Archive for the ‘Cardiovascular’ Category

FDA adds warnings to Statin Label

Thursday, March 1st, 2012

Reed Miller posted this latest FDA move on Statin Label on Heartwire on 28 Feb 2012. It is interesting to note that the FDA action came after our posting on WHI  findings on the increased risk of diabetes in women on statins.

February 28, 2012 (Silver Spring, Maryland) — Taking a statin can raise blood sugar and glycosylated hemoglobin HbA1c levels, according to a new labeling change approved by the Food and Drug Administration (FDA) today for the entire drug class. {{{0}}}

As reported by heartwire, recent studies of popular statins showed a significant increase in the risk of diabetes mellitus associated with high-dose statin therapy. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial showed a 27% increase in diabetes mellitus in patients taking rosuvastatin compared to placebo. Also, the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) substudy showed that high-dose atorvastatin can worsen glycemic control.

The labeling changes approved by the FDA also include new information on the potential for usually minor and reversible cognitive side effects. Also, the label for lovastatin has been significantly updated to provide information on contraindications and dose limitations for the drug in patients taking other medicines that may increase the risk for muscle injury.

The FDA says it is also eliminating the recommendation that patients on statins undergo routine periodic monitoring of liver enzymes, because this approach is ineffective in detecting and preventing the “rare and unpredictable” serious liver injuries related to statins. Statin therapy should be interrupted if the patient shows signs of serious liver injury, hyperbilirubinemia, or jaundice. The statin therapy should not be restarted if the drugs cannot be ruled out as a cause of the problems, the labeling will now state.

Statin use associated with significantly increased risk of diabetes: WHI analysis

Thursday, January 12th, 2012
The following article was published in Heartwire on JANUARY 9, 2012 by Michael O’Riordan

Boston, MA – Statin use in postmenopausal women is associated with a significantly increased risk of diabetes mellitus, research shows. New data from the Women’s Health Initiative (WHI) hint that the risk of diabetes is higher than suggested by previous studies, with investigators reporting a 48% increased risk of diabetes among the women taking the lipid-lowering medications.

“With this study, what we’re seeing is that the risk of diabetes is particularly high in elderly women, and this risk is much larger than was observed in another previous meta-analysis,” senior investigator Dr Yunsheng Ma (University of Massachusetts Medical School, Boston) told heartwire. “For doctors treating patients, we would like them to really look at the risk/benefit analysis, especially in different age groups, such as older women.” {{{0}}}

Annie Culver (Mayo Clinic, Rochester, MN), a pharmacist and lead investigator of the study, published online January 9, 2012 in the Archives of Internal Medicine, said that “close monitoring and an individualized risk-vs-benefit assessment is really a good thing, as well as an emphasis on continued lifestyle changes.” Culver added that as the population ages, and because these patients have a higher vulnerability to diabetes anyway, monitoring for diabetes in statin-treated patients becomes more important.

“I think the risk [of diabetes] is definitely there for statins,” Culver told heartwire, “and I think physicians are probably aware of this risk. I think we now need more information and more research about precisely how this risk translates to different people and different populations.”


Previously published data on statins and diabetes risk

Recently published data reported by heartwire highlighted the potential risk of diabetes with statin therapy. In June,Dr Kausik Ray (St George’s University of London, UK) and colleagues published a meta-analysis of PROVE-IT, A to Z,TNT, IDEAL, and SEARCH—five trials testing high-dose statin therapy—and found a significant increase in risk of diabetes with higher doses of the lipid-lowering drugs. A meta-analysis published in the Lancet in 2010 by Dr Naveed Sattar (University of Glasgow, Scotland) also showed that statin therapy was associated with a 9% increased risk of diabetes.

In the present study, Culver, Ma, and colleagues analyzed data from the WHI, an analysis that included 153 840 postmenopausal women aged 50-79 years old. Information about statin use was obtained at enrollment and year 3; the current analysis includes data until 2005. At baseline, 7.0% of women were taking statins, with 30% of women takingsimvastatin, 27% taking lovastatin, 22% taking pravastatin, 12.5% taking fluvastatin, and 8% taking atorvastatin. During the study period, 10 242 incident cases of diabetes were reported.

In an unadjusted risk model, statin use at baseline was associated with a 71% (95% CI 1.61-1.83) increased risk of diabetes. After adjustment for potential confounding variables, the risk of diabetes associated with statin therapy declined to 48% (95% CI 1.38-1.59). The association was observed for all types of statins.

“The association between diabetes risk and statin therapy was not observed with any one type of statin, and it seems to be a class effect,” said Ma.


Subgroup risk

A significantly increased risk of diabetes was observed in white, Hispanic, and Asian women (an increased risk of 49%, 57%, and 78%, respectively). Among African Americans, who made up 8.3% of the population studied, there was a nonsignificant 18% increased diabetes risk associated with statin use at baseline. Statin use and diabetes risk was also observed in women across a range of body-mass indices (BMIs <25.0, 25.0-29.9, and >30.0 kg/m2). Women with the lowest BMI (<25.0 kg/m2), appeared to be at higher risk of diabetes compared with obese women, a finding the investigators speculate is related to phenotype or hormonal differences between the women.

In an editorial, Dr Kirsten Johansen (University of California, San Francisco), editor of the Archives, noted that the increased risk of diabetes in women without CVD has “important implications for the balance of risk and benefit of statins in the setting of primary prevention, in which previous meta-analyses show no benefit on all-cause mortality.”

Ma agreed, noting to heartwire that statins are used with increasing frequency, including in primary prevention, and—based on the JUPITER trial—in patients with normal LDL cholesterol but elevated C-reactive protein (>2.0 mg/L). In the present study, baseline statin therapy was associated with a significant 46% and 48% increased risk of diabetes in women with CVD and without CVD, respectively.

Just 7% of women in the WHI study were taking statins in the analysis, but today that number would be significantly higher, making the potential risk of diabetes at the population level much more widespread. Ma said that physicians need to evaluate the risk of diabetes as well as the potential benefits of statin therapy in elderly female patients and start statins after lifestyle interventions have been attempted.

Low Cholesterol in Elderly Doubles Risk of Early Death

Thursday, December 22nd, 2011

Study Finds that Low Cholesterol in Elderly Doubles Risk of Early Death

Study finds that elderly with cholesterol less that 189 had a double risk of dying.

Physicians were informed to consider very low levels of cholesterol as potential warning signs of a serious disease or as signals of rapidly declining health. {{{0}}}

The study included 4520 men and women between the ages of 65-84.

The study concluded that low total cholesterol was associated with a higher risk of death

Low cholesterol level is a robust predictor of mortality in the nondemented elderly and may              be a surrogate of frailty or subclinical disease according to the research team.

References:

Brescianini S, Maggi S, Farchi G, Mariotti S, Di Carlo A, Baldereschi M, Inzitari D; ILSA Group. Low total cholesterol and increased risk of dying: are low levels clinical warning signs in the elderly? Results from the Italian Longitudinal Study on Aging. J Am Geriatr Soc. 2003 Jul;51(7):991-6.

Schupf N, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R. Relationship between plasma lipids and all-cause mortality in nondemented elderly. J Am Geriatr Soc. 2005 Feb;53(2):219-26.

 

Total plaque score by CT angiography does not correlate with NCEP and Framingham risk scores

Monday, April 4th, 2011

It is interesting to note that both the NCEP and Framingham risk scores correlate poorly with physical plaque burden on CT coronary angiography in 1653 patients with no history of CAD but who were experiencing atypical chest pain, were smokers, or had a family history of CAD, high blood pressure, or hypercholesterolemia. Amount of atherosclerotic plaque in different segments of the coronary tree, or degree of stenosis in each imaged segment, were used to derive a total plaque score. Roughly 30% of men and 46% of women were found to have no detectable plaque by coronary CT.{{{0}}}

When these were correlated with 10-year risk estimates using Framingham and the NCEP risk categories, the rank correlation coefficient was 0.49-0.55 and 0.5 respectively. The correlation is rather “modest”.

By contrast, more than one in 10 patients with no visible plaque on CT were deemed to be “moderately high” or “high-risk” according to NCEP, and 32% of patients with no detectable plaque were taking statins. Of all patients taking statins, 26% had plaque burden scores of zero.

Conversely, when both CT angiography-derived plaque scores and NCEP risk criteria were used to determine whether a patient not taking a statin should be taking one, 21% of patients would have their “perceived need for a statin” altered if the plaque score, as opposed to the NCEP risk-stratification scheme, was employed.

“Under the risk-factor approach, many patients with little or no plaque would be subjected to lifelong drug therapy, whereas many others with substantial plaque would be undertreated or not treated at all,” the authors write.

But an overarching limitation of Johnson et al’s study is that the studies conclusively linking findings on CT angiography to clinical outcomes have not been completed.

Source

  1. Johnson KM, Dowe DA, Brink JA. Traditional clinical risk assessment tools do not accurately predict coronary atherosclerotic plaque burden: a CT angiography study. Am J Roentgenol 2009; 192:235-243

 

Understanding Apoproteins and lipid transport and regulation

Monday, April 4th, 2011

Lipoproteins are specialized proteins with a single spherical layer of phospholipids and cholesterol membrane and content of cholesterol esters, TG and proteins. The protein concentration determines the density of the lipoprotein. HDL has the highest protein content while chylomicron with the lowest protein.  Another critical structure that is in the membrane are the apoproteins which serve to differentiate the lipoproteins and interact with specific receptors in the various tissues involved in lipid regulation. {{{0}}}

The lipoproteins are involved in the well-orchestrated transport system of lipids for metabolic and synthetic purposes in the body.  The distribution and metabolic role of various types of  lipoproteins involves an interplay of enzymes such as LCAT and CETP and the interaction of various receptors and the apoproteins on the surface of the lipoproteins for the distribution of lipids at the site of synthesis in the liver and absorption in the gut to the various peripheral tissues such as adipocytes, muscles, brain and the other organs. In this discussion, our focus is on the adipocytes and the atherogenic plaques. The transport is a 2 way traffic between the liver and the peripheral tissues involving 2 main types of lipoproteins – distinguished by their integral apoproteins .

There are 2 kinds of apoproteins –

  1. Integral proteins that straddles across the membrane such as Apo-A1 and Apo-B. The integral apoprotein defines the type of lipoproteins – HDL has Apo A and the non-HDL, chymicron, VLDL, IDL and LDL have Apo B.
    1. Role of Apo B lipoprotein is to distribute fatty acids and glycerol in TG and less so, cholesterol from the liver synthesis site and the gut absorption site to the peripheral organs for energy and synthesis requirements. The composition and size of the B apolipoproteins changes as the TG is off loaded to the various organs from chylomicron to VLDL to IDL to LDL in that order of decreasing content of TG and increasing relative content of cholesterol esters (see table for composition of lipids in the types of lipoproteins).
    2. Role of Apo A lipoprotein HDL is the reverse transport of cholesterol and its ester from the peripheral tissues to the liver for excretion via the biliary system into the feces.
    3. Apart from the exchange between the liver and the adipocytes, there is also a less known direct interaction between the Apo B and Apo A lipoproteins in the one-for-one exchange of TG and cholesterol respectively mediated by the enzyme Cholesterol Ester Transferase Protein that plays a part in the overall lipid regulation.

Structure, composition and blood level of the various lipoproteins:

Chylomicron VLDL IDL LDL HDL
mg/dl mg/dl mg/dl
Normal blood level >30 mg/dL Adult 130 Male: > 45
Children: 110 Female: >55m
Protein 1% 10% 10% ~20 ~50
Triglyceride 88% 56% 29% 13% 13%
Cholesterol 1% 8% 9% 10% 6%
Cholesterol ester 3% 15% 34% 48% 30%
Integral apoprotein B48 B100 B100 B100 A1
Peripheral apoprotein E E E
C C C
Apo E – binds to LDL Receptor (Liver will refill to carry more TG to adipocytes)
Apo C bind to LPL – lipoprotein lipase surface receptor of adipocyte and the TG is broken down to FA and glycerol
This reaction will reduce the VLDL to LDL as it loses its TG content
LDL remains longer in the blood as it does not have the liver receptor LDL binding ApoE.
Apo B 100 binding affinity is less and therefore its entry to the liver is low
The high LDL could be oxidised by free radicals and the oxidised LDL gets into the intimal layer of blood endothelial initiating atherogenesis

Let’s start with the discussion on the role of various Apo B lipoproteins in the distribution mainly of TG in the body:

  1. Chylomicrons – their main role is to transport ingested fats from the gut to the liver or adipose tissue. Ingested fats when reached the duodenum, stimulate cholecytokinins, CCK in the gall bladder to release bile salts into the duodenum to emulsify and digest fats. The fat and cholesterol will be packaged when absorbed via the enterocytes into the lacteal into chylomicron which has an integral protein called Apo B 48. The chylomicron is then transported via the lacteal to the thoracic duct into the main blood stream. Here the chylomicron acquires 2 peripheral apoproteins – apo-C and apo-E. These peripheral apoproteins are critical to the role of chylomicron as they interact with specific receptors in the liver and adipocytes.
    1. Apo E is needed to attach to the LDL-receptor on the hepatocytes for the chylomicron to be absorbed by the liver for the breakdown of TG into fatty acids and glycerol.
    2. Apo C especially apo-C2 on the chylomicron activates the LPL (lipoprotein lipase) on the surface of the endothelial layer of the capillaries, which hydrolyzes the TG into free fatty acids and glycerol. These then diffuses through the capillaries to the muscles or adipose cells. for. As the TG are absorbed, the chylomicron loses apo C and is now known as chylomicron remnant. The remnant is now transported back to the liver and now the apo E is bound to the chylomicron remnant receptor on the hepatocyte surface for the remaining TG to be taken up by the liver.
  2. VLDL, IDL and LDL lipoproteins:
    1. VLDL – its role is to transport lipids from the liver to the other peripheral tissues such as adipocytes and muscles – VLDL is synthesized in the liver and when produced has a integral apoprotein called apo B100. In the blood, it picks up 2 peripheral apoprotein apo-C and apo-E like chylomicrons. The apo-C on VLDL like chylomicrons attaches to the lipoprotein lipase of the adipocytes where TG is broken down to FA and glycerol for fat storage. The VLDL will reduce in size to IDL and LDL as its TG content is reduced. The VLDL has 2 fates after its TG content is reduced to 50%:

i.      It goes to the liver where the apo-E binds to the LDL receptor or Lipoprotein related protein (LRP) on the heptocyte surface to be refilled with TG from the liver and release back for distribution to the peripheral tissues

ii.      It binds through apo-C to lipase of other adipocytes to discharge more TG; and when the TG is down to 30% it is known as IDL.

2. IDL – like VLDL could either recirculate to the liver to pick up more TG to form VLDL for further distribution of TG to the peripheral tissues or continue to bind to lipase on adipocytes discharging further TG. Once the TG content reduces to 10% , it becomes LDL shedding the apo-C and apo-E. The LDL structure is now similar to the VLDL when it was first released from the liver where it has not acquired any peripheral apoproteins apo C and E. Both LDL and VLDL have integral apo-B100 but differ in its content. VLDL at this stage is rich in TG while LDL is now highly concentrated with cholesterol esters.

It is believed that the source of peripheral apoproteins is from HDL showing yet again the complexity of the interactions between the lipoproteins in the regulation of lipid distribution in the body.

3. LDL is the main carrier of cholesterol esters.

i.      It lacks apo-E and apo-C and its integral apo-B100 has low affinity for lipase enzyme of the adipocytes and LDL receptor of the liver. As such, its half life is prolong in blood circulation which increases its chance of being oxidized and taken up by the macrophage scavenger via binding with its receptors CD36 and SR-A. The uptake of LDL cholesterol turns the macrophage into foam cells in the intimal layer of the blood vessels that is the nidus for atheroma.

ii.      LDL is often mislabeled as “bad cholesterol”. Its cholesterol source is important for the production of bile salts, steroid hormones such as vitamin D, sex hormones and catecholamines.

4. HDL – reverse transport of cholesterol from peripheral tissues to the liver for hormone and bile synthesis and also for excretion to bile. HDL is also an antioxidant. The distinctive integral apoprotein is Apo-A1.

HDL is synthesized mainly in the liver and some in the gut. When it is released in the blood stream, it is poorly lipidated and is ready to collect cholesterol especially from the endothelial cells of blood vessels. In the blood, HDL acquires an enzyme called LCAT, lecithin cholesterol acyl transferase that is attached to its surface.

HDL with its LCAT binds to the hydroxyl group cholesterol of the cell membrane of endothelium of the blood vessels and other tissues to form cholesterol ester which is much more hydrophobic than cholesterol. The ester therefore, leaves the membrane and are stored in the HDL.

HDL will then transport the collected cholesterol via its ester salt to the liver.  The Apo-A1 of HDL binds to the Apo A receptor on the hepatocyte surface and cholesterol is absorbed in the liver and is finally excreted as bile. HDL plays a critical role in removing cholesterol particularly from the endothelium of the blood vessels preventing and minimizing cholesterol plaques. HDL is an independent negative risk factor in CVS diseases. It is increased by niacin and exercise.

Mechanism of HDL in cholesterol transport:

i.      Excess cholesterol in the macrophages triggers up-regulation of the ABCA1 transporter and  hydrolase that converts the cholesterol esters in the foam cells to free cholesterol.

ii.      The ABCA1  transporter delivers the free cholesterol to the cell membrane. It is then absorbed by the poorly lipidated HDL apo-A1 to form nascent HDL.

iii.      The free cholesterol in the HDL is esterified by the LCAT on the HDL surface and the cholesterol ester then moves to the lipoprotein core forming the more spherical mature HDL 3

iv.      HDL 3 removes more cholesterol through its binding with another membrane receptor SR-B1. The free cholesterol collected gets esterified and expand the HDL 3 to HDL 2.

v.      ABCA1 transporter and SR-B1 are critical membrane receptors for cholesterol efflux.

vi.      HDL also collects cholesterol in the lipid raft and caveoli within the cell membrane of the macrophage.

  1. The fate of the cholesterol ester rich HDL 2 is as follows:

i.      Exchange with apo-B lipoproteins VLDL, IDL and LDL for TG mediated by Cholesterol ester transferase protein (CETP).  This is a one-to-one exchange of cholesterol for TG.

ii.      There are 3 possible fates of the now TG-enriched HDL 2

    1. It may be hydrolysed by adipocyte lipase converting it back to HDL 3 or
    2. Return to the liver interacting with hepatocyte SR-B1 that removes the cholesterol ester converting it back to HDL 3 or
    3. Catabolise by the liver.

Another biomarker of interest is lipoprotein (a) Lp(a). It is now known if this lipoprotein has a role in the lipid transport system. This is a low density lipoprotein-like particle that shares many characteristics of plasminogen. Although it has been associated with higher risk of myocardial infarction and angina pectoris, there is no evidence that decreasing Lp(a) reduces CHD risk. Simple and accurate methods are not yet available and currently its measure is confined to research. There is no effective therapy for Lp(a) except for higher doses of niacin which is not well tolerated by patients.

The complimentary transport system works in elegant harmony to choreograph the body’s lipid needs and as science continues to unravel the intricacies of normal lipid metabolism, our ability to understand, diagnose and manage dyslipidemia continues to improve. The focus in the past of LDL cholesterol as the main contributing factor to CHD is extended to the total non-HDL cholesterol. Other emerging risk factors part from dyslipidemia would need to be considered in the overall strategy to reduce CHD. These include inflammatory markers such as HsCRP, imbalance in omega fatty acids, pro-thrombotic factors, homocysteine and Lp(a).

I refer you to an excellent Youtube video clip that summarizes the role of lipoproteins in the transport of lipids.  http://www.youtube.com/watch?v=97uiV4RiSAY&feature=related.