vascular disease occurred very rapidly in a third trial involving almost 18,000 subjects. We therefore remain without a proven effective agent that acts by raising HDL cholesterol in our patients.

News from the NLA

2009-12-16

The NLA offers Masters Summit symposiums twice a year to provide members with cutting-edge information from the leaders in our field. If you missed the Masters Summit we held at AHA in November, keep an eye on lipid.org and at Medscape, where highlights from the Summit, “Overcoming Challenges in CVD Prevention,” will be posted soon.

HDL as a treatment target†

W. Virgil Brown, H. Bryan Brewer, Daniel J. Rader, Ernst J. Schaefer — 2009-12-28

W. Virgil Brown, MD: I have taken advantage of having some of the most noted experts in lipoprotein metabolism gathered during the 2009 American Heart Association Scientific Sessions to have a roundtable discussion of a most difficult topic in clinical lipidology. Our topic is “high-density lipoprotein (HDL) as a potential target of treatment.” The major issues are whether HDL truly offers an opportunity for therapeutic intervention, what aspect of this complex system do we modify, and how do we do it. I would like to begin by discussing our current state of knowledge about HDL metabolism and its biochemical and physiological role in vascular disease. Second, we should discuss the effectiveness of current methods of modifying HDL. Finally, I hope to hear your opinions as to the research efforts that hold promise of giving clinicians a better set of tools to change HDL metabolism with resulting beneficial effect on arteriosclerosis.

Altered cholesterol and fatty acid metabolism in Huntington disease

2009-12-10

Abstract: Huntington disease is an autosomal-dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins that result in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state, resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.

Carotid intima-media thickness for the practicing lipidologist

Lea Liviakis, Bryan Pogue, Pathmaja Paramsothy, Alicia Bourne, Edward A. Gill — 2009-12-16

Abstract: Background: It is well known that cardiovascular disease is the number one killer of men and women in the United States and in many parts of the developed world. However, early detection of atherosclerosis remains a challenging area of research and development.Stress echo and myocardial perfusion studies were not designed to be screening tests and the majority of literature using these tests is in populations with a high probability of disease. It must be emphasized that negative stress echo and stress MPI tests only imply a lack of flow limiting disease; they do not indicate lack of atherosclerotic disease. It is important to remember that when these tests are “negative,” the implication is favorable short-term prognosis rather than any implication regarding lack of disease.In contrast, carotid intima-media thickness (CIMT) scanning protocols can detect atherosclerotic disease in early and asymptomatic stages. For a number of reasons reviewed in this article, CIMT may be a more optimal screening and risk-stratifying technology: CIMT directly visualizes vasculature unlike biomarkers such as LDL cholesterol, hsCRP, or PLA2.Methods: We performed medline searches for original articles and reviews of carotid IMT from 1985 to the present. We particularly emphasized large multi-center epidemiologic studies of the natural history of patients with carotid IMT measurements.Conclusion: There is substantial evidence that CIMT is a suitable surrogate for the coronary tree. CIMT is also (along with coronary calcium scoring) recognized by the American Heart Association as a surrogate marker for coronary artery disease. A recent commentary by Stein, et al reviewed the comparison of CIMT to coronary calcium scoring, with favorable findings for CIMT especially in the healthy young and middle-aged populations, as well as women and African American individuals where coronary calcification has more limited utility. Recent findings of the Multi-Ethnic Study of Atherosclerosis indicate further that increased CIMT predicted CVD events in individuals without coronary calcification.

Another treatment gap: Restarting secondary prevention medications: The Women's Health Initiative

2009-12-28

Background: Women's long-term patterns of evidence-based preventive medication use after a diagnosis of coronary heart disease have not been sufficiently studied.Methods: Postmenopausal women ages 50 to 79 years were eligible for randomization in the Women's Health Initiative's hormone trials if they met inclusion and exclusion criteria and were >80% adherent during a placebo-lead-in period and in the dietary modification trial if they were willing to follow a 20% fat diet. Those with adjudicated myocardial infarction or coronary revascularization after the baseline visit were included in the analysis (n = 2627). Baseline visits occurred between 1993 and 1998, then annually until the trials ended in 2002 through 2005; medication inventories were obtained at baseline and years 1, 3, 6, and 9.Results: Use at the first Women's Health Initiative visit after a coronary heart disease diagnosis increased over time for statins (49% to 72%; P < .0001), beta-blockers (49% to 62%; P = .003), and angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers (ACEI/ARBs; 26%-43%; P < .0001). Aspirin use remained stable at 76% (P = .09). Once women reported using a statin, aspirin, or beta-blocker, 84% to 89% reported use at 1 or more subsequent visits, with slightly lower rates for ACEI/ARBS (76%). Statin, aspirin, beta-blocker, or ACEI/ARB use was reported at 2 or more consecutive visits by 57%, 66%, 48%, and 28%, respectively. These drugs were initiated or resumed at a later visit by 24%, 17%, 15%, and 17%, respectively, and were never used during the period of follow-up by 19%, 10%, 33%, and 49% respectively.Conclusions: Efforts to improve secondary prevention medication use should target both drug initiation and restarting drugs in patients who have discontinued them.

A secondary prevention lipid clinic reaches low-density lipoprotein cholesterol goals more often than usual cardiology care with coronary heart disease

2009-12-14

Objective: The objective of this study was to determine whether enrollment in a multidisciplinary secondary prevention lipid clinic (SPLC) for 3 or more years was associated with improved adherence to lipid guidelines as compared with usual care provided by cardiologists.Methods: Patients with documented coronary artery disease (CAD), enrolled in a SPLC, and followed for at least 3 years were identified by the use of a computer database. The comparison group included patients with CAD who received usual care from a cardiologist during the same time period. The percentage of patients achieving low-density lipoprotein cholesterol (LDL-C) goals at enrollment and after at least 3 years of follow-up was determined for both groups. The average total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides were determined after at least 3 years of follow-up for both groups.Results: Patients enrolled in the SPLC reached the LDL-C goals more often than usual care cardiology patients (goal <100mg/dL: 81.9% vs. 72.8%, P < .001; optional goal <70mg/dL: 41.9% vs. 28.6%, P < .001). The patients enrolled in the SPLC had lower average total cholesterol, triglycerides, and LDL-C and greater average HDL-C after 3 years. All the lipid parameters decreased for patients in usual cardiology care, but these changes were not statistically significant.Conclusions: This multidisciplinary secondary prevention lipid clinic achieved the LDL-C goals (<100mg/dL and optional goal <70mg/dL) more often than usual cardiology care for patients with CAD after 3 years of lipid management.

Prevalence of dyslipidemia and its associated factors among Jordanian adults

2009-12-21

Background: Dyslipidemia, which has been closely linked to pathophysiology of cardiovascular diseases, is a key independent modifiable risk factor for cardiovascular diseases. Estimation of the prevalence of dyslipidemia ensures proper planning of health actions for both primary and secondary prevention of cardiovascular diseases.Objectives: To estimate the prevalence of various types of dyslipidemia and determine their associated factors among adults in north of Jordan.Method: Data were analyzed from a cross-sectional study that included a random sample of 1121 Jordanians aged 25 years and older. High total cholesterol (TC) was defined as TC ≥200mg/dL and hypertriglyceridemia as serum triglycerides level ≥150mg/dL. Low high-density lipoprotein cholesterol (HDL-C) was defined as serum HDL-C <40mg/dL. High low-density lipoprotein cholesterol (LDL-C) was defined as serum LDL-C ≥130mg/dL.Results: Of a total of 1121 subjects, 48.8% had high TC level, 40.7% had high LDL-C, 40.1% had low HDL-C, 43.6% had high triglyceride levels, and 75.7% had at least one abnormal lipid level. Age was associated with high triglycerides, high LDL-C, and high TC. Men were more likely than women to have a high triglycerides level and low HDL-C. Compared with people with a body mass index <25, overweight and obese subjects had greater odds of having high triglycerides, high TC, and low HDL-C. Diabetes was associated with increased odds of high triglycerides only.Conclusion: The prevalence dyslipidemia is high in Jordan, which necessitates appropriate the institution of community-based intervention strategies to prevent and manage cardiovascular risk factors.

Subjects with elevated LDL cholesterol and metabolic syndrome benefit from supplementation with soy protein, phytosterols, hops rho iso-alpha acids, and Acacia nilotica proanthocyanidins

2009-12-04

Background: Metabolic syndrome is associated with increased cardiovascular disease (CVD) risk, a risk that is significantly increased when accompanied by elevated low-density lipoprotein cholesterol (LDL-C). Whereas lifestyle therapies are the initial intervention of choice for both of these risk factors, it has not been clearly determined that this approach is efficacious when they occur concomitantly.Objective: To evaluate effects of supplementing a lifestyle program with a medical food and nutraceutical in individuals with metabolic syndrome and elevated LDL-C.Methods: We conducted a subgroup analysis of a 12-week, randomized trial in adults with metabolic syndrome; data from those with LDL-C ≥ 160 mg/dL were analyzed. Control-arm subjects were instructed to consume a modified Mediterranean-style, low-glycemic-load diet (MED, n = 12). Treatment-arm subjects received a phytochemical-enhanced diet (PED, n = 12) consisting of the same low-glycemic-load diet plus a medical food containing soy protein and plant sterols and a nutraceutical containing hops rho iso-alpha acids and acacia proanthocyanidins. All subjects received identical aerobic exercise counseling.Results: At 12 weeks, mean weight loss did not differ between arms. However, the PED arm exhibited greater improvement than the MED arm (P < .05) in total cholesterol, LDL-C, non−high-density lipoprotein cholesterol (non-HDL-C), cholesterol/HDL-C, triglyceride/HDL-C, apolipoprotein (apo) B, apo B/apo A-1, homocysteine, total LDL particle number, and large HDL particle number. All individuals in the PED arm but only one third in the MED arm achieved LDL-C levels < 160 mg/dL.Conclusion: Individuals at high CVD risk benefit from a soy/phytosterol containing medical food and phytochemical supplemented lifestyle program.

Point: Low-density lipoprotein cholesterol goals in patients with diabetes are not adequately based on evidence

Aidar R. Gosmanov — 2009-12-21

Contemporary management of diabetes mellitus (DM) is complex. One of the aims is to prevent vascular complications associated with DM. Attainment of adequate glycemic control has been shown to be beneficial in the prevention of microvascular complications in both type 1 and type 2 DM. However, internists and endocrinologists should also focus on prevention of macrovascular complications of DM. The most recent Position Statement from the American Diabetes Association (ADA) emphasizes that, in patients with DM, control of low-density lipoprotein cholesterol (LDL-C) and hypertension, use of aspirin, and smoking cessation are paramount in primary prevention of cardiovascular disease (CVD).

Counterpoint: Low-density lipoprotein cholesterol goals in patients with diabetes are adequately based on evidence

Michael H. Davidson — 2010-01-08

Should patients with diabetes with one additional risk factor have an LDL-C target <70mg/dL? Dr. Gosmanov has raised the POINT that this guideline is premature and recommends caution because this target is not yet supported by the clinical trial evidence. As a member of the ADA and the American College of Cardiology Foundation Consensus Conference Report on Lipoprotein Management in Patients with Cardiometabolic Risk, this was an issue of heated debate among the consensus committee. Many panel members supported Dr. Gosmanov's position that the evidence for a LDL-C target <70mg/dL for patients with type 2 diabetes without CVD was insufficient. There were several factors we weighed in making our recommendation that the LDL-C target of LDL-C <70mg/dL should be expanded to include patients with type 2 diabetes and one additional risk factor. First, the panel recognized that patients with diabetes have a very high lifetime risk of CVD. Therefore, waiting for an event to occur before targeting an LDL-C <70mg/dL is unnecessary, especially in light of the fact that patients with diabetes and CVD have a poor prognosis and have a high residual risk despite statin therapy. Second, patients with diabetes frequently have relatively low LDL-C levels but elevated LDL particles and apolipoprotein (ApoB). This discordance between LDL-C and ApoB in patients with high cardiometabolic risk results in the underappreciation of the true risk of CVD events in these patients. The panel encouraged the assessment of ApoB or LDL-particle number in these patients once LDL-C and non-HDL-C targets are achieved. Although clinical trial evidence is not yet conclusive, there is a strong rationale to achieve lifelong low ApoB levels in patients with diabetes.

Rebuttal to Counterpoint

Aidar R. Gosmanov — 2010-01-08

I completely agree that we must manage LDL-C and classic CV risk factors in patients with diabetes mellitus. The issue in question is how low we should go with the LDL-C level in diabetics without evidence of active disease? Contrary to the current guidelines, most recent meta-analyses demonstrate lack of statin benefit in prevention of first CVD event in diabetic patients. In the absence of trials comparing the effects of LDL-C <70 mg/dL versus 100 to 130 mg/dL for primary prevention of CVD in DM, we must rely on the expert recommendations. Interestingly, recent evidence obtained from high-risk nondiabetic and diabetic subjects argues that a mere lowering of LDL-C <70 mg/dL for primary CVD prevention does not decrease the incidence of clinical or surrogate CV outcomes compared with greater LDL-C targets. As Dr. Davidson stated, upcoming clinical trials targeting ApoB, non-HDL-C, HDL-C, and/or triglycerides might identify new clinically meaningful target(s) for assessment and therapy of residual CVD risk in diabetes. Unfortunately, diabetes with associated comorbidities is a chronic disease requiring life-long therapy with multiple medications which, in turn, may affect compliance. One approach for statin use assessment in diabetic patients without CVD could be to determine first CVD risk category based on CV risk factors and then choose LDL-C target. In the end, I believe a physician should expect recommendations from professional organizations that may affect millions of patients to be buttressed by strong science as well as expert opinion. Some caution should be expressed in such guideline when opinion predominate and this calls for more careful consideration of potential side effects when prescribing a statin or doubling its dose.

Erratum

2009-11-23

In the April 2009 issue of Journal of Clinical Lipidology, in the article by Su and colleagues titled “Postprandial lipemia as an early predictor of cardiovascular complications in childhood obesity” (2009;3:78-84; doi:10.1016/j.jacl.2009.02.006), a co-author was inadvertently omitted from the original manuscript as submitted to the journal. Please recognize Mary M. Jetha, MD as one of the contributing authors.