Monday, March 31, 2014

Patients Managed to Target LDL Particle Number Experience Fewer Cardiovascular Events

Patients Managed to Target LDL Particle Number Experience Fewer Cardiovascular Events Than Patients Managed to Target LDL Cholesterol, According to Study

Data demonstrates that the NMR LipoProfile® test provides clinically reliable information to help reduce cardiovascular events, especially in patients with diabetes and those on statin therapy

WASHINGTON, March 31, 2014 /PRNewswire/ -- LipoScience, Inc. (NASDAQ: LPDX), a diagnostic company pioneering a new field of personalized nuclear magnetic resonance (NMR) diagnostics to advance the quality of patient care in cardiovascular, metabolic and other diseases, today announced data showing that patients managed to a target LDL particle (LDL-P) number, as measured by LipoScience's NMR LipoProfile test, achieved a 22 to 25 percent greater reduction in the risk of cardiovascular (CV) events over a three-year period compared to patients who attained LDL cholesterol (LDL-C) targets.
These data, presented in a poster session at the 63rd American College of Cardiology (ACC) Scientific Sessions in Washington, D.C., are derived from a real-world sample of commercially insured patients who were at a high risk of CV events, including patients with Coronary Heart Disease and Diabetes Mellitus. The investigators found that patients who achieved target LDL-P levels (<1000 aggressive="" concentrations="" dl="" ldl-c="" lipid-lowering="" mg="" more="" nmol="" p="" reaching="" received="" target="" than="" those="" treatment="">
Those treatment differences were associated with better outcomes (as measured by the reduction in CV event rates) over one to three years of follow-up. The study was sponsored by LipoScience and jointly designed by LipoScience and HealthCore, with clinical input from Terry A. Jacobson, MD, Professor of Medicine at Emory University, Atlanta, and Peter P. Toth, MD, PhD, Director of Preventive Cardiology at CGH Medical Center in Sterling, Ill.
"These new data add to the growing body of evidence suggesting that NMR measurement of LDL particle number, when used in conjunction with other lipid measurements, is a valuable cardiovascular risk management tool," commented Dr. Jacobson, the lead author of the study. "Due to the wide variance in the cholesterol content of LDL particles among individuals, measurements of LDL cholesterol and LDL particle number frequently disagree, especially in patients with insulin resistance and those treated with lipid-lowering therapies. When a disagreement between LDL-P and LDL-C is present, quantification of LDL particle number is a more clinically reliable measure of LDL and of treatment outcomes than measurement of LDL cholesterol."
Dr. Jacobson and colleagues analyzed data from more than 4,000  high-risk patients (over 2,000 with LDL-P < 1000 nmol/L and over 2,000 with LDL-C < 100 mg/dL) selected from the HealthCore Integrated Research DatabaseSM who were followed for as long as three years. Those who achieved LDL-P target <1000 100="" 22="" 25="" a="" above="" achieved="" as="" at="" baseline="" below="" but="" compared="" concentrations="" cv="" dl.="" event="" follow-up.="" group="" higher-potency="" in="" ldl-c="" ldl-p="" levels="" likely="" lower="" measured="" medications="" mg="" more="" nmol="" not="" noted="" of="" one="" over="" p="" patients="" percent="" receive="" risk="" statin="" target="" than="" the="" three="" to="" was="" were="" who="" whose="" years="">
Dr. Jacobson's poster, "Comparison of cardiovascular events between patients achieving low-density lipoprotein particle targets and patients achieving low-density lipoprotein cholesterol targets," will be presented Monday, March 31 from 9:30 a.m. to 12:30 p.m. in Hall C of the Washington Convention Center. The poster number is 150.
"The HealthCore data add an important, real-world, analysis to the ongoing discussion of how best to optimize individual patient management. These findings are consistent with the recommendations of various expert panels and organizations such as the National Lipid Association, the American Association for Clinical Chemistry, and the American Association of Clinical Endocrinologists, each of which advocates the use of LDL-P as a target of therapy in managing at-risk patients," stated William C. Cromwell, MD, Chief Medical Officer of LipoScience.  "We hope the findings encourage greater adoption by clinicians to manage their patients to an LDL-P target to reduce CVD events."
The ACC Scientific Session also includes the following poster presentations that support the clinical utility of NMR-based lipoprotein particle measurement:
  • Poster #143: May HT, et al. Utility of high-density lipoprotein cholesterol, particle concentration, and size in predicting future major adverse cardiovascular events among patients undergoing angiography: The Intermountain Heart Collaborative Study.
    • Saturday, March 29, 9:30am to 12:30pm, Hall C
  • Poster #146: Muhlestein JB, et al. GlycA and GlycB, novel NMR biomarkers of inflammation, strongly predict future cardiovascular events, but not the presence of coronary artery disease (CAD), among patients undergoing coronary angiography: The Intermountain Heart Collaborative Study.
    • Sunday, March 30, 9:30am to 12:30pm, Hall C
  • Poster #128: Koren MJ, et al. Effects of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, on lipoprotein particle concentrations determined by nuclear magnetic resonance: Substudy of a randomized double-blind phase II clinical trial.
    • Sunday, March 30, 9:30am to 12:30pm, Hall C
  • Poster #134: Xu R, et al. Effects of evolocumab on lipoprotein particles and subclasses in hypercholesterolemic and heterozygous familial hypercholesterolemia subjects on statin therapy
    • Sunday, March 30, 9:30am to 12:30pm, Hall C
  • Poster #141 Alexander V, An antisense inhibitor of apolipoprotein C-III significantly decreases apolipoprotein C-III, triglycerides, Very-Low-Density Lipoprotein cholesterol and particle number, and increases High-Density Lipoprotein cholesterol and particle number in hypertriglyceridemic patients on a fibrate.
    • Monday, March 31, 9:30am to 12:30pm, Hall C
Read the complete article here.

Thursday, March 20, 2014

Ezetimibe Prescribing Fails to Keep Up With Evidence - JAMA

Ezetimibe Prescribing Fails to Keep Up With Evidence     
Mike Mitka, MSJ 
JAMA. Published online March 19, 2014. doi:10.1001/jama.2014.2896
Although physicians like to think they practice evidence-based medicine, that appears to not be the case with prescribing the cardiovascular drug ezetimibe. And some critics say that use of surrogate markers to guide practice rather than clinical outcomes such as occurrence of myocardial infarction, stroke, or death has likely played a role.
Ezetimibe is an intestinal cholesterol absorption inhibitor found to reduce low-density lipoprotein cholesterol (LDL-C) levels by about 20% when given alone. It also further reduces LDL-C levels when added to statin therapy, which blocks cholesterol synthesis in the liver by inhibiting HMG-CoA reductase.
The Food and Drug Administration approved ezetimibe in 2002 for use in the United States primarily because it lowered LDL-C levels, a surrogate marker for prevention of cardiovascular disease. Whether ezetimibe improved clinically meaningful outcomes remained a question.
That question was somewhat answered in January 2008, with the announcement that the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, sponsored and conducted by industry, found that the addition of ezetimibe failed to reduce atherosclerosis progression compared with simvastatin alone, despite lowering LDL-C levels. Atherosclerosis progression was determined by a change in the intima-media thickness of the walls of the carotid and femoral arteries—yet another surrogate end point (Kastelein JJP et al. N Engl J Med. 2008;358[14]:1431-1443).
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US and Canadian physicians continue to prescribe ezetimibe even after a study found giving the drug with a statin failed to reduce atherosclerosis progression compared with the statin alone.
The ENHANCE result prompted some leaders in the cardiology community to question ezetimibe’s place in cardiovascular disease treatment. Harlan Krumholz, MD, professor of medicine and epidemiology and public health at Yale University in New Haven, Connecticut, said the study should change practice. “Although not definitive, [ENHANCE] increases our uncertainty about the clinical value of this novel drug. Without some evidence of improved outcomes associated with its use, ezetimibe should be relegated to a last option for patients who need medication for hypercholesterolemia, and even in these cases, it is reasonable for clinicians and their patients to wait for further information before considering it,” he wrote in NEJM Journal Watch (http://tinyurl.com/pk9xr29).
So did the ENHANCE results change practice? In the United States, the answer is “somewhat,” while in Canada, the answer appears to be “no.”
In a study published in the American Heart Journal, researchers looked at ezetimibe prescription trends before and after ENHANCE, using data collected from CompuScript in Canada and IMS Health in the United States from January 1, 2002, to December 31, 2009. The researchers found the monthly number of ezetimibe prescriptions per 100 000 population rose from 6 to 1082 in the United States from November 2002 to January 2008 and then declined to 572 per 100 000 population by December 2009, a decrease of 47.1%. In Canada, however, use continuously increased from 2 to 495 per 100 000 from June 2003 (when the drug was approved in Canada) to December 2009 (Lu L et al. Am Heart J. doi:10.1016/j.ahj.2014.01.014 [published online February 27, 2014]).
Coauthor Cynthia A. Jackevicius, PharmD, MSc, a professor of pharmacy practice and administration at Western University of Health Sciences in Pomona, California, and an adjunct scientist, Institute for Clinical Evaluative Sciences, in Toronto, said her team was initially surprised by the Canadian results.
“Previous findings showed ezetimibe use in Canada experienced a more conservative uptake, so we expected to see a decrease in use in response to the ENHANCE study,” Jackevicius said. “So we looked for different factors, and one is the Canadian lipid guidelines, which specifically said ezetimibe could be added to statins, and that didn’t change after ENHANCE came out.”
A study of ezetimibe use in Saskatchewan, the only Canadian province that lists the drug for open formulary access, even though guidelines say it’s a second-line agent for lowering cholesterol, reflects Jackevicius’s team’s findings. Using data from provincial health administrative databases, the Saskatchewan researchers found that ezetimibe prescriptions were 2.5% of cholesterol-lowering dispensations in 2004 and 8.8% of such dispensations in 2011 (Alsabbagh WM et al. Can J Cardiol. 2014;30[2]:237-243). The authors concluded that allowing unrestricted use of ezetimibe in Saskatchewan may have led to a large number of inappropriate prescriptions, at odds with Canadian clinical guidelines.
And although ezetimibe use declined in the United States, its use per 100 000 population is still greater than Canada’s, generating US expenditures of more than $2.2 billion in 2009.
Krumholz, one of the coauthors on the study with Jackevicius, remains perplexed as to the continuing popularity of ezetimibe. “The drug continues to defy gravity, and that’s probably a result of really strong marketing and the singular focus on cholesterol numbers,” he said.
Krumholz said heart health campaigns urging patients to “know your numbers” and treatment goals based on cholesterol measurements, such as getting asymptomatic individuals’ LDL-C levels below 130 mg/dL, have worked in ezetimibe’s favor at the expense of evidence-based medicine. “Is this the drug that lowers your LDL-C and helps you? We don’t know that,” he said. “The comfort of hitting a target offers little benefit if you don’t know that it is really protecting you.”
Although ENHANCE has not derailed ezetimibe prescribing, the newest cholesterol management guidelines just might. The guidelines, issued late last year by the American College of Cardiology and the American Heart Association, abandon the idea of reaching a target level for LDL-C, instead recommending the use of statins to reduce LDL-C levels only for certain types of patients.
Will this change in the guidelines affect ezetimibe prescribing? “It will be interesting to see what the guidelines will do,” Krumholz said.
Read the complete article here.

Friday, March 14, 2014

Researchers pronouncing ‘statins are safe’ are undermined by their own observations - Briffa

Researchers pronouncing ‘statins are safe’ are undermined by their own observations

Listen to most ‘key opinion leaders’ talk about statinsand you will hear soothing reassurances about their safety. Yet, my experience as a doctor suggests that adverse effects such as fatigue and muscle pain occur more commonly than ‘official statistics’ suggest. However, a study published this week claims to provide evidence that, for the most part, statin side effects are ‘imagined’ [1].

In this research, the adverse effect rates from statins was compared with those seen in individuals taking placebo (dummy) pills in a total of 29 studies. The conclusion was that apart from increasing the risk of diabetes, statins don’t generally have any more adverse effects than placebo. The actual words the authors use in their conclusion are: “Only a small minority of symptoms reported on statins are genuinely due to the statins: almost all would occur just as frequently on placebo.”

This is confident, seemingly ‘evidence-based’ stuff, indeed. However, these findings do appear to me to be at odds with what I and many other doctors observe in real life: that a significant number of people who take statins have side-effects that resolve (sometimes slowly) on discontinuation of their medication. Of course, as the authors of this most recent study allude to, these side-effects may be nothing more than a negative placebo response – sometimes referred to a ‘nocebo’ response.
However, is there anything about the way statin trials may be designed and conducted that could jeopardise our ability to get accurate data on the adverse effects of these drugs?

Several explanations are possible. First, commercial sponsors of clinical trials may not be motivated to search exhaustively for potential side effects. One pointer towards this is that, although evidence of liver damage is documented in the majority of trials, diabetes diagnoses were only documented in three of the 29 trials assessed in the recent study.

Second, many trials do not state clearly how and how often adverse effects were assessed. Because of this, it far from certain that all adverse events were ‘caught’ and logged appropriately.

Third, some trials’ exclude patients with severe diabetes, kidney failure or high blood pressure. In reality, though, these individuals may come to be prescribed and take statins.

Fourth, trial volunteers tend to be enthusiastic, and may therefore be less likely to report side effects than patients in routine clinical practice.

Fifth, many trials have a ‘run-in’ period where individuals are given a placebo to help ensure adequate compliance with medication. This can cause studies to be ‘enriched’ with highly motivated individuals who, again, may be less likely to complain of side-effects.

Finally, many trials excluded patients on medication sharing the same liver metabolic pathway as statins (e.g. fibrates and macrolide antibiotics). Patients on such drugs, in the real world, might well suffer higher rates of pharmacologically mediated effects.

I make no secret of the fact that I think the benefits of statins are over-hyped and that the adverse effects are generally downplayed. As a result, a cynical observer might read my reservations here and think ‘well, he would say that’.

But, here the kicker: those six issues I detail above were plucked from the very same study that trumpets the safety of statin [1]. Much of what is written in this section of the post was actually lifted verbatim from the study.

So, by the authors’ own admission, there are many reasons why the adverse effect rates seen in statin studies may not accurately reflect the rates seen in the real world. But then how can the authors conclude that: “Only a small minority of symptoms reported on statins are genuinely due to the statins: almost all would occur just as frequently on placebo.”

The reality is the deficiencies of the studies do not allow the authors (or anyone) to conclude that at all. The authors’ pronouncement on safety is utterly undermined by their own admissions about the incompleteness and untrustworthiness of the study data.

The opening line of the study is this: “Patients and doctors need clear reliable information
about benefits and risks to make informed decisions.” The only clear thing about the risks of statins, to my mind, is that there isn’t much clarity. Making bold pronouncements on the safety of statins without us having the facts is potentially misleading, and may cause many to come to considerable harm, needlessly.

1. Finegold JA, et al. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. European Journal of Preventive Cardiology March 12, 2014

Thursday, March 6, 2014

Early atherogenesis and visceral fat in obese adolescents


Early atherogenesis and visceral fat in obese adolescents

A H Slyper, H Rosenberg, A Kabra, M J Weiss, B Blech, S Gensler and M Matsumura
Little information is available as to the cause of increased thickening of the intima-media of the carotid artery (cIMT) in the pediatric population. Therefore, cIMT was compared in obese adolescents and normal-weight controls, and associations between cIMT and lipid and non-lipid cardiovascular risk factors were assessed.

Subjects included 61 obese non-diabetic male and female volunteers aged 12–18 years inclusive with a body mass index (BMI) >95th percentile for age and 2-h blood glucose <200 class="mb" span="">
mgdl−1 matched to 25 normal-weight control volunteers with normal glucose levels. Each subject underwent a 2-h glucose tolerance test and measurement of hemoglobin A1c, ultrasensitive C-reactive protein, fasting insulin, blood lipids, visceral, subcutaneous abdominal and hepatic fat, and cIMT.
Maximum cIMT was 0.647±0.075mm in the obese subjects versus 0.579±0.027mm in normal-weight controls (P<0 .001="" 2-h="" and="" assessment="" between="" bmi="" cholesterol="" cimt="" correlations="" difference="" fasting="" female="" glucose="" hdl="" high-density="" homeostasis="" in="" insulin="" ldl="" lipoprotein="" low-density="" male="" maximum="" model="" no="" significant="" sub="" subjects.="" there="" total="" very="" was="" were="" z-score="">2
cholesterol, HDL3 cholesterol, triglycerides, remnant lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, lipoprotein(a), apoprotein B100, abdominal subcutaneous fat volume, visceral fat volume and hepatic phase difference. On multiple regression analysis, visceral fat was the most significant predictor of maximum cIMT. Two-hour blood glucose, HOMA and systolic blood pressure were also significant predictors of maximum cIMT.
cIMT was increased in the obese adolescents compared with the normal-weight-matched controls. Visceral fat was a key predictor of arterial wall thickening in these subjects. The results suggest that the focus of cardiovascular disease prevention in the adolescent obese should be visceral obesity, and not blood lipids or lipid subclasses.