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Archive for the ‘Lipid metabolism’ Category


Hypertriglyceridemia: Evaluation and Treatment Guideline

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Severe and very severe hypertriglyceridemia increase the risk for pancreatitis, whereas mild or moderate hypertriglyceridemia may be a risk factor for cardiovascular disease. Individuals found to have any elevation of fasting triglycerides should be evaluated for secondary causes of hyperlipidemia including endocrine conditions and medications. Patients with primary hypertriglyceridemia must be assessed for other cardiovascular risk factors, such as central obesity, hypertension, abnormalities of glucose metabolism, and liver dysfunction. The aim of this study was to develop clinical practice guidelines on hypertriglyceridemia.

The diagnosis of hypertriglyceridemia should be based on fasting levels, that mild and moderate hypertriglyceridemia (triglycerides of 150–999 mg/dl) be diagnosed to aid in the evaluation of cardiovascular risk, and that severe and very severe hypertriglyceridemia (triglycerides of >1000 mg/dl) be considered a risk for pancreatitis. The patients with hypertriglyceridemia must be evaluated for secondary causes of hyperlipidemia and that subjects with primary hypertriglyceridemia be evaluated for family history of dyslipidemia and cardiovascular disease.

The treatment goal in patients with moderate hypertriglyceridemia should be a non-high-density lipoprotein cholesterol level in agreement with National Cholesterol Education Program Adult Treatment Panel guidelines. The initial treatment should be lifestyle therapy; a combination of diet modification, physical activity and drug therapy may also be considered. In patients with severe or very severe hypertriglyceridemia, a fibrate can be used as a first-line agent for reduction of triglycerides in patients at risk for triglyceride-induced pancreatitis.

Three drug classes (fibrates, niacin, n-3 fatty acids) alone or in combination with statins may be considered as treatment options in patients with moderate to severe triglyceride levels. Statins are not be used as monotherapy for severe or very severe hypertriglyceridemia. However, statins may be useful for the treatment of moderate hypertriglyceridemia when indicated to modify cardiovascular risk.

 

References:

 

https://www.medpagetoday.com/clinical-connection/cardio-endo/77242?xid=NL_CardioEndoConnection_2019-01-21

https://www.ncbi.nlm.nih.gov/pubmed/19307519

https://www.ncbi.nlm.nih.gov/pubmed/23009776

https://www.ncbi.nlm.nih.gov/pubmed/6827992

https://www.ncbi.nlm.nih.gov/pubmed/22463676

https://www.ncbi.nlm.nih.gov/pubmed/17635890

 

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Benefits of Fiber in Diet

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

UPDATED on 1/15/2019

This is How Much Daily Fiber to Eat for Better Health – More appears better in meta-analysis — as in more than 30 g/day

by Ashley Lyles, Staff Writer, MedPage Today

In the systematic review, observational data showed a 15% to 30% decline in cardiovascular-related death, all-cause mortality, and incidence of stroke, coronary heart disease, type 2 diabetes, and colorectal cancer among people who consumed the most dietary fiber compared to those consuming the lowest amounts.

Whole grain intake yielded similar findings.

Risk reduction associated with a range of critical outcomes was greatest when daily intake of dietary fibre was between 25 g and 29 g. Dose-response curves suggested that higher intakes of dietary fibre could confer even greater benefit to protect against cardiovascular diseases, type 2 diabetes, and colorectal and breast cancer.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(18)31809-9.pdf

Eating more dietary fiber was linked with lower risk of disease and death, a meta-analysis showed.

According to observational studies, risk was reduced most for a range of critical outcomes from all-cause mortality to stroke when daily fiber consumption was between 25 grams and 29 grams, reported Jim Mann, PhD, of University of Otago in Dunedin, New Zealand, and colleagues in The Lancet.

By upping daily intake to 30 grams or more, people had even greater prevention of certain conditions: colorectal and breast cancer, type 2 diabetes, and cardiovascular diseases, according to dose-response curves the authors created.

Quantitative guidelines relating to dietary fiber have not been available, the researchers said. With the GRADE method, they determined that there was moderate and low-to-moderate certainty of evidence for the benefits of dietary fiber consumption and whole grain consumption, respectively.

Included in the systematic review were 58 clinical trials and 185 prospective studies for a total of 4,635 adult participants with 135 million person-years of information (one trial in children was included, but analyzed separately from adults). Trials and prospective studies assessing weight loss, supplement use, and participants with a chronic disease were excluded.

 

Food is digested by bathing in enzymes that break down its molecules. Those molecular fragments then pass through the gut wall and are absorbed in our intestines. But our bodies make a limited range of enzymes, so that we cannot break down many of the tough compounds in plants. The term “dietary fiber” refers to those indigestible molecules. These dietary fibers are indigestible only to us. The gut is coated with a layer of mucus, on which sits a carpet of hundreds of species of bacteria, part of the human microbiome. Some of these microbes carry the enzymes needed to break down various kinds of dietary fibers.

 

Scientists at the University of Gothenburg in Sweden are running experiments that are yielding some important new clues about fiber’s role in human health. Their research indicates that fiber doesn’t deliver many of its benefits directly to our bodies. Instead, the fiber we eat feeds billions of bacteria in our guts. Keeping them happy means our intestines and immune systems remain in good working order. The scientists have recently reported that the microbes are involved in the benefits obtained from the fruits-and-vegetables diet. Research proved that low fiber diet decreases the gut bacteria population by tenfold.

 

Along with changes to the microbiome there were also rapid changes observed in the experimental mice. Their intestines got smaller, and its mucus layer thinner. As a result, bacteria wound up much closer to the intestinal wall, and that encroachment triggered an immune reaction. After a few days on the low-fiber diet, mouse intestines developed chronic inflammation. After a few weeks, they started putting on fat and developing higher blood sugar levels. Inflammation can help fight infections, but if it becomes chronic, it can harm our bodies. Among other things, chronic inflammation may interfere with how the body uses the calories in food, storing more of it as fat rather than burning it for energy.

 

In a way fiber benefits human health is by giving, indirectly, another source of food. When bacteria finished harvesting the energy in the dietary fiber, they cast off the fragments as waste. That waste — in the form of short-chain fatty acids — is absorbed by intestinal cells, which use it as fuel. But the gut’s microbes do more than just make energy. They also send messages. Intestinal cells rely on chemical signals from the bacteria to work properly. The cells respond to the signals by multiplying and making a healthy supply of mucus. They also release bacteria-killing molecules. By generating these responses, gut bacteria help to maintain a peaceful coexistence with the immune system. They rest on the gut’s mucus layer at a safe distance from the intestinal wall. Any bacteria that wind up too close get wiped out by antimicrobial poisons.

 

A diet of fiber-rich foods, such as fruits and vegetables, reduces the risk of developing diabetes, heart disease and arthritis. Eating more fiber seems to lower people’s mortality rate, whatever be the cause. Researchers hope that they will learn more about how fiber influences the microbiome to use it as a way to treat disorders. Lowering inflammation with fiber may also help in the treatment of immune disorders such as inflammatory bowel disease. Fiber may also help reverse obesity. They found that fiber supplements helped obese people to lose weight. It’s possible that each type of fiber feeds a particular set of bacteria, which send their own important signals to our bodies.

 

References:

 

https://www.nytimes.com/2018/01/01/science/food-fiber-microbiome-inflammation.html

 

 

https://www.ncbi.nlm.nih.gov/pubmed/29276171

 

https://www.ncbi.nlm.nih.gov/pubmed/29276170

 

https://www.ncbi.nlm.nih.gov/pubmed/29486139

 

https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/fiber/art-20043983

 

https://nutritiouslife.com/eat-empowered/high-fiber-diet/

 

http://www.eatingwell.com/article/287742/10-amazing-health-benefits-of-eating-more-fiber/

 

http://www.cookinglight.com/eating-smart/nutrition-101/what-is-a-high-fiber-diet

 

https://www.helpguide.org/articles/healthy-eating/high-fiber-foods.htm

 

https://www.gicare.com/diets/high-fiber-diet/

 

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 Cholesterol Lowering Novel PCSK9 drugs: Praluent [Sanofi and Regeneron] vs Repatha [Amgen] – which drug cuts CV risks enough to make it cost-effective?

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 1/15/2019

In the patent fight over PCSK9 inhibitors, the Supreme Court refused to hear Amgen’s appeal of a 2017 court decision allowing Sanofi and Regeneron to continue selling alirocumab (Praluent). Amgen still has a new patent trial starting in Delaware federal court next month, FiercePharma reports.

Amgen’s Repatha hits wall at SCOTUS but presses ahead—new price breaks included

Amgen has been trying since 2015 to protect its PCSK9 cholesterol drug Repatha by keeping Sanofi and Regeneron’s rival Praluent off the market, even going as far as to ask the U.S. Supreme Court to review an ongoing patent fight.

But that attempt fell short this week as SCOTUS refused to hear the company’s appeal of a 2017 court decision allowing Sanofi and Regeneron to continue selling its head-to-head rival.

Amgen isn’t giving up the fight, though. The company is prepping for a new patent trial starting in Delaware federal court next month. And it’s responding to long-standing criticism of the high cost of PCSK9 drugs, which hit the market in 2015 at list prices of about $14,000 a year.

Amgen had already brought the price of the biweekly version of Repatha down to $5,850 per year before discounts and rebates, and late Monday it said it would lower cost of the monthly injectable dose to that same level.

SOURCE

UPDATED on 11/13/2018

ODYSSEY OUTCOMES: Alirocumab Cost-effective at $6000 a Year

Marlene Busko

November 11, 2018

CHICAGO — Treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab (Praluent, Sanofi/Regeneron) is cost-effective at $6319 a year when the willingness-to-pay threshold is the generally accepted $100,000 per quality-adjusted life-year (QALY), new research reports.

Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts, presented these cost-effectiveness findings for alirocumab, based on data from the ODYSSEY OUTCOMES trial, here at the American Heart Association (AHA) 2018 Scientific Sessions

As previously reported, results from ODYSSEY OUTCOMES were presented at American College of Cardiology (ACC) 2018 Annual Scientific Session in March and the study was published November 7 in the New England Journal of Medicine.

Strengths of the current cost analysis include that it used actual trial data as opposed to modeling estimates, Bhatt pointed out to theheart.org | Medscape Cardiology.

SOURCE

https://www.medscape.com/viewarticle/904744?nlid=126063_3866&src=WNL_mdplsfeat_181113_mscpedit_card&uac=93761AJ&spon=2&impID=1799507&faf=1

 

Did Amgen’s Repatha cut CV risks enough to make it cost-effective? Analysts say no

Sanofi, Regeneron’s Praluent pulls off PCSK9 coup with 29% cut to death risks in most vulnerable patients
SEE our curations on PCSK9 drugs:

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ODYSSEY Outcomes trial evaluating the effects of a PCSK9 inhibitor, alirocumab, on major cardiovascular events in patients with an acute coronary syndrome to be presented at the American College of Cardiology meeting on March 10.

Reporter: Aviva Lev-Ari, PhD, RN

 

For PCSK9 inhibitors, the effect on major adverse cardiovascular events has always fallen short of expectations based on cholesterol lowering.

But cardiovascular risk reduction is complicated. There is more to the puzzle than cholesterol. Some drugs lower both cholesterol and prevent cardiovascular events, but some people think that the two effects are actually not that closely related.

Milton Packer MD

https://www.medpagetoday.com/blogs/revolutionandrevelation/71435

In a previous trial (FOURIER), another PCSK9 inhibitor had only a modest benefit on its primary endpoint, and it did not reduce cardiovascular death, although the magnitude of cholesterol lowering was striking.

In another trial (SPIRE), a third PCSK9 inhibitor, the clinical trial was terminated prematurely by Pfizer because of reduction of the effect of the drug (a humanized but not fully humanized antibody) due to development of neutralizing antibodies in some of the patients. Actually, in patients treated for more than a year who did not develop neutralizing antibodies, a beneficial effect was seen.

The ODYSSEY Outcomes trial is evaluating the effects of a PCSK9 inhibitor,alirocumab, on major cardiovascular events in patients with an acute coronary syndrome within the prior year. The drug lowers serum cholesterol dramatically, and some are hopeful that that effect will translate into an important reduction in the risk of major adverse cardiovascular events. If you believe that cholesterol reduction inevitably leads to the prevention of cardiovascular death, myocardial infarction and stroke, then you would have high expectations for the ODYSSEY trial.

ODYSSEY. The trial uses a somewhat more aggressive treatment strategy and has a longer follow-up period than its predecessors. So maybe the benefit will be large. Maybe the drug will even reduce cardiovascular death or all-cause mortality.

In order to enrich the population for cardiovascular events, the trial enrolled patients with an acute coronary syndrome within the prior year. These patients are at high risk of having a recurrence. The problem is that risk is not necessarily related to changes in cholesterol, especially the events occurring early in the trial. And in this type of trial, the analysis tends to give extra weight to early events.

Trials like ODYSSEY are often designed to stop early if the results are unbelievably impressive. The ODYSSEY trial wasn’t stopped early.

the patients entering the ODYSSEY trial are starting out with a serum LDL <100 mg/dL or even <90 mg/dL. Is cholesterol really playing an important role at that level, especially when compared with noncholesterol factors?

SOURCE

https://www.medpagetoday.com/blogs/revolutionandrevelation/71435

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  1. Lungs can supply blood stem cells and also produce platelets: Lungs, known primarily for breathing, play a previously unrecognized role in blood production, with more than half of the platelets in a mouse’s circulation produced there. Furthermore, a previously unknown pool of blood stem cells has been identified that is capable of restoring blood production when bone marrow stem cells are depleted.

 

  1. A new drug for multiple sclerosis: A new multiple sclerosis (MS) drug, which grew out of the work of UCSF (University of California, San Francisco) neurologist was approved by the FDA. Ocrelizumab, the first drug to reflect current scientific understanding of MS, was approved to treat both relapsing-remitting MS and primary progressive MS.

 

  1. Marijuana legalized – research needed on therapeutic possibilities and negative effects: Recreational marijuana will be legal in California starting in January, and that has brought a renewed urgency to seek out more information on the drug’s health effects, both positive and negative. UCSF scientists recognize marijuana’s contradictory status: the drug has proven therapeutic uses, but it can also lead to tremendous public health problems.

 

  1. Source of autism discovered: In a finding that could help unlock the fundamental mysteries about how events early in brain development lead to autism, researchers traced how distinct sets of genetic defects in a single neuronal protein can lead to either epilepsy in infancy or to autism spectrum disorders in predictable ways.

 

  1. Protein found in diet responsible for inflammation in brain: Ketogenic diets, characterized by extreme low-carbohydrate, high-fat regimens are known to benefit people with epilepsy and other neurological illnesses by lowering inflammation in the brain. UCSF researchers discovered the previously undiscovered mechanism by which a low-carbohydrate diet reduces inflammation in the brain. Importantly, the team identified a pivotal protein that links the diet to inflammatory genes, which, if blocked, could mirror the anti-inflammatory effects of ketogenic diets.

 

  1. Learning and memory failure due to brain injury is now restorable by drug: In a finding that holds promise for treating people with traumatic brain injury, an experimental drug, ISRIB (integrated stress response inhibitor), completely reversed severe learning and memory impairments caused by traumatic brain injury in mice. The groundbreaking finding revealed that the drug fully restored the ability to learn and remember in the brain-injured mice even when the animals were initially treated as long as a month after injury.

 

  1. Regulatory T cells induce stem cells for promoting hair growth: In a finding that could impact baldness, researchers found that regulatory T cells, a type of immune cell generally associated with controlling inflammation, directly trigger stem cells in the skin to promote healthy hair growth. An experiment with mice revealed that without these immune cells as partners, stem cells cannot regenerate hair follicles, leading to baldness.

 

  1. More intake of good fat is also bad: Liberal consumption of good fat (monounsaturated fat) – found in olive oil and avocados – may lead to fatty liver disease, a risk factor for metabolic disorders like type 2 diabetes and hypertension. Eating the fat in combination with high starch content was found to cause the most severe fatty liver disease in mice.

 

  1. Chemical toxicity in almost every daily use products: Unregulated chemicals are increasingly prevalent in products people use every day, and that rise matches a concurrent rise in health conditions like cancers and childhood diseases, Thus, researcher in UCSF is working to understand the environment’s role – including exposure to chemicals – in health conditions.

 

  1. Cytomegalovirus found as common factor for diabetes and heart disease in young women: Cytomegalovirus is associated with risk factors for type 2 diabetes and heart disease in women younger than 50. Women of normal weight who were infected with the typically asymptomatic cytomegalovirus, or CMV, were more likely to have metabolic syndrome. Surprisingly, the reverse was found in those with extreme obesity.

 

References:

 

https://www.ucsf.edu/news/2017/12/409241/most-popular-science-stories-2017

 

https://www.ucsf.edu/news/2017/03/406111/surprising-new-role-lungs-making-blood

 

https://www.ucsf.edu/news/2017/03/406296/new-multiple-sclerosis-drug-ocrelizumab-could-halt-disease

 

https://www.ucsf.edu/news/2017/06/407351/dazed-and-confused-marijuana-legalization-raises-need-more-research

 

https://www.ucsf.edu/news/2017/01/405631/autism-researchers-discover-genetic-rosetta-stone

 

https://www.ucsf.edu/news/2017/09/408366/how-ketogenic-diets-curb-inflammation-brain

 

https://www.ucsf.edu/news/2017/07/407656/drug-reverses-memory-failure-caused-traumatic-brain-injury

 

https://www.ucsf.edu/news/2017/05/407121/new-hair-growth-mechanism-discovered

 

https://www.ucsf.edu/news/2017/06/407536/go-easy-avocado-toast-good-fat-can-still-be-bad-you-research-shows

 

https://www.ucsf.edu/news/2017/06/407416/toxic-exposure-chemicals-are-our-water-food-air-and-furniture

 

https://www.ucsf.edu/news/2017/02/405871/common-virus-tied-diabetes-heart-disease-women-under-50

 

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FDA approval on 12/1/2017 of Amgen’s evolocumb (Repatha) a PCSK9 inhibitor for the prevention of heart attacks, strokes, and coronary revascularizations in patients with established cardiovascular disease

Reporter: Aviva Lev-Ari, PhD, RN

 

Evolocumab was first FDA approved in 2015 for patients with

  • familial hypercholesterolemia and
  • others who fail to achieve LDL cholesterol lowering through diet and maximally-tolerated statin therapy.

In the Repatha cardiovascular outcomes study (FOURIER), Repatha reduced the risk of

  • heart attack by 27 percent, the risk of
  • stroke by 21 percent and the risk of
  • coronary revascularization by 22 percent.2

 

U.S. Repatha Indication

Repatha is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody indicated:

  • to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease.
  • as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia [HeFH]) to reduce low-density lipoprotein cholesterol (LDL-C).
  • as an adjunct to diet and other LDL‑lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL‑C.

The safety and effectiveness of Repatha have not been established in pediatric patients with HoFH who are younger than 13 years old.

The safety and effectiveness of Repatha have not been established in pediatric patients with primary hyperlipidemia or HeFH.

Eligible patients with high cholesterol (LDL-C ≥70 mg/dL or non-high-density lipoprotein cholesterol [non-HDL-C] ≥100 mg/dL) and established cardiovascular disease at more than 1,300 study locations around the world were randomized to receive Repatha subcutaneous 140 mg every two weeks or 420 mg monthly plus high- or moderate-intensity effective statin dose; or placebo subcutaneous every two weeks or monthly plus high- to moderate-intensity statin dose. Statin therapy was defined in the protocol as at least atorvastatin 20 mg or equivalent daily with a recommendation for at least atorvastatin 40 mg or equivalent daily where approved. The study was event driven and continued until at least 1,630 patients experienced a key secondary endpoint.

About Repatha® (evolocumab)
Repatha® (evolocumab) is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Repatha binds to PCSK9 and inhibits circulating PCSK9 from binding to the low-density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, Repatha increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.1

About Amgen in the Cardiovascular Therapeutic Area
Building on more than three decades of experience in developing biotechnology medicines for patients with serious illnesses, Amgen is dedicated to addressing important scientific questions to advance care and improve the lives of patients with cardiovascular disease, the leading cause of morbidity and mortality worldwide.8 Amgen’s research into cardiovascular disease, and potential treatment options, is part of a growing competency at Amgen that utilizes human genetics to identify and validate certain drug targets. Through its own research and development efforts, as well as partnerships, Amgen is building a robust cardiovascular portfolio consisting of several approved and investigational molecules in an effort to address a number of today’s important unmet patient needs, such as high cholesterol and heart failure.

Homozygous Familial Hypercholesterolemia (HoFH): In 49 patients with homozygous familial hypercholesterolemia studied in a 12-week, double-blind, randomized, placebo-controlled trial, 33 patients received 420 mg of Repatha subcutaneously once monthly. The adverse reactions that occurred in at least 2 (6.1 percent) Repatha-treated patients and more frequently than in placebo-treated patients, included upper respiratory tract infection (9.1 percent versus 6.3 percent), influenza (9.1 percent versus 0 percent), gastroenteritis (6.1 percent versus 0 percent), and nasopharyngitis (6.1 percent versus 0 percent).

Immunogenicity: Repatha is a human monoclonal antibody. As with all therapeutic proteins, there is a potential for immunogenicity with Repatha.

Please contact Amgen Medinfo at 800-77-AMGEN (800-772-6436) or 844-REPATHA (844-737-2842) regarding Repatha® availability or find more information, including full Prescribing Information, at www.amgen.com and www.Repatha.com.

References

  1. Repatha® U.S. Prescribing Information. Amgen.
  2. Sabatine MS, Giugliano RP, Keech AC, et al, for the FOURIER Steering Committee and Investigators. N Engl J Med. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. 2017;376:1713-22.
  3. Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.
  4. LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435.
  5. Pederson TR, et al. JAMA. 2005;294:2437-2445.
  6. Search Collaborative Group Lancet 2010;376:1658–69.
  7. Cannon CP, et al. N Engl J Med. 2015;372:2387-2397.
  8. World Health Organization. Cardiovascular diseases (CVDs) fact sheet. http://www.who.int/mediacentre/factsheets/fs317/en/. Accessed October 30, 2017.

 

SOURCE: Amgen

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The Biologic Roles of Leptin in Metabolism, Leptin Physiology and Obesity: On the Mechanism of Action of the Hormone in Energy Balance

Reporter: Aviva Lev-Ari, PhD, RN

 

More than $140 billion is spent each year in the United States to treat obesity-related diseases, according to the CDC.

Worldwide obesity rates have doubled since 1980, and most people now live in countries where more deaths are caused by overweight and obesity than by malnourishment, according to the World Health Organization.

Treatment with leptin was approved in the United States in 2014 for use in congenital leptin deficiency as well as in an unusual syndrome of lipodystrophy, but the protein has not been readily available for clinical experiments.

These are the conclusions in a commentary published June 22 in Cell Metabolism by Harvard Medical School metabolism experts Jeffrey Flier and Eleftheria Maratos-Flier.

Flier, the HMS George Higginson Professor of Physiology and Medicine, and Maratos-Flier, HMS professor of medicine at Beth Israel Deaconess Medical Center, have made significant contributions to the understanding of the metabolism of obesity and starvation in general, and of leptin in particular.

The role for leptin as a starvation signal is now well established. [T]he physiologic role of leptin in most individuals may be limited to signaling the response to hunger or starvation, and then reversing that signal as energy stores are restored

Conclusion

“We continue to believe that healthy and lean individuals exist who resist obesity at least in part through their leptin levels, and that some individuals develop obesity because they have insufficiently elevated leptin levels or cellular resistance to leptin,” Flier said.

“But in science, belief and knowledge are two different things, and as much as we may lean toward this belief, we ought to develop evidence for this hypothesis or abandon it in favor of new potential mechanisms for the regulation of body weight,” he said.

SOURCES

Leptin’s Physiologic Role: Does the Emperor of Energy Balance Have No Clothes?

Jeffrey S. Flier'Correspondence information about the author Jeffrey S. Flier

,

Eleftheria Maratos-Flier
Publication stage: In Press Corrected Proof

Seeking evidence for anti-obesity claim – Does the Emperor Have Clothes?

Importance of leptin signaling and signal transducer and activator of transcription-3 activation in mediating the cardiac hypertrophy associated with obesity

Maren Leifheit-Nestler12, Nana-Maria Wagner13, Rajinikanth Gogiraju1,Michael Didié14, Stavros Konstantinides15, Gerd Hasenfuss1and Katrin Schäfer1*

J Translational Medicine: Cardiovascular, Metabolic and Lipoprotein Translation. 2013; 11:170.  http://www.translational-medicine.com/content/11/1/170

http://dx.doi.org/10.1186/1479-5876-11-170

 

Other related articles on LEPTIN published in this Open Access Online Scientific Journal include the following:

 

Leptin signaling in mediating the cardiac hypertrophy associated with obesity

Larry H Bernstein, MD, FCAP, Reviewer, and Aviva Lev-Ari, PhD, RN

 

Leptin and Puberty

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Pregnancy with a Leptin-Receptor Mutation

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

New Insights into mtDNA, mitochondrial proteins, aging, and metabolic control

Curator: Larry H. Bernstein, MD, FCAP

Adipocyte Derived Stroma Cells: Their Usage in Regenerative Medicine and Reprogramming into Pancreatic Beta-Like Cells

Curator: Evelina Cohn, PhD

Fat Cells Reprogrammed to Make Insulin

Curator: Larry H. Bernstein, MD, FCAP

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Trends in HealthCare Economics: Average Out-of-Pocket Costs, non-Generics and Value-Based Pricing, Amgen’s Repatha and AstraZeneca’s Access to Healthcare Policies

Reporter: Aviva Lev-Ari, PhD, RN

 

1.   AstraZeneca’s access to healthcare strategy is made up of three elements:

  • Provide high-quality, effective and appropriate medicines to those who need them. Improve affordability, particularly among the growing middle class in Emerging Markets.
  • Bring down healthcare barriers, particularly in developing countries. Our strategy helps us to address affordability and other healthcare barriers, while ensuring we continue to provide high-quality medicines to those who need them.
  • Key Target exceeded Full target achieved Ongoing progress Target not achieved, some progress AstraZeneca has extensively expanded and updated their access strategy identifying those areas where they are best placed to provide support and are now well positioned for future progress.”
  • Access to Medicine Index Access to healthcare Goals Target progress Progress highlights Expand sustainable patient access to our medicines to reach 3 million patients by 2016 4.49 million patients in Emerging Markets served by patient access programmes
  • Young Health Programme After exceeding initial goal to reach 1 million people through the Young Health Programme by 2015, aim to renew in five markets and expand into three markets by 2018 Renewed in Canada, Germany, China and India and expanded into Kenya
  • Total reach in 2016 of 166,000 and 1.6 million youth since 2010
  • Proposals for expansion are in development for Brazil and Australia and for renewal in Portugal
  • Healthy Heart Africa Reach 10 million hypertensive patients across Sub-Saharan Africa by 2025 Since 2014, we have conducted over 2.7 million screenings and started treatment for over 100,000 hypertensive patients

SOURCE

https://www.astrazeneca.com/sustainability/access-to-healthcare.html

Click to access Access%20to%20healthcare.pdf

2.   Co-Development and Commercialization by Territory

AstraZeneca has paid $45 million and committed to up to $2.1 billion in milestones to team with Pieris Pharmaceuticals. The agreement sets Pieris up to move respiratory candidate PRS-060 into the clinic on AstraZeneca’s dime and pull in milestones as it and other pipeline prospects advance.

Tiny Pieris is due to receive the first, $12.5 million milestone when it moves moderate to severe asthma candidate PRS-060 into phase 1. AstraZeneca will fund clinical development of the interleukin-4 receptor alpha-targeting protein. If the asset reaches phase 2a, Pieris has the option to codevelop and commercialize it in the U.S., bumping up the royalties or gross margin share it receives in the process.

Pieris has a similar codevelopment option on other assets covered by the agreement. The biotech will develop four other proteins against undisclosed respiratory targets. If Pieris wants, it can sign up to codevelop and commercialize two of these programs in the U.S. Milestones and commercial payments across the deal could ultimately total $2.1 billion.

SOURCE

http://www.fiercebiotech.com/biotech/astrazeneca-pays-45m-commits-to-2b-to-team-pieris?utm_medium=nl&utm_source=internal&mrkid=993697&mkt_tok=eyJpIjoiT1RjMlpqWTFOakpsWVRVMyIsInQiOiI2dEgzSVFxWWZweDFiZ2JcL2EwbDk5MW1VcHJ6WnNNaGFmSEdLb2VnSTQ2QjRMUGpqcFFCQjM1dkVFT3dtNFMxaFZ4cXRhMTRQc0dxM28zVG5YM1FhM0hrQkhoS2ZDdWVickFGaWlOK2drRlwvdThzU1FcL05iY0FVSkNjXC9zMmNFSnkifQ%3D%3D

3.  Prescriptions Dispensed at Zero Patient Out-of-Pocket Cost Reached Thirty Percent in 2016

29.9% of prescriptions have been dispensed at zero patient out-of-pocket cost, including brands and generics, up 1.5% since 2015, all due to increased use of zero cost generics.
The total share of prescriptions where patients paid some amount less than $50 declined by 1.3% to 67.8% in 2016.
The proportion of claims with patient cost exposure greater than $50 increased also declined slightly from 2.5% to 2.3% in 2016.

Since 2013, Average Out-of-Pocket Costs for All Brand and Generic Prescriptions has Decreased by $1.19

Average patient out of pocket costs declined from $9.66 in 2013 to $8.47 in 2016, with 2016 brand costs declining to $28.31 from $32.36 in 2013 and generics dipping to $5.54 from a high of $6.05 in 2013.
The list prices of brands continue to be far higher than the average paid by patients, as few patients are exposed to those costs in their insurance plans.
The average list price for brands averaged 12 times higher than the average out of pocket cost for patients in 2016 compared to 3 times higher for generics.

SOURCE

http://www.imshealth.com/en/thought-leadership/quintilesims-institute/reports/medicines-use-and-spending-in-the-us-review-of-2016-outlook-to-2021#form
For Immediate Release Contact: Joan Fallon

May 2, 2017 joan_fallon@harvardpilgrim.org

617-509-7458

4.   Harvard Pilgrim Signs Second Groundbreaking Contract with Amgen For Repatha

HPHC and its members will receive full refund if a cardiac event occurs while on the drug

(WELLESLEY, MA) – Harvard Pilgrim Health Care has entered into a first-of-its-kind contract with Amgen for its LDL cholesterol lowering drug, Repatha, that guarantees the health plan and its members will receive a full refund of their costs for the drug if a member is hospitalized for a myocardial infarction or stroke after taking Repatha for six months or more and maintaining an appropriate level of compliance on the drug.

Repatha is one of a new class of biotechnology medicines known as PCSK9 inhibitors that have demonstrated a promising new approach for treating elevated LDL cholesterol in patients whose levels are not able to be controlled by current treatment options. The medication is designed to target a protein that prevents the body from removing artery-blocking LDL cholesterol from the bloodstream. Repatha works differently than statin drugs that prevent the liver from making cholesterol.

Given by injection every two or four weeks, Repatha is intended for patients who have an inherited disorder resulting in high levels of LDL cholesterol or have high-risk atherosclerotic cardiovascular disease conditions, such as heart attack or stroke, that have been resistant to treatment.

“Repatha has been shown to have a significant outcome on reducing cardiovascular morbidity for high risk individuals with elevated LDL cholesterol,” said Harvard Pilgrim Chief Medical Officer Michael Sherman. However, there have been concerns raised about the cost of this new drug relative to existing statin treatments. We hope to negotiate more contracts of this type, in which a pharmaceutical company truly has ‘skin in the game’ going forward. This agreement is the first we have signed in which there is a full refund of all costs related to the medication if the patient experiences a heart attack or stroke while taking it.”

“Cardiovascular disease is the largest public health concern in the world and for high-risk patients who have already had a cardiovascular event or whose genetics puts them at risk, it is important that these patients have access to an effective treatment shown to lower their

elevated LDL cholesterol in addition to their current lipid lowering regimen,” said Joshua J. Ofman, M.D., MSHS, senior vice president of Global Value, Access & Policy. “Amgen’s agreement with Harvard Pilgrim demonstrates our commitment to seeking innovative approaches that help break down the barriers of access to Repatha.”

This is the second patient-focused outcomes contract Harvard Pilgrim has negotiated with Amgen for Repatha. In the fall of 2015, the health plan signed an outcomes guarantee through which Amgen provided HPHC with an enhanced discount if the reduction in LDL levels for Harvard Pilgrim members is less than what was observed during Repatha’s clinical trials. In addition, the agreement provides for additional discounts if the utilization of the drug exceeds certain levels. This enables those patients who can most benefit from the drug to receive it while continuing to encourage utilization of lower cost statins for the majority of patients.

SOURCE

From: “Fallon, Joan” <joan_fallon@harvardpilgrim.org>

Date: Tuesday, May 2, 2017 at 1:09 PM

Subject: press release from Harvard Pilgrim Health Care

Read Full Post »


Highlights – LIVE Day 2: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017  BOSTON, MA • UNITED STATES

 

Leaders in Pharmaceutical Business Intelligence (LPBI) Group will cover the event in

REAL TIME

Aviva Lev-Ari, PhD, RN will be streaming live from the floor of the Westin Hotel in Boston on May 1-3, 2017

@pharma_BI

@AVIVA1950

#WMIF17

Forthcoming SEVEN e-Books in 2017 AND Eight e-Books on Amazon.com

https://pharmaceuticalintelligence.com/2016/04/24/new-e-book-titles-forthcoming-on-amazon-com-in-2016-from-lpbi-groups-biomed-e-series-forthcoming-cover-pages/

Biggest Voices in Cardiovascular Care

2017 World Medical Innovation Forum: Cardiovascular, May 1-3, 2017, Partners HealthCare, Boston, at the Westin Hotel, Boston

https://worldmedicalinnovation.org/agenda/

Tuesday, May 2, 2017

7:00 am – 8:00 am
Lilly Foyer
7:00 am – 7:45 am
Pfizer Ballroom
FOCUS SESSION: Japan Today: Advancing Cardiometabolic Therapies

Discussion on unique aspects of cardiometabolic market in Japan, its projected trend over the next 5 years and explore transformative models of open innovation to accelerate development of new therapeutic options.

  • Yoshiro Miwa Associate Chair and Founding Director, Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital
  • Head of Pharmaceuticals, Americas Region, Bayer
  • Director, Health & Welfare Department, JETRO New York
  • President, Japan Agency for Medical Research and Development
  • President, Head of Global Business Development, Mitsubishi Tanabe Pharma Holdings America, Inc.
  1. Complications of Toxin absorption and metabolic disease
  2. Collaboration with Academia: @ representatives are on two West Coast and 2 on the East Coast
  3. CVD and HTN related to aging is on the rise National Initiative to encourage change in Life Style
7:50 am – 8:00 am
Boston Scientific Ballroom
Opening Remarks
  • Chief Innovation Officer, Partners HealthCare
8:00 am – 8:50 am
Boston Scientific Ballroom
Pricing to Enable Affordability and Innovation

Balancing acceptable answers to high and escalating drug prices in the United States while making strides in medical innovation. Leaders in innovation, policy, care delivery, academia, and insurance discuss potential collaborative solutions.

 

Moderator: Peter Slavin, MD
  • President, Massachusetts General Hospital
  1. American Consumer of Healthcare pays more and it is not justifiable
  2. Pay for Value, pay for Outcomes
  • Physician-in-Chief, Department of Medicine, Massachusetts General Hospital
  • Jackson Professor of Clinical Medicine, Harvard Medical School
  1. Challenges understand PCP services and SPacialty medicine
  2. Adding fluids or taking it away is the majority of the decisions
  3. In cancer treatment 40% of prescriptions are not filled due to out of pocket cost increase
  4. In drugs Innovation are more expensive not less expensive
  5. Economists: Physicians are irrational
  6. Patient engagement, own health in their hands for compliance with treatment
  7. Assist MDs with the right data for their decision on what drugs to use
  8. Two key ways : Complications of Drugs, drive drug cost – Personalized medicine – improve outcomes on an Individual Patient basis
  9. How important is the question, affordable drugs is more important than anything in the delivery of care
  • CEO, Boehringer Ingelheim USA
  1. Many stakeholders are involved
  2. Pricing of Pharmaceutical in last 10 years, “List price” and the “Net Price” collected by Pharma has widen,
  3. high deductable plans are prevalent 40%-50% – out of pocket cost increased
  4. backlog of generic drugs – it takes 36 month to approve vs 12 month of non-generic
  5. Value-based pay, drug is only one enabler in MDs tool kit
  6. Out of pocket cost: Exposure is largest on the drug-side, that is preventive to avoid hospitalization
  7. Unfair pricing leading to not be active in certain markets, Price control outside the US, take position on Importation, not disrable to import drugs into the US, we do not wish drug shortage around the world, Canada is a Small market US is a huge market
  8. FDA on Oncology drug-device, potential exists for existing drugs
  9. Continue to do Clinical Trials in the US, claims orientations exacerbation, describe the benefit
  • EVP, Medical Devices, Abbott
  1. Who will pay and why?
  2. How we challenge development team to bring down cost of technology and plans showing cost savings in 12 month not few years down the road
  3. Selection of areas: ORTHO – hip replacement and Pain management
  4. Establish Global Pricing Models in USD, Premium, fair Price, desperative Prices is not good for the system
  • Director of Innovation, Cardiovascular Division, Senior Investigator, TIMI Study Group, Brigham and Women’s Hospital
  • Associate Professor of Medicine Harvard Medical School
  1. Cardiometabolic diseases  – drugs available to avoid events down the road
  2. new drugs at $20,000 cost per year vs Generic drugs – Economic responsibility in the Lipids area is long term
  3. MI many types bundling cost is more difficult that in Ortho
  4. Chronic disease, therapeutics, diagnostics, How to reduce cost? – Best utilization of drugs
  5. Durable response to drug, not enough data in hands of MDs
  6. Randomize Placibo and Randomize the drug, Placibo – requires better engagement
  7. After MI – 6 MEDS, compliance
  8. Clinical Trial very expensive, FDA requires PRAGMATIC TRIAL DESIGN, IDENTIFY DIFFERENT POPULATION FOR EXISTING DRUGS
  9. develop platform to test simple questions, in Cardiology
8:50 am – 9:40 am
Boston Scientific Ballroom
CLINICAL HIGHLIGHT: Emerging Devices for Complex Structural Heart Disease

Evolution of mitral disease management, current practice and impact of new technologies on both repair and replacement, implications of a heterogeneous patient population, triage, timing of intervention.

Moderator: Jason Mills
  • Managing Director, Head of US Healthcare Research, Canaccord Genuity
  1. What patient to target
  2. Heterogenous population – definitive data, how it is achieved
  • Divisional VP and General Manager, Structural Heart, Abbott
  1. Homogenous or heterogenous
  2. Standard of Care- restore normal function, patient outcomes more fragile as disease progresses
  3. Paradigm, measurable reduction of regurgitation
  4. Design of Clinical Trials: MR treatment around the World,
  5. MitralClip reduce MR reduction is not resolution
  6. 1000 publication on MitralClip – data gather indicate improvement in life quality
  7. TEE alone for use of MitralClip is nor enough, need to see to do the procedure
  • EVP, Global CMO, Boston Scientific
  1. State of the Art, Mitral regurgitation and degenerative Mitral valve: mechanism and elements responsible for regurgitation, repair of Annuals vs replacement of the valve.
  2. Options at different stage of the disease
  3. Functional Mitral Regurgitation: care pathways, compounding effects, two little too late
  4. AF can cause Valve dilatation and regurgitation
  5. Treatment, patient less symptomatic
  6. HTN cause of LV systolic disfunction – treated first – improve the Mitral regurgitation
  7. Mechanism under pinning in the decision process, CLinical Trials – Device may not work for all patients in the Study
  8. leaflet condition dealt in repair strategy vs device selection
  9. Having devices focus the clinical pathways for therapeutic options, TAILORING OF DEVICES TO SPECIFIC STRUCTURAL CONDITION OF THE HEART
  • Watkins Family Distinguished Chair in Cardiology, Brigham and Women’s Hospital
  • Professor of Medicine, Harvard Medical School
  1. Structural Heart disease: Hole in Heart,
  2. 5 1/2 years approved for TARV
  3. TAVR will exceed Open Heart Surgery next year
  4. Mitral valve growth is in  >75 y-o more cases than Aorta
  5. Aorta Valve – seen on Echogram stenosis seen
  6. Mitral Valve – concert of several elements, very complicated, Coordination among: Device, FDA, CMS, MDs, Hospitals
  7. DO  doctors wait to long to intervene: Moderate to severe: Foundational approach Ventricular dysfunction, late stage not continue to progress.
  8. MI
  9. drivers of cords,
  10. identify Patient – can be improved by PCPs, NPs, PAs, assess severity, Center for evaluate consensus on timing the intervention
  11. relay on the Cardiologist in the Community – context: Not all MR needs surgery
  12. Functional Mitral Regurgitation, poor LV function, the valve intervention will not improve longevity may improve quality of life for two years
  13. 20% survival after MI in LV dysfunction post MI then Mitral valve intervention will not improve longevity
  14. For older pation with Functional MR and moderate LV dysfunction – trial design on utility of the intervention.
  15. More patients will be included for treatment as recognition of the disease matures
  16. WHO should do that procedue : Interventional Cardiologist or Cardiac SUrgeons: HARD procedure NOT fixing Coronary artery
  17. Set up regional centers of Care links to maintain quality and PATIENT MUST DO BETTER
  18. 200 centers in the US do MitralClip procedure
  19. Procedure expensive BEYOND THE DEVICE cost

 

  • CVP, Advanced Technology, CSO, Edwards Lifesciences
  1. 60,000 procedures in the US vs. 2.4 million patients with the MR condition
  2. Percutanious is an opportunity not to damage the heart, challenge, how to attach  to the heart and how much regorgitation to get clinical benefit, optimal benefit to patient: Multiple products are in development
  3. Aortic stenosis: we learned which patient will benefit, clinical studies, cost effective, two companies validated the approach
  4. Mitral Valve is in early stage Trans catheter is the direction
  5. PATIENT ACCESS – who will benefit
  6. devices will Improve Patient conditions
  • SVP and President, Coronary & Structural Heart, Medtronic
  1. MR at medtronic: degenerative disease, repair the valve, average surgeon does 6 procedures a year,
  2. Toolbar approach, how to do it safely no complication repeatable to know the reduction level
  3. population exists to do the development early in the stage of MR
9:40 am – 10:10 am
Boston Scientific Ballroom
1:1 Fireside Chat: John Lechleiter, PhD, Chairman, Eli Lilly
Moderator: Susan Dentzer
  • CEO, Network for Excellence in Health Innovation
  • Chairman, Eli Lilly and Company
  1. Two approaches to Beta Ameloid – fail to meet Endpoint: Mild patient Solismad 24% improvement vs placibo
  2. Dementia not AD – mild to moderate patients, only.
  3. Move faster is desiable, turnaround time need be faster
  4. Would do over again, tap best minds in the World,
10:10 am – 10:25 am
Lilly Foyer
10:25 am – 11:15 am
Boston Scientific Ballroom
Personal Monitoring for Disease Management

Considering the evolving trends in viability and utilization and the opportunities wearables may present for real-world clinical decision making.

 

Moderator: Joe Kvedar, MD
  • VP, Connected Health, Partners HealthCare
  • Associate Professor of Dermatology, Harvard Medical School
  1. Evidence on monitoring Patients while @Home, pros and cons
  2. 2016, review evidence, recommendation for monitoring Patients while @Home
  3. Continuing care and continuing data collection
  4. Hospital administrator need a path to have more patients coming to the hospital
  5. Implement technology for quality care, access and lower cost
  • CIO, VP, Brigham and Women’s Hospital
  • Course Co-Director, Harvard Medical School
  1. CHF, HF, – recognize that Technology alone is not enough
  2. People and Technology intervention targeting
  3. Academic medical centers – monitoring Patients while @Home is a mechanism to deliver care
  • COO, Siemens Healthineers
  1. Outcome-based evidence – innovation exited 15 years ago
  2. at Present time the market is accepting
  3. Medical Systems do not have enough capacity – shortage of MDs
  4. Monitoring Patients while @Home is to free time of MDs in the Office
  • CEO, Zoll Medical
  1. Outcome-based research on a wearable cardio-devibrilator, Arrhythmic death protection
  2. Policy: talk about reimbursement
  3. Patient data collected, histories of ECG before cardiac arrest
  4. what diagnostics to be used with this data: do not drive, do not be alone at home
  • CSO, One Brave Idea, Brigham and Women’s Hospital
  • Associate Dean for Executive Education, Harvard Medical School
  1. Evidence and publishing results, MDs and Patient’s perspective on Autonomy vs monitoring Patients while @Home
  2. DIgital Health Comapny vs Academic Study on monitoring Patients while @Home – Wearable Patch surpass wearing a holter
  3. External wearable now acceptable and clinical evidence will convince all stakeholders
  4. Realization by physicians that monitoring Patients while @Home is a TIME SAVER in their practice will endore the technology at a rapid pace
  5. Published studies: Sharing genetic information with Academic Centers: Verily, AstraZeneca and AHA partnership
  6. Information in the Periphery but adopted in the center of Unifies healthcare eco system not in Silos anymore
11:15 am – 11:45 am
Boston Scientific Ballroom
1:1 Fireside Chat: Robert Bradway, CEO, Amgen
Moderator: Scott Sperling
  • Co-President, Thomas H. Lee Partners
  1. Amgen –>>> Biotech to Pharma
  • CEO, Amgen
  1. Six areas: CVD, Cancer, Inflammation,
  2. CVD opportunities: Science and commercial – Heart disease, tools of Human genetics for drug development in CVD: REPATA a molecule targeting PCSK9 – variant on gene associated with LDL Pathways – genetic clue
  3. Innovation in Human genetics new sequencing technologies allowed to see disease in Human populations, disease and pathways
  4. Aging associated with risks of CVD, How we pay for innovative therapies?
  5. Benefit from innovation – 800,000 in US have a stroke every year $60 Billion treatment for patient of CVD
  6. Value of innovation at a price that allows access and lowering cost of care
  7. Cardiologist prescribed the medication for himself it took 6 month for insurance to approve
  8. Utilization management – move to innovative technologies if current therapies do not work
  9. Pay for benefit and for outcome, no pay if med does not do what it was supposed to do – refund patients
  10. focus on right patient get access. if LDL is so high – the therapy is there – the payers, enable access
  11. Access challenge: Discount, Rebates, Co-pay assistance to access therapy as REPATA at $5 a day value is high,
  12. A single payer is the Government in other countries
  13. Future at Amgen: Potential for Innovation to improve Medicine, paying for innovation needs to be strainten
  14. Coming drug is Pharmcogenetics for atherosclerosis
12:00 pm
GE Ballroom
12:15 pm – 12:30 pm
GE Ballroom
Austen-Braunwald Award

Awarded to one BWH and one MGH First Look participant who embodies the innovative, entrepreneurial, and visionary spirit of cardiovascular legends W. Gerald Austen, MD and Eugene Braunwald, MD. Granted based on select criteria, including overall presentation quality, innovativeness, commercial potential, caliber of disruption, and market need.

  • Ben Olenchock, BWH
  • Steven Lubitz, MGH
12:30 pm – 1:00 pm
GE Ballroom
1:1 Fireside Chat: Frans van Houten, CEO, Philips
Moderator: Gregg Meyer, MD
  • CCO, Partners HealthCare
  1. Why Healthcare?
  2. How your approach to innovation enable to move fast?
  3. Develop technologies that are more affordable
  4. Data, Insight, How to get insight from data about a deterioration
  • CEO, Philips
  1. A 125 year company, shade lighting business to focus of Healthcare, global challenge a goal in Humanity for solution, services, products
  2. R&D diagnostics, Informatics to integrate data
  3. Africa and India – emerging markets with infant mortality high — develop a clinic as franchise for every price point
  4. shift from Products to Cloud-based solutions – Prevention, Diagnostics, @Home care: Neuro, Cancer, CVD
  5. Academic Institutions: Karlinska in Sweden – Stroke solution in partnership with Philips
  6. Affordability, maximum of the technology, partnership with Industry consultants, does not work everywhere, took in house the Services part and developed algorithms to assist MDs in interpretation of radiological data
  7. Patient monitoring 24×7 in ICUs,
  8. eICU – measure evolution to forcast 6 hours in advance a deterioration – highest performance, reduction 40% of death by insight from data
  9. Complex diseases created enormous data,
  10. Measuring progression of AM – AI algorithms for a digital platform
  11. Data integration, oncology patients: Genomics, Pathology, Clinical Data Scientist,
  12. R&D will be co-creation with clinical validation and publication for Market adoption
  13. Head of Radiology across several Hospitals – Better Outcomes Operations improvement due to technology
  14. Rural Africa market connected to a Hospital in a city — working on that teleconference
  15. UAE – crowdsource for nearest AED – locate incidence like UBER for CVD
  16. AI in Pathology – genomics and patient targeting – Lab in Cambridge, Big Data
1:00 pm – 1:10 pm
1:10 pm – 2:00 pm
Boston Scientific Ballroom
Global Clinical Trials: Next Generation Design and Scalability

Cardiovascular trials currently account for 10 percent of all clinical trial participants. Discussion on design and implementation of clinical studies globally, considering strategies for patient access, regulatory implications, cost containment and management of relationships with global service providers.

 

  • Chairman, TIMI Study Group, Lewis Dexter, MD Distinguished Chair in Cardiovascular Medicine, Brigham and Women’s Hospital
  1. Bar is very high, events went down, that necessitates very large studies 30,000 patients, 12 sites around the globe, acquisition of data
  2. Outcomes, where is Pharma in development of a compound
  3. Other indications that LIPIDS
  4. surrogate outcomes
  5. Diabetes: requirements mutual effect on CVD, benefit of DM drugs for CVD OutcomesGathering data on approved drugs, looking at different doses
  6. A model for dosing compounds per each patient
  7. Benefit or harm different in the US and in other sites
  8. genetics, how it inform in drug development, validation to pan out
  9. Real World evidence in 21 Affordable Act – randomize
  10. multivariable adjustment on how many variable affect the Power of the study
  • VP, Cardiovascular & Metabolic Disease Head, Global Medicines Development, AstraZeneca
  1. Patient population,
  2. new medicine vs existing registries
  3. Real World evidence include observational dat after the drug is on the market
  4. Randomization – identify population, register, randomize, collect
  • SVP, Global Clinical Research, Therapeutic Area Head, Cardiometabolic & Womens Health, MRL Lead, China R&D, Merck
  1. data from medical record
  2. investigational drugs more difficult
  • VP Cardiovascular Medicine, Covance
  1. Productive sites, approaches: Russia, Russia-Georgia, dishonest recruitment, combine resources to find sites
  2. 50% of blood analysis at sites that do not recruit at all
  3. Internal vs External validity: Early on in drug development, protocol deviation, drug MOA, variability off set by study power
  4. Patient reporting outcomes
  • Director, Division of Cardiovascular and Renal Products, Food and Drug Administration
  1. Surrogates: likely outcome endpoint for decision,
  2. CVD is difficult, graveyard of program that failed, inotropic drugs were stopped
  3. Global trial, most expensive to do in the US – in the US the care given need be comparable to the care in the US
  4. Requirement that the results will be relevant to type of care in the US
  5. Preserve randomization is key
  • VP, Cardiovascular Medicine,  Global Development, Amgen
  1. What is the hypothesis for testing, population match, understand the molecule for the modality
  2. Decode, benefits and risks – phynotype
  3. aggregation of data with investigational therapies,
  4. AI will become part of Clinical Trial
2:00 pm – 2:50 pm
Boston Scientific Ballroom
Precision Cardiovascular Medicine: What is Different This Time

Explore how precision medicine is changing the face of cardiovascular medicine specifically. The session will examine the impact of combined phenotypic and genotypic characterization on optimizing response to therapeutics, trial design, improving outcomes, and redefining reimbursement.

  • EVP, R&D, Amgen
  1. Outcomes for RAPATA – a pharmacogenomic drug
  2. Precision medicine in CVD – optimistic
  3. CVD – phynotype more determinative then genotyping vs Oncology, complex traits
  4. Bippharma moves away from big public health diseases, trials are expensive, FDA harch requirements
  5. Investors:to Biotech – works on Oncology and on Orphan drugs
  6. Methodology for targeting by using genetics are more precise
  7. In Phase III a drug where biology is very well understood
  • VP, Head Translational Medicine Merck
  1. CVD in Merck – rearrange resources in South SF on
  2. Arrhythmia: Mutation if down played causes Arrhythmia if Overexpressed causes Arrhythmia – caution in terapeutics tatgets – gene indication not to develop therapy
  3. Diastolic HF – make a drug, pick up one signaling cascade and show efficacy not in all pathways
  4. Populations that are resilient in diseases as HF
  • Assistant in Medicine, Massachusetts General Hospital
  • Assistant Professor, Harvard Medical School
  1. AF model in Translational medicine, metabolites
  2. moderately optimistic
  3. molecular phynotyping
  • Director, Cardiovascular Genetics Center, Brigham and Women’s Hospital
  • Thomas W. Smith Professor of Medicine and Genetics, Harvard Medical School
  1. Genetic in CVD – Cardiomyopathy and genetics
  2. target molecule for therapy of genetic
  3. gene mutation variants are different the genes are the same
  4. LDL receptor led to development of Statins
  5. PCSK9 was developed from genetic observation on familial
  6. protein profiles very important
  7. Genotype more informative than phynotypes
  8. Genetic tools to direct drug discovery

Kevin Hrusovsky, Quanterix

  • Biomarkers at the bedside
  • Protein of inflammation in DM – phynotype, genotype – stratify population of patients for targeting therapeutics
  • 6 inhibitions, role of protein, multiple cytokines involved
  • Head injury – diagnostics must be very quick
  • Insurance will require prevention emphasis
  • Early diagnosis is facilitated by genokmics

 

2:50 pm – 3:40 pm
Boston Scientific Ballroom
CV Investing in the Next Decade

View on investing landscape, opportunities in the CV/metabolic marketplace, the drugs, devices and diagnostics currently in pipelines and notable positive trends.

Moderator: Meg Tirrell
  • Reporter, CNBC
  1. M&A landscape
  • Managing Director, Healthcare, GE Ventures
  1. Advanced diagnostics
  2. value-based care
  3. no investment in drugs
  4. Insurance are into the Game of Data Analytics – fast adoption to become standard of care
  5. Reimbursement:  Tech investors and Healthcare investors with having in mind FDA approval process
  6. Mobile health cool: eye disease, DM, skin care ECG, few specialists in China, mobile tools
  7. Interoperability in Digital Health
  • Partner, Atlas Venture
  1. Only investment in drug discovery
  2. Segment genotypes – pure innovations as differentiators
  3. Patient Analytics, Physician-Patient SW development applications – scale broad audience – value add
  4. Focus on Medical Professions tool development for this sector
  5. Learning curve for novel productivity tools Cardiac MR – Imaging Analytics – Precision medicine not in drugs but in imaging
  6. M&A – activity 4 years time horizon, new biology new modality – risk is higher
  7. First in Class
  8. Translational Research and Drug discovery are two different beasts, doing drug development inside a basic research organization
  9. Coolest technology: CRISPR – one injection reduction in a genetic disease
  • Managing Director, US Medical Technology, Equity Research, Bank of America Merrill Lynch
  1. Medtech, CVD is exciting , i.e., Valve area, ICD, Stents, Stroke, AF,
  2. Medical devices – exciting
  3. No clear leader in Mitral Valve repair and Replacement by 2019 – approved products in Europe: Abbott, Medtronic (12), Edwards
  4. Value in the market exists for investors
  5. coolest technology: Stroke – stents in the barin
  • VP, Venture, Partners HealthCare
  1. 165million fund: Drugs, devices, diagnostics – ONLY from Partner COMMUNITY developed IP
  2. Orphan CVD driven by genomics
  3. Stratify the patients to show effects
  4. Exit for medical devices is longer than drugs with innovative business models
  5. Wearables are medical devices
  6. Data will be huge and valuable
  7. Skill set needed for Drug discovery and Academic science — DOES work well in one place
  8. Editas – Academic Center: Innovations everywhere
  • Managing General Partner, Frazier Healthcare Partners
  1. Drug development investment in early stage and in late stage
  2. Focus opportunities
  3. 3 to 5 years time horizon
  4. $50 – $60million investment range
  5. FDA – is central to HC investment
  6. FDA – changed regulation to enable antibiotics development
  7. FDA in Oncology – risk reward equation – FDA played great role in drug development
  8. Leukemia, non-Hodkin Limphoma
3:40 pm – 4:30 pm
Boston Scientific Ballroom
CLINICAL HIGHLIGHT: Optimizing Care for the 51%: New Market Opportunities

Introduction: Cathy Minehan, Chair, MGH Corporation

Address implications of gender as a key biological factor for personalized medicine. Stroke is likely to be the first cardiovascular event, tied to AF and secondarily to hypertension. Opportunities for medication utilization and optimization in context of, manifestation of disease and understanding the biology, complications, strategies to collect relevant clinical evidence, and treatment response.

 Nancy Brown,
  • CEO, AHA
  1. Biology or bias
  • Director, Center for Arrhythmia Prevention, Brigham and Women’s Hospital
  • Professor of Medicine, Harvard Medical School
  1. Focus on Women
  2. Diagnostics requires women – large trials and power studies by gender
  3. CRT,
  4. Optimizing care for Women
  5. EF, CHF, MI are prevalent in Women
  6. Migraine in Women – related to CVD
  • EVP & Head, Global Commercial Development, Mylan
  1. Information on differences between women and men – Cholesterol
  2. Woman present with different symptoms – more progress because care is delayed
  3. Stable angina and zero plaque cardiac rehab
  4. Female specific guidelines
  5. wholistic approach, girl scouts as a start
  • CV Therapeutic Area Lead, Global Business Development, Pfizer
  1. Number of women in trials? 25% – how to extrapulate from this data?
  2. How to design trials, powering, endpoints, clinical trials, FDA – mandates reporting of Women representation in studies
  3. Data Gap – retrospective study – 30% women, guidelines based on 70% Men data
  4. Awareness – who is the PCP to close the Gap
  5. OBGYN is often the PCP, the only Annual a Women goes to
  6. Precision medicine in Women, what is actionable what is not
  7. Harness Phynotypic leverage repository
  • Medical Director, Boston Scientific
  1. Women vs Minority Women – Improvement will occur if tools and strategies will represent all demographic
  2. Accurate measurements, Women participation in trials, Latinos, Minority Women – not as % in the population
  3. best practices and guidelines
  4. Awareness, nosea and fatigue as symptoms,
  • Co-Director, MGH Heart Center Corrigan Women’s Heart Health Program, Massachusetts General Hospital
  • Associate Professor, Harvard Medical School
  1. Heart attacks in Women and prevention, awareness among women
  2. Impact of Pregnancy: Preeclemxia, HTN, DM, hematologic disease, small gestation newborn, Minority Pregnant women – diet
  3. 30% less referred for Aortic stenosis or transplantation
  4. Care for Patient vs Episodic Care
  5. Stress in Women – metric to measure in PCP
  6. AI to be used in referral based on Medical data
  7. Migrane – several medications need to be studied on Women with the disease
4:30 pm – 5:20 pm
Boston Scientific Ballroom
Disruptive Therapeutic Platforms: New Tools, New Outcomes

Recent advances of biological drugs have broadened the scope of therapeutic targets for a variety of human diseases. This holds true for dozens of RNA-based therapeutics currently under clinical investigation for diseases including heart failure. These emerging drugs could be considered in context of genomic/germ line screening, family history and epigenetics.

Moderator: Tony Coles, MD
  • CEO, Yumanity Therapeutics
  1. one of three death in the World
  2. Limb Ischemia
  • CEO, Moderna
  1. mRNA, clinical stage, published Human data Immuno oncology, VGEF therapeutics after MI
  2. Recombinant VGEF, PK goes to the heart mascle if goes to serum is degraded by nucleatase
  3. Post MI in pigs, Phase I, Phase II
  4. Chronic response formulation short half life (6 days)
  5. Step by step, get the right protein
  6. Cardiology – mRNA drug for one patient
  • CEO, Editas Medicine
  1. CRISPR technology – translational medicine changes in DNA
  2. viral vector therapy delivery: Eye liver, blood — easier for delivery
  3. Immune response from delivery of CRISPR molecule: control over the time response of the molecule: Immunogenicity
  4. Using biology knowledge
  • Center for Cancer Immunology, Massachusetts General Hospital
  • Member of the Faculty of Medicine, Harvard Medical School
  1. Cancer Immune response plays a role
  2. CVD and the Immune System: Transfer from Oncology to CVD: Mutations on genes mutations are not silent to the immune systems — development of Vaccine
  3. Oncologists  in lung cancer saw immune response against their own tumors
  4. macrophage in the heart
  • CEO, Alnylam
  1. CVD Program – Phase III
  2. PCSK9 – as a target genetically defined mutation, Hyper-cholesteronemia – subcutaneous delivery – Lowering LDL by bi-annual injection or quarterly – non-complaint with Statin
  3. ADVANCED medicine for CVD
  • Founder, AnGes
  1. Gene therapy – pipeline of 8  –
  2. DNA Vaccine for HTN
  3. Muscular therapy – Ischemia
  4. CVD – Reduction comorbidity and mortality
5:20 pm – 6:00 pm
Novartis Foyer

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Regulatory MicroRNAs in Aberrant Cholesterol Transport and Metabolism

Curator: Marzan Khan, B.Sc

Aberrant levels of lipids and cholesterol accumulation in the body lead to cardiometabolic disorders such as atherosclerosis, one of the leading causes of death in the Western World(1). The physical manifestation of this condition is the build-up of plaque along the arterial endothelium causing the arteries to constrict and resist a smooth blood flow(2). This obstructive deposition of plaque is merely the initiation of atherosclerosis and is enriched in LDL cholesterol (LDL-C) as well foam cells which are macrophages carrying an overload of toxic, oxidized LDL(2). As the condition progresses, the plaque further obstructs blood flow and creates blood clots, ultimately leading to myocardial infarction, stroke and other cardiovascular diseases(2). Therefore, LDL is referred to as “the bad cholesterol”(2).

Until now, statins are most widely prescribed as lipid-lowering drugs that inhibit the enzyme 3-hydroxy-3methylgutaryl-CoA reductase (HMGCR), the rate-limiting step in de-novo cholesterol biogenesis (1). But some people cannot continue with the medication due to it’s harmful side-effects(1). With the need to develop newer therapeutics to combat cardiovascular diseases, Harvard University researchers at Massachusetts General Hospital discovered 4 microRNAs that control cholesterol, triglyceride, and glucose homeostasis(3)

MicroRNAs are non-coding, regulatory elements approximately 22 nucleotides long, with the ability to control post-transcriptional expression of genes(3). The liver is the center for carbohydrate and lipid metabolism. Stringent regulation of endogenous LDL-receptor (LDL-R) pathway in the liver is crucial to maintain a minimal concentration of LDL particles in blood(3). A mechanism whereby peripheral tissues and macrophages can get rid of their excess LDL is mediated by ATP-binding cassette, subfamily A, member 1 (ABCA1)(3). ABCA1 consumes nascent HDL particles- dubbed as the “good cholesterol” which travel back to the liver for its contents of triglycerides and cholesterol to be excreted(3).

Genome-wide association studies (GWASs) meta-analysis carried out by the researchers disclosed 4 microRNAs –(miR-128-1, miR-148a, miR-130b, and miR-301b) to lie close to single-nucleotide polymorphisms (SNPs) associated with abnormal metabolism and transport of lipids and cholesterol(3) Experimental analyses carried out on relevant cell types such as the liver and macrophages have proven that these microRNAs bind to the 3’ UTRs of both LDL-R and ABCA1 transporters, and silence their activity. Overexpression of miR-128-1 and miR148a in mice models caused circulating HDL-C to drop. Corroborating the theory under investigation further, their inhibition led to an increased clearance of LDL from the blood and a greater accumulation in the liver(3).

That the antisense inhibition of miRNA-128-1 increased insulin signaling in mice, propels us to hypothesize that abnormal expression of miR-128-1 might cause insulin resistance in metabolic syndrome, and defective insulin signaling in hepatic steatosis and dyslipidemia(3)

Further examination of miR-148 established that Liver-X-Receptor (LXR) activation of the Sterol regulatory element-binding protein 1c (SREBP1c), the transcription factor responsible for controlling  fatty acid production and glucose metabolism, also mediates the expression of miR-148a(4,5) That the promoter region of miR-148 contained binding sites for SREBP1c was shown by chromatin immunoprecipitation combined with massively parallel sequencing (ChIP-seq)(4). More specifically, SREBP1c attaches to the E-box2, E-box3 and E-box4 elements on miR-148-1a promoter sites to control its expression(4).

Earlier, the same researchers- Andres Naars and his team had found another microRNA called miR-33 to block HDL generation, and this blockage to reverse upon antisense targeting of miR-33(6).

These experimental data substantiate the theory of miRNAs being important regulators of lipoprotein receptors and transporter proteins as well as underscore the importance of employing antisense technologies to reverse their gene-silencing effects on LDL-R and ABCA1(4). Such a therapeutic approach, that will consequently lower LDL-C and promote HDL-C seems to be a promising strategy to treat atherosclerosis and other cardiovascular diseases(4).

References:

1.Goedeke L1,Wagschal A2,Fernández-Hernando C3, Näär AM4. miRNA regulation of LDL-cholesterol metabolism. Biochim Biophys Acta. 2016 Dec;1861(12 Pt B):. Biochim Biophys Acta. 2016 Dec;1861(12 Pt B):2047-2052

https://www.ncbi.nlm.nih.gov/pubmed/26968099

2.MedicalNewsToday. Joseph Nordgvist. Atherosclerosis:Causes, Symptoms and Treatments. 13.08.2015

http://www.medicalnewstoday.com/articles/247837.php

3.Wagschal A1,2, Najafi-Shoushtari SH1,2, Wang L1,2, Goedeke L3, Sinha S4, deLemos AS5, Black JC1,6, Ramírez CM3, Li Y7, Tewhey R8,9, Hatoum I10, Shah N11, Lu Y11, Kristo F1, Psychogios N4, Vrbanac V12, Lu YC13, Hla T13, de Cabo R14, Tsang JS11, Schadt E15, Sabeti PC8,9, Kathiresan S4,6,8,16, Cohen DE7, Whetstine J1,6, Chung RT5,6, Fernández-Hernando C3, Kaplan LM6,10, Bernards A1,6,16, Gerszten RE4,6, Näär AM1,2. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. . Nat Med.2015 Nov;21(11):1290

https://www.ncbi.nlm.nih.gov/pubmed/26501192

4.Goedeke L1,2,3,4, Rotllan N1,2, Canfrán-Duque A1,2, Aranda JF1,2,3, Ramírez CM1,2, Araldi E1,2,3,4, Lin CS3,4, Anderson NN5,6, Wagschal A7,8, de Cabo R9, Horton JD5,6, Lasunción MA10,11, Näär AM7,8, Suárez Y1,2,3,4, Fernández-Hernando C1,2,3,4. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med. 2015 Nov;21(11):1280-9.

https://www.ncbi.nlm.nih.gov/pubmed/26437365

5.Eberlé D1, Hegarty B, Bossard P, Ferré P, Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 2004 Nov;86(11):839-48.

https://www.ncbi.nlm.nih.gov/pubmed/15589694

6.Harvard Medical School. News. MicoRNAs and Metabolism.

https://hms.harvard.edu/news/micrornas-and-metabolism

7. MGH – Four microRNAs identified as playing key roles in cholesterol, lipid metabolism

http://www.massgeneral.org/about/pressrelease.aspx?id=1862

 

Other related articles published in this Open Access Online Scientific Journal include the following:

 

  • Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics,

on Amazon since 11/29/2015

http://www.amazon.com/dp/B018PNHJ84

 

HDL oxidation in type 2 diabetic patients

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2015/11/27/hdl-oxidation-in-type-2-diabetic-patients/

 

HDL-C: Target of Therapy – Steven E. Nissen, MD, MACC, Cleveland Clinic vs Peter Libby, MD, BWH

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/11/07/hdl-c-target-of-therapy-steven-e-nissen-md-macc-cleveland-clinic-vs-peter-libby-md-bwh/

 

High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/

 

Risk of Major Cardiovascular Events by LDL-Cholesterol Level (mg/dL): Among those treated with high-dose statin therapy, more than 40% of patients failed to achieve an LDL-cholesterol target of less than 70 mg/dL.

Reporter: Aviva Lev-Ari, PhD., RN

https://pharmaceuticalintelligence.com/2014/07/29/risk-of-major-cardiovascular-events-by-ldl-cholesterol-level-mgdl-among-those-treated-with-high-dose-statin-therapy-more-than-40-of-patients-failed-to-achieve-an-ldl-cholesterol-target-of-less-th/

 

LDL, HDL, TG, ApoA1 and ApoB: Genetic Loci Associated With Plasma Concentration of these Biomarkers – A Genome-Wide Analysis With Replication

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/18/ldl-hdl-tg-apoa1-and-apob-genetic-loci-associated-with-plasma-concentration-of-these-biomarkers-a-genome-wide-analysis-with-replication/

 

Two Mutations, in the PCSK9 Gene: Eliminates a Protein involved in Controlling LDL Cholesterol

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/15/two-mutations-in-a-pcsk9-gene-eliminates-a-protein-involve-in-controlling-ldl-cholesterol/

Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/15/artherogenesis-predictor-of-cvd-the-smaller-and-denser-ldl-particles/

 

A Concise Review of Cardiovascular Biomarkers of Hypertension

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/04/25/a-concise-review-of-cardiovascular-biomarkers-of-hypertension/

 

Triglycerides: Is it a Risk Factor or a Risk Marker for Atherosclerosis and Cardiovascular Disease ? The Impact of Genetic Mutations on (ANGPTL4) Gene, encoder of (angiopoietin-like 4) Protein, inhibitor of Lipoprotein Lipase

Reporters, Curators and Authors: Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/03/13/triglycerides-is-it-a-risk-factor-or-a-risk-marker-for-atherosclerosis-and-cardiovascular-disease-the-impact-of-genetic-mutations-on-angptl4-gene-encoder-of-angiopoietin-like-4-protein-that-in/

 

Excess Eating, Overweight, and Diabetic

Larry H Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2015/11/15/excess-eating-overweight-and-diabetic/

 

Obesity Issues

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2015/11/12/obesity-issues/

 

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