Lyme Disease Support Group

By Kristina Fiore, Staff Writer, MedPage Today

Published: August 23, 2011

Reviewed by

Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Video Source: JAMA

Eating a predominantly vegetarian diet focused on lowering cholesterol -- and getting advice on how to do so effectively -- can drop LDL levels more than a diet focused only on reducing saturated fat, researchers found.

A diet rich in cholesterol-lowering foods dropped LDL by 13% to 14% over six months, depending on the level of accompanying counseling, compared with a drop of just 3% for patients on a control diet, David Jenkins, MD, of St. Michael's Hospital in Toronto, and colleagues reported in the August 24/31 issue of the Journal of the American Medical Association.

"Our data demonstrate the cholesterol-lowering potential of a dietary portfolio intervention that counsels participants to increase consumption of cholesterol-lowering foods denoted by the FDA to have a heart-health benefit," they wrote.

Action Points

■Explain that a dietary intervention study of cholesterol-lowering foods with either two or seven counseling sessions significantly lowered LDL cholesterol compared with a control diet emphasizing reduced saturated fat consumption.

■Note that the results between the groups receiving two versus seven counseling sessions were not significantly different.

Foods with known cholesterol-lowering properties -- such as nuts, soy, and barley -- have been shown to be effective in lowering serum cholesterol in metabolically controlled conditions, the researchers said.

So they assessed whether eating a diet consisting of these foods decreased LDL cholesterol compared with a control diet that emphasized eating fiber and whole grains.

They enrolled 351 patients with hyperlipidemia at four centers across Canada, who were given one of three diet plans:

a "dietary portfolio" that emphasized plant sterols, soy protein, viscous fibers, and nuts with either two counseling sessions or seven sessions over six months,

or a control diet focused on lowering saturated fats without counseling.

Control patients were not allowed to eat foods in the intervention portfolio, the researchers said.

The 51 patients who were taking statins before the study had discontinued them at least two weeks prior.

Mean LDL cholesterol at baseline was 171 mg/dL.

In the modified intention-to-treat analysis of 345 patients, the researchers saw significant reductions in LDL cholesterol only for patients in both arms of the portfolio diet:

a 13.8% reduction for those who had intensive counseling and a

13.1% drop for those with "routine" counseling (P<0.001 for both) compared with a nonsignificant 3% drop for those on the control diet.

Jenkins and colleagues said the LDL reductions were "approximately half those observed with early statin trials, that were associated with 20% reductions in coronary heart disease mortality."

"Further study is needed to determine whether cholesterol reduction using these portfolio components is associated with lower rates of coronary heart disease events," they wrote.

They also noted that more frequent visits to the clinic appear to be unnecessary in achieving significant reductions in LDL.

"The near maximal effectiveness of only two clinic visits enhances the suitability of this dietary approach for clinical application," they added.

The portfolio diet also improved the ratio of total cholesterol to HDL cholesterol, dropping 8.2% for the routine counseling and 6.6% for the intensive counseling (P<0.001 for both).

Those reductions were significantly greater than those for the control diet, but weren't significantly different from each other, the researchers said.

The cholesterol-lowering diet also reduced the calculated 10-year heart risk by 10.8% for those on routine counseling and by 11.3% for those on intense counseling, which was significantly greater than the nonsignificant 0.5% drop in risk for those on the control diet.

The researchers noted that reductions in LDL were associated with dietary adherence for those on the cholesterol-lowering diet (P<0.001).

"Convincing people to change dietary patterns is difficult, much less convincing them to become vegetarians," Jana Klauer, MD, a primary care physician in New York, said in an email to MedPage Today and ABC News.

"But it can be done -- just look at Bill Clinton," noting the former president and heart disease patient who recently became a vegan in order to glean its benefits to lower his cardiovascular risk.

But Merle Myerson, MD, EdD, of St. Luke's and Roosevelt Hospitals in New York, said the counseling component is perhaps the trickiest part.

"Medicare and most insurances do not reimburse for one session of nutrition counseling, unless you have diabetes or end-stage renal disease, much less the kind of patients in this study," she said, adding that she doubts patient adherence would be sufficient in the long run.

The study was limited because the intervention was complex and lipid-lowering effects couldn't be pegged to specific components. Also, they cautioned about its high overall dropout rate of 22.6%, though they noted this is "an attrition rate common to dietary studies at these levels of intensity."

As well, the study may lack generalizability because its population was predominantly white, with low-to-intermediate risk of cardiovascular disease, and may not translate to those with a higher risk of disease.

Still, they concluded that "a meaningful 13% LDL reduction can be obtained after only two clinic visits of approximately 60- and 40-minute sessions."

The study was supported by CRCE of the Federal Government of Canada, CIHR, AFM Net, Loblaw Brands, Solae, and Unilever, and St. Michael's Hospital.

Unilever provided the margarines used in the study, and Can-Oat Milling provided an oat bran.

The researchers reported relationships with

Unilever, Sanitarium Company, California Strawberry Commission, Loblaw Supermarket, Herbal Life International, Nutritional Fundamental for Health, Pacific Health Laboratories, Metagenics, Bayer Consumer Care, Orafti,

Dean Foods, Kellogg's, Quaker Oats, Procter & Gamble, Coca-Cola, NuVal Griffin Hospital, Abbott, Pulse Canada, Saskatchewan Pulse Growers, and Canola Council of Canada, the Almond Board of California, International Tree Nut Council, Barilla, Oldways, Dean Foods, Haine Celestial, Alpro Foundation, Danone, Enzymotec, Atrium Innovations, and Viterra.

Primary source: Journal of the American Medical Association

Source reference:

Jenkins DJA, et al "Effect of a dietary portfolio of cholesterol-lowering foods given at two levels of intensity of dietary advice on serum lipids in hyperlipidemia" JAMA 2011; 206(8): 831-839.

View Comments By: Healthcare Professionals All

LEK, MS - Aug 24, 2011

doctorsh is right on. And just look at the relationships the researchers have.

Eat real food, including healthy animal products.

The point is becoming replete in nutrients, including fat-soluble vitamins (which, by the way, are transported from the liver to the cell via LDL) and minerals.

Let's move on from this idea that the lower LDL the better...

© 2011 Everyday Health, Inc. All rights reserved.

http://www.medpagetoday.com/PrimaryCare/DietNutrition/28168? utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

Post edited by: Bettyg, at: 08/25/2011 01:35 AM

By Crystal Phend, Senior Staff Writer, MedPage Today

Published: March 21, 2012

2 comment(s)

Action Points

Three small phase I studies showed that REGN727, an investigational monoclonal antibody, significantly lowered serum LDL whether or not the volunteer was receiving atorvastatin or had familial or nonfamilial hypercholesterolemia.

REGN727, directed against PCSK9 (a serine protease that binds to LDL receptor facilitating degradation), did not cause significant adverse events, whether given intravenously or subcutaneously.

An investigational monoclonal antibody substantially cuts low density lipoprotein (LDL) cholesterol levels whether given alone or in addition to statin therapy, according to early phase findings.

The biologic agent REGN727 dropped serum LDL by 39 to 61 percentage points more than placebo across doses tried on healthy volunteers and those with familial or nonfamilial hypercholesterolemia, Evan A. Stein, MD, PhD, of the Metabolic and Atherosclerosis Research Center in Cincinnati, and colleagues reported.

These results from a series of three phase I trials with the proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease inhibitor, which targets LDL receptors to keep the lipid inside cells, appeared in the March 22 issue of the New England Journal of Medicine.

Phase II results are slated for release at a late-breaking clinical trials session at the American College of Cardiology meeting Monday, March 26.

If the drug pans out as a nontoxic way to cut cholesterol via a different mechanism than statins, it could be a breakthrough, meeting co-chair Patrick O'Gara, MD, of Brigham & Women's Hospital in Boston, said on a conference call with reporters.

These results are exciting because lipid management has plateaued over the past decade, explained E. Murat Tuzcu, MD, an interventional cardiologist at the Cleveland Clinic.

"We tried and we're still working with the HDL and additive agents to lower LDL, but we've really not been able to make a big jump," he said at the same press teleconference.

A monoclonal antibody is likely to be much more expensive than current lipid-lowering options, especially now that statins are starting to go generic, so their reach won't be as great, Stein suggested in an interview with MedPage Today.

Even so, if the safety and efficacy from early phase results like these pan out in pivotal trials, "I think these will be as big an advance for cardiovascular disease and clinical medicine as the statins have been over the last 20 years," Stein predicted.

Despite the wild success of statins, there's plenty of room for improvement, noted an editorial accompanying the NEJM paper.

Statins cut cholesterol by typically no more than 40% to 55%, which still leaves many high-risk patients above the recommended 70 mg/dL target for LDL cholesterol, Stephen G. Young, MD, and Loren G. Fong, PhD, both of UCLA, wrote.

Those patients and others who can't tolerate statins "could benefit greatly" from PCSK9 inhibition, the editorialists suggested. "At this point, the status of PCSK9 therapeutics appears to be full speed ahead."

PCSK9 is produced largely in the liver, where it enters the circulation, binds to hepatic LDL receptors to mark them for degradation, and thus reduces the capacity of the liver to remove LDL from circulation.

The first two of the phase I studies with the PCSK9 inhibitor reported included healthy volunteers randomized to single ascending doses of REGN727 or placebo. One included 40 patients treated intravenously; the other, 32 treated subcutaneously. The primary outcome was safety, with effect on lipids a secondary outcome.

Every dosage tested, whether subcutaneous or intravenous, was significantly better than placebo (all P<0.001).

But the higher doses had a bigger impact on LDL cholesterol. The reductions from baseline ranged from 28 to 57 percentage points greater than with placebo for IV doses of 0.3 mg to 12 mg and from 33 to 46 percentage points greater with 50 mg to 250 mg subcutaneously.

The third study included 21 adults with familial hypercholesterolemia on atorvastatin (Lipitor), 30 nonfamilial cases with LDL over 100 mg/dL on atorvastatin, and 10 with LDL over 130 mg/dL who were on a modified diet instead of a statin.

They got three subcutaneous shots at 50, 100, or 150 mg of REGN727 or placebo.

Again, the proportionate LDL reductions were dose-dependent and similar whether high cholesterol levels were inherited or not. The declines included the following (both P<0.001):

41 to 56 percentage points greater versus placebo in the familial atorvastatin-treated cases

38 to 65 percentage points greater versus placebo in the nonfamilial atorvastatin-treated cases

Nonfamilial cases treated without a statin also showed a significant 57 percentage points greater reduction in LDL with 150 mg REGN727 than with placebo. But their levels didn't fall as far as with the statin-monoclonal antibody combination (from a mean 179 mg/dL to 81 mg/dL versus from 112 mg/dL to 47 mg/dL).

That finding suggests an additive, rather than synergistic, impact on LDL levels for use with a statin, the researchers noted.

The maximum LDL lowering occurred within two weeks, after which the effect began to wear off, suggesting a two-week dosing interval is best, according to Stein.

Benefits were also seen for total and HDL cholesterol as well as for apolipoprotein B, which were expected, and lipoprotein(a), which was a surprise as no other lipid-lowering agents do so and it wasn't thought to be cleared through LDL receptors, his group pointed out.

But there was "no clear evidence" of drug-related adverse events in any of the three trials.

Five participants in the multiple-dose trial getting REGN727 with atorvastatin had brief elevations in creatine kinase beyond three times the upper limit of normal.

"Given the small number of subjects and the short duration of exposure, our ability to evaluate the safety profile of REGN727 in these trials was limited," the researchers cautioned.

The study was funded by Regeneron Pharmaceuticals and Sanofi.

Stein reported receiving grant funds to his institution from the Metabolic and Atherosclerosis Research Center and Medpace Reference Labs.

Many of the co-authors were employees of Regeneron, one of whom jointly wrote the paper with Stein.

Fong reported grant funds from the National Institutes of Health.

Young reported consulting for Genentech; employment with the American Society of Biochemistry and Molecular Biology and eLife; grant funds from the NIH to his institution; and payment for lectures from Merck; and royalties from UCLA and Gladstone.

Young also reported having co-authored a commentary article about PCSK9 with a scientist employed by Genentech.

http://www.medpagetoday.com/Cardiology/Atherosclerosis/ 31757?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

© 2012 Everyday Health, Inc. All rights reserved.

By Crystal Phend, Senior Staff Writer, MedPage Today

Published: March 26, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, Nurse Planner

1 comment(s)

ACTION Points

A novel monoclonal antibody when added to statin therapy substantially cuts LDL cholesterol levels beyond reductions achieved with statin therapy alone.

The agent, dubbed REGN727 or SAR236553 for now, is the furthest along in a new class of biologics that boost liver absorption of cholesterol by blocking serum proprotein convertase subtilisin kexin 9 (PCSK9).

CHICAGO -- A novel monoclonal antibody when added to statin therapy substantially cuts LDL cholesterol levels beyond reductions achieved with statin therapy alone, a phase II study found.

Subcutaneous injection every two weeks dropped LDL by 40% to 72% more than placebo across the doses tested among patients uncontrolled on their background regimen of atorvastatin (Lipitor), James M. McKenney, PharmD, of National Clinical Research in Richmond, Va., reported here at the American College of Cardiology meeting and simultaneously in the Journal of the American College of Cardiology.

"If the drug continues to show this kind of efficacy and especially if it shows safety, it could be a new era in the treatment of lipid disorders," McKenney said at a press conference after the late-breaking clinical trial session.

"This is a wow," said conference co-chair Rick A. Nishimura, MD, of the Mayo Clinic in Rochester, Minn., calling the monoclonal antibody a potential game changer at the press conference.

The agent, dubbed REGN727 or SAR236553 for now, is the furthest along in a new class of biologics that boost liver absorption of cholesterol by blocking serum proprotein convertase subtilisin kexin 9 (PCSK9).

That protein is produced largely in the liver, where it binds to hepatic LDL receptors to mark them for degradation, and thus reduces the capacity of the liver to remove LDL from circulation.

In the phase II trial, the LDL reductions seen among the 183 patients with LDL levels of 100 mg/dL or above at baseline atop their regimen of atorvastatin were (all P<0.0001):

5.1% with placebo

39.6% with 50 mg of the PCSK9 inhibitor every two weeks

64.2% with 100 mg of the monoclonal antibody every two weeks

72.4% with 150 mg of the agent every two weeks

43.2% with 200 mg of the PCSK9 inhibitor every four weeks

47.7% with 300 mg of the agent every four weeks

These reductions appeared additive to the the typically 40% to 50% reductions these patients typically achieve with statin treatment, McKenney noted.

The vast majority of patients randomized to the PCSK9 inhibitor on any schedule or dose got their LDL levels under control to less than 100 mg/dL, with rates ranging from 89% with the lowest monthly dose to 100% with the highest biweekly dose.

The proportion who got to goal with LDL levels under 70 mg/dL over the 12 weeks of treatment ranged from 47% with the lowest biweekly dose to 100% with the highest biweekly dose.

"It's great to finally be able to treat virtually 100% of patients and get them down to optimal levels, levels we never dreamed of getting patients to 10 years ago," co-author Evan A. Stein, MD, PhD, of the Metabolic and Atherosclerosis Research Center in Cincinnati, told MedPage Today.

There are still many patients who can't get to the more aggressive goals for LDL lowering with statins alone, not to mention the patients who don't tolerate statin therapy, said Steve Nissen, MD, from the Cleveland Clinic, who called the agent exciting in an interview.

Sequestering away extra cholesterol in the cells shouldn't be a problem, Stein explained, because cells compensate by reducing their own endogenous production of this lipid, which is used in cell walls and important tasks like production of vitamin D, steroid hormones, and bile.

Safety in the phase II trial largely looked the same as in the series of phase I trials with the same PSCK9 inhibitor. Stein reported those findings in the New England Journal of Medicine last week.

Liver enzymes and kidney function markers weren't elevated above the normal range in any patients on the monoclonal antibody in the phase II trial.

Muscle pain or weakness occurred in one or two patients in every dose and placebo group, each with 30 or 31 patients.

Treatment emergent serious adverse events weren't dose-dependent, and only one was thought related to the study drug.

That patient developed diarrhea followed by a rash on his limbs and trunk nine days after his first injection, diagnosed as leukocytoclastic vasculitis, which rapidly resolved with prednisone treatment. There was no organ involvement and no anti-drug antibodies seen before or after the event.

That event isn't likely to be a hurdle to development of the monoclonal antibody, which is entering phase III testing now, McKenney said.

Nissen said he was comfortable that there weren't any emergent safety issues.

But because there is some risk of immunity with an agent like this, it will be important to see further data on that risk, noted study discussant Karol E. Watson, MD, of the University of California Los Angeles.

"There's no question we need longer-term outcome studies," she said at the session.

The study was financially supported by Sanofi and Regeneron Pharmaceuticals.

McKenney reported being an employee of a research company that has received research funding from Regeneron and Sanofi.

Stein reported receiving grant funds to his institution from the Metabolic and Atherosclerosis Research Center and Medpace Reference Labs.

Primary source: Journal of the American College of Cardiology

Source reference:

McKenney JM, et al "Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy" J Am Coll Cardiol 2012; DOI: 10.1016/j.jacc.2012.03.007.

http://www.medpagetoday.com/MeetingCoverage/ACCMeeting/ 31862?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

© 2012 Everyday Health, Inc. All rights reserved.

Download Complimentary Source PDF

By Todd Neale, Senior Staff Writer, MedPage Today

Published: July 18, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Take Posttest

Action Points

This randomized study showed that a polypill combining three antihypertensives and a statin significantly lowered blood pressure and LDL cholesterol in patients 50 and older with reasonable magnitudes of effect.

Note that the concept of a polypill has been proposed previously, but earlier trials did not demonstrate the expected magnitude of reductions in blood pressure and cholesterol, in part due to poor adherence.

A polypill combining three antihypertensives and a statin significantly lowered blood pressure and LDL cholesterol in patients 50 and older, a randomized, crossover study showed.

Through 12 weeks of treatment, the reductions were

17.9 mm Hg (95% CI 15.7 to 20.1) for systolic blood pressure,

9.8 mm Hg (95% CI 8.1 to 11.5) for diastolic pressure, and

54 mg/dL (95% CI 46 to 62) for LDL cholesterol, according to David Wald, MD, of Queen Mary University of London, and colleagues.

Although the study was too short to assess the impact on cardiovascular events, sustained reductions at those levels would be expected to reduce rates of ischemic heart disease events and stroke by a relative 72% and 64%, respectively, the researchers reported online in PLoS One.

"This polypill, designed principally for primary prevention, therefore has considerable potential for the prevention of cardiovascular disease," they wrote.

The World Heart Federation has backed the polypill approach -- added to smoking cessation and weight loss -- to lessen the burden of cardiovascular disease around the globe.

In the last decade, several studies have evaluated polypills. In one study -- The Indian Polycap Study (TIPS) -- the combination of three antihypertensives, a statin, and aspirin in a single capsule significantly reduced blood pressure and LDL cholesterol, though the cholesterol-lowering effect was slightly blunted.

Wald and colleagues noted that most of the trials of polypills have resulted in lower-than-expected reductions in blood pressure and cholesterol, likely because of poor adherence to treatment or use of some components of the polypills in the control groups.

In the current study, the researchers selected patients 50 and older (mean age 59) who did not have a history of cardiovascular disease but who were already taking components of the polypill for primary prevention. Blood pressure and cholesterol levels were not considered for enrollment.

The polypill contained amlodipine 2.5 mg, losartan 25 mg, and hydrochlorothiazide 12.5 mg -- all half of the standard doses -- in addition to a standard 40-mg dose of simvastatin.

The 84 patients in the crossover study were randomized to take the polypill nightly for 12 weeks and then placebo nightly for 12 weeks, or vice versa.

At baseline, the average blood pressure was 143/86 mm Hg and the average LDL cholesterol level was 143 mg/dL.

Compared with placebo, active treatment was associated with relative reductions of systolic blood pressure, diastolic blood pressure, and LDL cholesterol of 12%, 11%, and 39%, respectively.

Those figures are consistent with previous trials of the individual components of the polypill after taking into account the lower baseline levels in the current trial, according to the researchers.

There also were significant reductions in apolipoprotein B, total cholesterol, and triglycerides, with no effect on HDL cholesterol.

Adherence to treatment was high, with 98% of the patients taking more than 85% of their allocated pills.

Side effects were more frequent on active treatment (29% versus 13%, P=0.01), although none was serious enough to cause the patient to discontinue the trial.

Muscle ache was more common with the polypill compared with placebo (11% versus 1.2%, respectively).

The researchers noted that the study was limited in that the high adherence rate cannot be extrapolated to the general population and that the rates of side effects are not applicable to patients who have not taken the components of the polypill before.

One of Wald's co-authors jointly holds European and Canadian patents for a combination pill for the prevention of cardiovascular disease (pending in U.S.) and together with Wald has an interest in its development.

From the American Heart Association:

Resistant Hypertension: Diagnosis, Evaluation, and Treatment

Primary source: PLoS One

Source reference:

Wald D, et al "Randomized polypill crossover trial in people aged 50 and over" PLoS One 2012.

http://www.medpagetoday.com/Cardiology/Hypertension/33806? utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

© 2012 Everyday Health, Inc. All rights reserved.

By David Pittman, Washington Correspondent, MedPage Today

Published: October 18, 2012

WASHINGTON -- An FDA advisory panel recommended approval for two drugs as add-on therapy for the rare lipid disorder homozygous familial hypercholesterolemia (HoFH), saying the benefits overrode safety concerns in both instances.

One drug, mipomersen, gained a tepid endorsement with a 9-6 vote Thursday, and a day earlier the same panel -- the Endocrinologic and Metabolic Drugs Advisory Committee -- signaled stronger favorable sentiment voting 13-2 for approval of lomitapide as adjuvant therapy for HoFH and other severe lipid disorders.

The agency usually follows the recommendations of its advisory panels, although it is not required to do so.

Mipomersen's maker, Cambridge, Mass.-based Genzyme, is seeking an indication to treat HoFH as an adjunct to maximally tolerated lipid-lowering medications.

HoFH is a rare genetic condition that if untreated can cause extremely high cholesterol levels, typically between 400 mg/dL and 1,000 mg/dL.

It affects roughly one in 1 million people in the U.S.

On Thursday members of the FDA's advisory panel -- those who supported and opposed approval -- expressed concern about mipomersen's safety profile but were swayed by testimony that argued doctors needed new tools to treat the rare disease.

The drug was studied in four phase III, randomized, double-blind, 6-month trials, and 18% (47 of 261) of patients treated with mipomersen dropped out of studies because of adverse events.

Reasons for discontinuing the trial included injection site infections, which afflicted 84% of mipomersen patients.

The drug is delivered once-weekly via subcutaneous injection.

Advisory committee members also expressed concern over liver toxicity.

Nonetheless, mipomersen patients achieved an average 24.7% decrease in LDL compared with a decline 3.3% of placebo patients.

However, the agency called into question the use of LDL as a surrogate endpoint for the ultimate goal of reducing cardiovascular disease.

"There was no evidence for a decrease in cardiovascular events in the mipomersen group as compared to the placebo group in these trials," the FDA said in briefing documents released ahead of Thursday's meeting.

The safety concerns and efficacy questions didn't sway support for the treatment of a severe condition for patients with a poor quality of life.

"Even if a third of the group benefits, that should be viewed as a win," Edward Gregg, PhD, chief of epidemiology in the division of diabetes translation at the CDC in Atlanta, said during the meeting.

The FDA in its briefing documents proposed a risk evaluation and mitigation strategy (REMS) that would require all prescribers and pharmacies to achieve special certification.

Prescribers would be educated on the approved indication, potential risks, and the need to monitor patients during treatment per the drug's labeling.

The FDA has a date of Jan. 29 for deciding whether to approve the drug.

The same panel on Wednesday voted 13-2 to recommend approval for the new drug lomitapide to treat certain severe lipid disorders, including HoFH, when used as an adjunct to a low-fat diet and other lipid-lowering therapies.

The once-daily capsule inhibits a particular protein which reduces the cholesterol that the liver and intestines assemble and secrete into the bloodstream. Right now, there is no such inhibitor approved by the FDA.

While statins are the standard method for treating high cholesterol, people with HoFH lack LDL receptors -- a deficiency which lowers statins' efficacy.

Lomitapide lowered LDL from an average of 336 mg/dL at the start of a 26-week trial to 190 mg/dL, a drop of more than 40% among the 29 patients in the trial.

"There was ... a positive correlation between mean dosage prescribed and observed LDL reduction at the population level," FDA reviewers stated in briefing documents released before the Wednesday meeting.

However, 10% of the 29 patients in the 26-week study had at least one serious adverse event. That percentage rose to 22% during the first 120 days of an extension trial.

Common adverse events included gastrointestinal (GI) disorders such as diarrhea, nausea, vomiting, dyspepsia, and abdominal pain.

Bristol-Myers Squibb abandoned development of the drug in 2000 over concerns of GI tolerability.

The FDA recommended a REMS for lomitapide similar to that for mipomersen; it would require all prescribers and pharmacies to achieve special certification.

Lomitapide was developed by Aegerion Pharmaceuticals of Cambridge, Mass. The FDA has set a date of Dec. 29 to decide on whether to approve it.

http://www.medpagetoday.com/Washington-Watch/FDAGeneral/ 35422?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

© 2012 MedPage Today, LLC. All rights reserved.

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 03, 2013

Excess cholesterol in macrophages within ocular blood vessels may help trigger neovascular, or "wet," age-related macular degeneration (AMD), a laboratory study suggested.

A series of experiments in mice showed that cholesterol levels in macrophages from older mice were higher than in younger animals, apparently because of impairments in the ABCA1 cholesterol efflux mechanism, according to Rajendra Apte, MD, PhD, of Washington University in St. Louis, and colleagues.

Topical as well as systemic treatment of older mice with a liver X receptor (LXR) agonist known as T0-901317, which boosts cholesterol efflux from cells, reduced the degree of choroidal neovascularization in a laser-induced model of the human disease, the researchers also reported in the April 2 issue of Cell Metabolism.

Apte and colleagues also confirmed in lab studies that human peripheral blood mononuclear cells show progressive ABCA1 impairment and cholesterol buildup with age.

However, despite headlines in consumer media suggesting that people with AMD could benefit immediately from anti-cholesterol medications, Apte and colleagues did not test whether the LXR agonist could prevent spontaneous neovascularization in mice, let alone humans.

Nor are there any LXR agonists approved for human use, although at least one has progressed as far as phase I clinical testing. Moreover, the study did not address "dry" AMD, the much more common but less severe form of AMD.

Nevertheless, Apte and colleagues argued that the results point to a new approach to treating wet AMD.

"Therapeutic intervention prior to the development of advanced disease with effective agents that upregulate macrophage cholesterol efflux in the eye might prevent progression and can be used as prophylaxis against the development of choroidal neovascularization and its blinding complications," they wrote.

LXR agonists have previously been suggested as treatments for Alzheimer's disease, glioblastoma, hypercholesterolemia, atherosclerosis, thrombosis, and a variety of other disorders.

View 1 comment or Add Your Knowledge ™

http://www.medpagetoday.com/Ophthalmology/ GeneralOphthalmology/38238?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

© 2013 MedPage Today, LLC. All rights reserved.