FDA Approves Leqvio (inclisiran), First-in-Class siRNA to Reduce Low-Density Lipoprotein Cholesterol (LDL-C)

                       In continuation of my update on inclisiran

                             Novartis today announced the US Food and Drug Administration (FDA) approval of Leqvio® (inclisiran), the first and only small interfering RNA (siRNA) therapy to lower low-density lipoprotein cholesterol (also known as bad cholesterol or LDL-C) with two doses a year, after an initial dose and one at three months.

"Leqvio is a revolutionary approach to lower LDL-C, and creates new possibilities for how  healthcare systems can impact cardiovascular disease, a defining public health challenge of our time," said Vas Narasimhan, Novartis CEO. "We now have the opportunity, working together with partners, to provide this first-ever approved LDL-C–lowering siRNA-based therapy to tackle ASCVD at scale across the United States."

Leqvio is indicated in the United States as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with clinical atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) who require additional lowering of LDL-C. The effect of Leqvio on cardiovascular morbidity and mortality is being explored in clinical trials currently underway.

"ASCVD is a substantial public health burden affecting 30 million Americans," said Norman Lepor, MD, a Los Angeles based cardiologist and a clinical investigator in the Phase III clinical program for Leqvio. "As a first-of-its-kind siRNA therapy, Leqvio works differently than other cholesterol treatments, with twice-yearly dosing that makes it a compelling option for the millions of people with ASCVD already on cholesterol-lowering medications struggling to reach their LDL-C target."

Leqvio reduces the amount of LDL-C in the bloodstream by improving the liver's natural ability to prevent the production of a protein that plays a role in keeping circulating cholesterol levels high6,7. It is a subcutaneous injection given by a healthcare provider with an initial dose, then again at three months, and then every six months1. This approach may help those who have trouble sticking to medicines that are self-administered and have greater dosing frequency. Leqvio will be available in early January 2022.

"People with ASCVD have most likely experienced a heart attack or stroke from high cholesterol, causing a burden on the family and having a negative impact on lives," said Andrea Baer, Executive Director of The Mended Hearts, Inc. "One of the first steps to improving patients' health is to manage high cholesterol and we're encouraged that this new twice-a-year treatment offers a new option." 

The FDA approval was based on results from the comprehensive Phase III ORION-9, -10 and -11 clinical trials, in which all 3,457 participants with ASCVD or HeFH had elevated LDL-C while receiving a maximally tolerated dose of statin therapy2,3. In the Phase III trials at month 17, Leqvio delivered effective and sustained LDL-C reduction of up to 52% vs. placebo and was reported to be well-tolerated with a safety profile shown to be comparable to placebo2,3. The most common side effects were mild to moderate injection site reaction (including pain, redness and rash), joint pain, urinary tract infection, diarrhea, chest cold, pain in legs or arms and shortness of breath2,3.

Novartis has obtained global rights to develop, manufacture and commercialize Leqvio under a license and collaboration agreement with Alnylam Pharmaceuticals, a leader in RNAi therapeutics.

https://en.wikipedia.org/wiki/Inclisiran

FDA Approves Leqvio (inclisiran), First-in-Class siRNA to Reduce Low-Density Lipoprotein Cholesterol (LDL-C)

Novartis  announced the US Food and Drug Administration (FDA) approval of Leqvio® (inclisiran), the first and only small interfering RNA (siRNA) therapy to lower low-density lipoprotein cholesterol (also known as bad cholesterol or LDL-C) with two doses a year, after an initial dose and one at three months.

"Leqvio is a revolutionary approach to lower LDL-C, and creates new possibilities for how healthcare systems can impact cardiovascular disease, a defining public health challenge of our time," said Vas Narasimhan, Novartis CEO. "We now have the opportunity, working together with partners, to provide this first-ever approved LDL-C–lowering siRNA-based therapy to tackle ASCVD at scale across the United States."

Leqvio is indicated in the United States as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with clinical atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) who require additional lowering of LDL-C. The effect of Leqvio on cardiovascular morbidity and mortality is being explored in clinical trials currently underway.

"ASCVD is a substantial public health burden affecting 30 million Americans," said Norman Lepor, MD, a Los Angeles based cardiologist and a clinical investigator in the Phase III clinical program for Leqvio. "As a first-of-its-kind siRNA therapy, Leqvio works differently than other cholesterol treatments, with twice-yearly dosing that makes it a compelling option for the millions of people with ASCVD already on cholesterol-lowering medications struggling to reach their LDL-C target."

Leqvio reduces the amount of LDL-C in the bloodstream by improving the liver's natural ability to prevent the production of a protein that plays a role in keeping circulating cholesterol levels high6,7. It is a subcutaneous injection given by a healthcare provider with an initial dose, then again at three months, and then every six months1. This approach may help those who have trouble sticking to medicines that are self-administered and have greater dosing frequency. Leqvio will be available in early January 2022.

"People with ASCVD have most likely experienced a heart attack or stroke from high cholesterol, causing a burden on the family and having a negative impact on lives," said Andrea Baer, Executive Director of The Mended Hearts, Inc. "One of the first steps to improving patients' health is to manage high cholesterol and we're encouraged that this new twice-a-year treatment offers a new option." 

The FDA approval was based on results from the comprehensive Phase III ORION-9, -10 and -11 clinical trials, in which all 3,457 participants with ASCVD or HeFH had elevated LDL-C while receiving a maximally tolerated dose of statin therapy2,3. In the Phase III trials at month 17, Leqvio delivered effective and sustained LDL-C reduction of up to 52% vs. placebo and was reported to be well-tolerated with a safety profile shown to be comparable to placebo2,3. The most common side effects were mild to moderate injection site reaction (including pain, redness and rash), joint pain, urinary tract infection, diarrhea, chest cold, pain in legs or arms and shortness of breath2,3.

Novartis has obtained global rights to develop, manufacture and commercialize Leqvio under a license and collaboration agreement with Alnylam Pharmaceuticals, a leader in RNAi therapeutics.

Ref : https://en.wikipedia.org/wiki/Inclisiran

https://www.bachem.com/news/galnac-delivering-promise-of-oligonucleotides/

FDA Approves Roszet (rosuvastatin and ezetimibe) to Reduce LDL-C in Hyperlipidemia and Homozygous Familial Hypercholesterolemia

Althera Pharmaceuticals, a company focused on heart health, announced the FDA approval of Roszet (rosuvastatin and ezetimibe) tablets, as an adjunct to diet, for treatment of elevated low-density lipoprotein cholesterol (LDL-C) in adult patients with primary non-familial hyperlipidemia and in adult patients with homozygous familial hypercholesterolemia. Roszet contains rosuvastatin, a powerful statin for LDL-C reduction, and ezetimibe, an efficacious cholesterol absorption inhibitor. The two components work through distinct but complimentary mechanisms to give Roszet the power to significantly lower LDL-C.

  

“The optimal LDL-C levels in guidelines across the world have been shifting lower and now many patients need to get their LDL-C below 70 mg/dL,” said Dr. Christie Ballantyne, Chief of Cardiology and Cardiovascular Research at Baylor College of Medicine. “These levels can be quite difficult to achieve with just a statin on top of diet and exercise. Rosuvastatin and ezetimibe have been extensively studied in combination therapy and have been shown to significantly reduce LDL cholesterol beyond the statin alone. Combination therapy has been widely used in hypertension to achieve lower blood pressure targets. This new therapy provides a high efficacy statin plus ezetimibe in a single once daily pill which is a powerful new option to help get patients to the desirable LDL goal without increasing pill burden or requiring addition of injectable therapies”

"With Roszet’s approval in the U.S., we reaffirm our commitment to improving cholesterol treatment options for physicians and patients," said Sanjeev Agarwal, CEO of Althera Pharmaceuticals. "We are on a mission to positively impact patients’ health. By making this highly effective medicine available and affordable, we hope to improve the long-term health of patients, including those with prior cardiovascular disease.”

While a patient's out-of-pocket costs will vary depending on insurance status, the Roszet Savings Program aims to reduce co-pays to as little as $20 per month for eligible patients with commercial insurance coverage. Althera is continuing to work with all stakeholders to ensure that Roszet is affordable and accessible to all. Please visit http://www.roszet.com for more information and updates about the Roszet Savings Program and eligibility.

Availability

Roszet will be available in pharmacies in June 2021.

Roszet Indications, Dosage and Other Select Information

Roszet is indicated, as an adjunct to diet, in adults with primary non-familial hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C), and alone or as an adjunct to other LDL-C lowering therapies in adults with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C.

Roszet is available as a once-daily tablet with rosuvastatin/ezetimibe dosages of 5 mg/10 mg, 10 mg/10 mg, 20 mg/10 mg and 40 mg/10 mg.

https://en.wikipedia.org/wiki/Ezetimibe

https://en.wikipedia.org/wiki/Rosuvastatin

Statin use alone or with metformin may increase survival in high-risk prostate cancer patients

In continuation of my update on metformin

Among high-risk prostate cancer patients - those with high PSA and Gleason scores of 8 or more - many will develop a difficult-to-treat disease. Preliminary research suggests that two commonly prescribed medications, cholesterol-lowering statins and the diabetes therapy metformin may have anticancer effects. However, it is unclear which of these two medications - commonly prescribed together -- contributes the most and whether they can impact high-risk prostate cancer. New research shows that statins, alone or with metformin, increase survival in men with high-risk prostate cancer.

"Both metformin and statins have been associated with longer life in prostate cancer patients, yet because they are commonly prescribed together, no study we know of has looked at these two medications separately," says senior author Grace Lu-Yao, PhD, associate director of Population Science at the Sidney Kimmel Cancer Center--Jefferson Health, one of only eight NCI-designated cancer centers nationwide with a prostate cancer program of excellence.

The study, published in Cancer Medicine on Feb 8th, looked at a number of statin therapies, and metformin, an anti-diabetic medication, in high-risk prostate cancer populations.

Using data from the Surveillance, Epidemiology and End Results (SEER-18) database linked with Medicare files, Dr. Lu-Yao and colleagues looked at patients diagnosed with cancer from 2007 through to 2011. Based on 12,700 patients, the researchers observed that statins alone or in combination with metformin was significantly associated with reduced mortality from all causes.

Dr. Lu-Yao and colleagues saw the highest median survival of 3.9 months in men who took both metformin and statins, 3.6 with statins alone and 3.1 years with metformin alone. The median survival for those who did not use either drug was also 3.1 years.

With respect to prostate mortality, metformin plus statin was associated with a 36% reduction in risk of death followed by statins alone. Those taking metformin alone were relatively rare, and there was no significant association with all-cause mortality."

Interestingly, the study revealed that men who took atorvastatin, pravastatin, or rosuvastatin - but not lovastatin - demonstrated a reduction in mortality compared with non-users, which is consistent with the findings from a recent population-based cohort study using Taiwan National Health Insurance Research Data. The Taiwanese research showed that these three statins are more effective at lowering triglycerides and low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol than other statins in patients with hypercholesterolemia.

Of the three statins studied, men on atorvastatin did have a longer median time to progression on androgen deprivation therapy compared to those who weren't treated with statins. "Although the exact mechanisms remain unknown, it is worth noting that atorvastatin exhibits a potent lipid-lowering effect per dose of any statin, and has the greatest bioavailability and one of the longest half-lives," says to Dr. Lu-Yao.

The data presented in the current study provide crucial insight for the design of future randomized clinical trials of statin for high-risk patients with prostate cancer. Based on the existing evidence, a well-designed clinical trial is warranted to investigate the roles of statins and combination statins/metformin to reduce the mortality cancer of the prostate.

"Our study showed that the effects were more pronounced in patients taking statins after the diagnosis of prostate cancer, 54% reduction in PCA mortality among patients with high-risk prostate cancer," says Lu-Yao. "This magnitude of reduction is comparable to the results of men treated with androgen signaling inhibitors." Statins are relatively inexpensive with good safety records. Further studies to understand the mechanisms of the observed association and its potential clinical utility are warranted.

https://onlinelibrary.wiley.com/doi/full/10.1002/cam4.2862

Statins May Protect Heart From Chemo for Early Breast Cancer

In continuation of my update on statins 

For women with early breast cancer treated with anthracyclines, statin exposure is associated with a lower risk for hospital presentation for heart failure, according to a study published online Jan. 6 in the Journal of the American Heart Association.

Husam Abdel-Qadir, M.D., Ph.D., from the Women's College Hospital in Toronto, and colleagues conducted a retrospective cohort study involving women aged 66 years and older without prior heart failure who received anthracyclines or trastuzumab for newly diagnosed early breast cancer. Using propensity scores, statin-exposed and unexposed women were matched in a 1:1 ratio. Data were included for 666 statin-discordant pairs of anthracycline-treated women and 390 pairs of trastuzumab-treated women.

The researchers found that the five-year cumulative incidence of heart failure hospital presentations after anthracyclines was 1.2 percent (95 percent confidence interval [CI], 0.5 to 2.6 percent) and 2.9 percent (95 percent CI, 1.7 to 4.6 percent) in statin-exposed and unexposed women, respectively (P = 0.01). In the anthracycline cohort, the cause-specific hazard ratio associated with statins was 0.45 (95 percent CI, 0.24 to 0.85; P = 0.01). The five-year cumulative incidence of heart failure hospital presentations after trastuzumab was 2.7 percent (95 percent CI, 1.2 to 5.2 percent) and 3.7 percent (95 percent CI, 2.0 to 6.2 percent) in statin-exposed and unexposed women, respectively (P = 0.09), with a cause-specific hazard ratio associated with statins of 0.46 (95 percent CI, 0.20 to 1.07; P = 0.07).

"This study does not conclusively prove statins are protective," Abdel-Qadir said in a statement. "However, this study builds on the body of evidence suggesting that they may have benefits."

AHA: Adding Omega-3 Fatty Acids Does Not Cut High CV Risk

In continuation of my update on omega-3 fatty acids

A carboxylic acid formulation of eicosapentaenoic acid and docosahexaenoic acid (omega-3 CA) does not improve outcomes among statin-treated patients at high cardiovascular risk, according to a study published online Nov. 15 in the Journal of the American Medical Association to coincide with the American Heart Association Scientific Sessions 2020, held virtually from Nov. 13 to 17.

Stephen J. Nicholls, M.B.B.S., Ph.D., from Monash University in Melbourne, Australia, and colleagues conducted a double-blind trial comparing omega-3 CA to corn oil in 13,078 statin-treated patients with high cardiovascular risk, hypertriglyceridemia, and low high-density lipoprotein cholesterol from 675 academic and community hospitals in 22 countries. Participants were randomly assigned in a 1:1 ratio to either 4 g/day omega-3 CA or corn oil (6,539 to each) in addition to usual background therapies, including statins.

The trial was halted prematurely based on an interim analysis indicating low probability of clinical benefit of omega-3 CA, when 1,384 patients had experienced a primary end-point event. The researchers found that the primary end point (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization) occurred in 12.0 and 12.2 percent of those treated with omega-3 CA and corn oil, respectively (hazard ratio, 0.99; 95 percent confidence interval, 0.90 to 1.09; P = 0.84).

"These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients," the authors write.

Several authors disclosed financial ties to pharmaceutical companies, including AstraZeneca, which funded the study.

AHA: Adding Omega-3 Fatty Acids Does Not Cut High CV Risk  

Aspirin May No Longer Have Effect in Primary CVD Prevention

Aspirin may not be effective for primary prevention of cardiovascular disease and cancer mortality, according to research published online Nov. 21 in Family Practice.

Frank Moriarty, Ph.D., from the Royal College of Surgeons in Dublin, and Mark H. Ebell, M.D., from the University of Georgia in Athens, compared the benefits and harms of aspirin for primary prevention before (1978 to 2002) and after (2005 onward) widespread use of statins and screening for colorectal cancer.

The researchers found that for older versus newer studies, the relative risks for vascular outcomes were 0.89 (95 percent confidence interval [CI], 0.83 to 0.95) versus 0.93 (0.86 to 0.99) for major adverse cardiovascular events; 1.73 (1.11 to 2.72) versus 1.06 (0.66 to 1.70) for fatal hemorrhagic stroke; 0.86 (0.74 to 1.00) versus 0.86 (0.75 to 0.98) for any ischemic stroke; 0.84 (0.77 to 0.92) versus 0.88 (0.77 to 1.00) for any myocardial infarction; and 0.79 (0.71 to 0.88) versus 0.94 (0.83 to 1.08) for nonfatal myocardial infarction. In newer studies, there was no significant decrease observed for cancer mortality (relative risk, 1.11; 95 percent CI, 0.92 to 1.34). Significant increases were seen in major hemorrhage (older studies, relative risk, 1.48 [95 percent CI, 1.25 to 1.76] versus newer studies, relative risk, 1.37 [95 percent CI, 1.24 to 1.53]).

"In a modern era characterized by widespread statin use and population-wide cancer screening, aspirin no longer reduces the absolute risk of cancer death or myocardial infarction when given as primary prevention," the authors write.

https://academic.oup.com/fampra/advance-article/doi/10.1093/fampra/cmz080/5637484

Statin Use Associated With Higher Incidence of Diabetes

In continuation of my update on statins

There may be a dose-dependent relationship between statin therapy and new-onset diabetes across the duration of statin use, according to a study recently published in Diabetes Metabolism Research and Reviews.

Victoria A. Zigmont, Ph.D., from The Ohio State University in Columbus, and colleagues used medical records to retrospectively assess the risk of dysglycemia and new-onset diabetes among 7,064 individuals with indications for statin use. At baseline, participants were candidates for statins based on heart disease risk but had not started taking the drugs; 755 patients were eventually prescribed statins during the study period (2011 to 2014).

The researchers found that a higher prevalence of elevated hemoglobin A1c occurred among incident statin users without diabetes. Statin users also had a higher risk of developing new-onset diabetes (adjusted hazard ratio, 2.20). The greatest risk of developing new-onset diabetes was seen among those taking statins for two years or longer (adjusted hazard ratio, 3.33), with no differences seen by statin class or intensity of dose.

"As lifestyle programs like the Diabetes Prevention Program are promoted in primary care settings, we hope physicians will integrate and insurers support healthy lifestyle strategies as part of the optimal management of individuals at risk for both new-onset diabetes and cardiovascular disease," the authors write.

https://medlineplus.gov/statins.html

Statins Help the Heart, No Matter What Your Age

Cholesterol-lowering statins are already known to help cut heart risks for seniors and the middle-aged. Now, research confirms the meds can also help people aged 75 and older.

"Statin therapy has been shown to prevent cardiovascular disease in a wide range of people, but there has been uncertainty about its efficacy and safety among older people," said lead investigator Anthony Keech. He's a professor of medicine, cardiology and epidemiology at the University of Sydney in Australia.

He and colleagues at the University of Oxford in England analyzed the findings of 28 large clinical trials of statins. The trials involved nearly 187,000 people in six age groups: younger than 55; 55 to 60; 60 to 65; 65 to 70; 70 to 75; and older than 75.

"Our study summarized all the available evidence from major trials to help clarify this issue. We found that there were significant reductions in major vascular events in each of the six age groups considered, including patients [who were] aged over 75 at the start of treatment," Keech said in an Oxford news release.

Major vascular events included heart attack, stroke and procedures to clear clogged arteries.

"Statin therapy appears to be just as effective in people aged over 75 years as it is in younger people," study co-investigator Jordan Fulcher said in the news release. Fulcher is a cardiovascular research fellow at the University of Sydney.

"We have definitive evidence that statins benefit older people who have suffered a heart attack or stroke. Fewer healthy older people were represented in these trials, so more information in this group of people would help confirm the same benefits that we see in our overall trials population," he said.

Fulcher noted that a new randomized trial in Australia is exploring whether statins prolong disability-free survival in a healthy population.

The risk of heart attacks and strokes rises sharply with age, yet statins are not used as widely in older people as they should be, study co-investigator Colin Baigent said in the news release. He's director of Oxford's Medical Research Council Population Health Research Unit.

"Since the risk of heart attack and stroke increases with age, the potential benefits are likely to be even greater for older people," he said.

"Therefore, there is a need to ensure that patients at risk of cardiovascular disease due to their age are offered statin therapy where there is good reason to believe that it will be beneficial," Baigent said.

Anyone with concerns about whether statin therapy is right for them should discuss it with their health care provider, he added.

Psoriasis Meds Might Help Fight Heart Trouble, Too

 Could the inflammation that drives psoriasis and other immune-linked illnesses be a major player in heart disease?

In a new study, certain psoriasis drugs appeared to help to keep arteries clear, suggesting such a link.

"Classically a heart attack is caused by one of five risk factors: diabetes, hypertension, high cholesterol, family history or smoking," explained study lead researcher Dr. Nehal Mehta.

"Our study presents evidence that there is a sixth factor, inflammation," she said.

Mehta heads the Laboratory of Inflammation and Cardiometabolic Diseases at the U.S. National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, Md.

Another cardiologist agreed the study could open doors to new research.

"The future of cardiovascular prevention may require a cholesterol reduction medication and an anti-inflammatory medication," said Dr. Guy Mintz, who directs heart health at Northwell Health's Sandra Atlas Bass Heart Hospital in Manhasset, N.Y.

"These are exciting times in the area of cardiovascular prevention," said Mintz, who wasn't involved with the study.

The new study involved 121 patients who had moderate to severe psoriasis and qualified for anti-inflammatory medicines called biologic therapies. These injected medicines are also used by people with immune-linked conditions such as lupus or rheumatoid arthritis, and include drugs such as Cimzia, Enbrel, Humira, Orencia and Remicade, among others.

All of these medicines work by helping to suppress pro-inflammatory immune system activity.

All participants enrolled in the new study were at low risk of heart disease at the beginning of the research.

Over a year of follow-up, the use of biologic therapy was associated with an 8 percent reduction in coronary artery plaque, the researchers said.

Specifically, use of biologic drugs appeared linked with a slowed buildup of fatty plaques in arteries. These are the plaques that can restrict blood flow and cause heart attacks and stroke.

The findings suggest that immunotherapies that treat inflammatory conditions might also help cut heart disease risk, Mehta and his colleagues reported.

The study authors pointed to prior research that tied psoriasis to the early development of high-risk "soft" arterial plaques. Biologic therapy might cut plaque formation, even in patients without other heart disease risk factors such as high cholesterol, blood sugar and blood pressure, they said.

"This appears to be an anti-inflammatory effect," Mehta explained in an NHLBI news release. "In the absence of improvement in other cardiovascular risk factors, and without adding new cholesterol medications, patients' soft plaque still improved."

However, a cause-and-effect relationship isn't clear from this type of study, so "the next steps should be randomized, controlled trials," Mehta said.

Dr. Michele Green is a dermatologist who treats psoriasis patients at Lenox Hill Hospital in New York City. She wasn't involved in the new study, but said that "treatments with biologics indeed shows great promise in treating cardiovascular disease."

As for Mintz, he called the new research "exciting and important, because it highlights the importance of inflammation associated with psoriasis causing blockages in the arteries of the heart to progress.

"The best statin in the world can only lower cardiovascular events by approximately 40 percent," Mintz pointed out. "So the question arises, what causes the other 60 percent of cardiovascular events?"

The new research "supports the hypothesis that inflammation contributes to cardiovascular disease," he said. "Physicians need to become aware that inflammation should be considered in patient cardiovascular risk assessment."

Fenofibrate drug may reduce risk of cardiovascular events in patients with type 2 diabetes

In continuation of my update on Fenofibrate

A new study shows that the drug fenofibrate might reduce the risk of cardiovascular events in patients with type 2 diabetes who have high levels of triglycerides and low levels of "good" cholesterol, despite being treated with statins. The study, funded by the National Heart, Lung, and Blood Institute (NHLBI), appears in the December 28 issue of JAMA Cardiology.

Fenofibrate is primarily used to help reduce elevated levels of triglycerides, or fat, in the blood. But the researchers wanted to know if the drug, when combined with statin treatment, could also reduce the risk of heart disease in people with type 2 diabetes. People with type 2 diabetes are at high risk of cardiovascular-related events, such as heart attacks, stroke, and even death, often because their levels of triglycerides are so high, and their high-density lipoprotein (HDL) cholesterol levels are low.

To answer their question, the researchers followed 4,640 participants from the NHLBI-funded Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study for five years after the conclusion of the trial in 2009. The findings suggest that fenofibrate therapy may be beneficial in the way the researchers hoped: by reducing cardiovascular events in patients with type 2 diabetes who take statins but still have especially high triglycerides levels and low HDL cholesterol levels. However, a randomized study is needed to confirm these findings, according to the authors.

In addition to NHBLI, the study received funding from the NIH's National Institute of Diabetes and Digestive and Kidney Disease, the National Institute of Aging, and the National Eye Institute.

WHO: Jerome Fleg, MD and Yves Rosenberg, MD, M.P.H., Division of Cardiovascular Sciences, NHLBI, NIH, are available to comment on the findings and implications of this research.

Statins may shield unborn babies from mother's stress, study suggests

In continuation of my update on statins

Scientists have discovered that the widely-prescribed drugs help to counteract the negative impact of stress hormones on fetal growth and heart development in mice.

The therapy could lower the chances of babies being born underweight and reduce their risk of health problems in later life, including heart disease, researchers say.

Further studies are needed to assess the long-term effects of statins in pregnancy, but the drugs are already used occasionally in pregnant women and should be suitable for clinical trials, the team says.

Babies that are exposed to excessive stress hormones in the womb are often born underweight and have a greater risk of heart disease in later life.

Normally, the unborn baby is protected by a key enzyme produced by the placenta that breaks down stress hormones and greatly limits the amount of active hormones that reach the baby's blood supply.

When the expectant mother is stressed, they produce less of this enzyme and the baby is less well protected.

Scientists at the University of Edinburgh studied mice that cannot produce the enzyme as a model of maternal stress.

They found that stress hormones stop the placenta from developing normal blood vessels, which cuts back the blood supply to the growing fetus.

The developing fetus does not grow to full size as a result, and its heart function does not develop normally.

Treating the mother with a type of statin triggers production of a molecule called VEGF, which stimulates the development of blood vessels in the placenta.

By re-establishing the blood supply, the treatment promotes normal development of the heart and helps the baby to grow to a healthy birthweight, the team showed.

Around 2.5 million people in the UK take statins to lower high cholesterol.

The study is published in the journal Proceedings of the National Academy of Sciences and was funded by the Wellcome Trust. The research also received funding from the Raine Medical Research Foundation, University of Western Australia.

Professor Megan Holmes, of the University of Edinburgh's British Heart Foundation Centre for Cardiovascular Sciences, said: "These are very exciting results suggesting that there may finally be a potential therapy for women whose placenta is unable to maintain the normal growth of her baby.

"At present there is no treatment and babies may be born prematurely or small, and will be at greater risk of developing cardiovascular disease, diabetes and even psychiatric disorders later in life. Although more work needs to be done to show statins are safe in human pregnancy, these results show a new way forward for the major unmet need of fetal growth retardation."

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said: "Low birthweight has been associated with maternal stress, and babies with low birthweights may be more prone to cardiovascular complications later in life.

"In this study the researchers have discovered that a drug called Pravastatin may counteract the consequences of increased levels of the stress hormone corticosterone within the placentas of mice. How Pravastatin counteracts the stress hormone is not yet understood, therefore more research is needed to see whether the drug will have the same effect in humans."

Ref : http://www.pnas.org/content/early/2016/05/10/1520356113

New molecule-building method may have great impact on pharmaceutical industry

Scientists at The Scripps Research Institute (TSRI) have devised a new molecule-building method that is likely to have a major impact on the pharmaceutical industry and many other chemistry-based enterprises.

The method, published as an online First Release paper in Science on April 21, 2016, allows chemists to construct novel, complex and potentially very valuable molecules, starting from a large class of compounds known as carboxylic acids, which are relatively cheap and non-toxic. Carboxylic acids include the amino acids that make proteins, fatty acids found in animals and plants, citric acid, acetic acid (vinegar) and many other substances that are already produced in industrial quantities.

"This is one of the most useful methods we have ever worked with, and it mostly involves materials that every chemist has access to already, so I think the interest in it will expand rapidly," said principal investigator Phil S. Baran, Darlene Shiley Professor of Chemistry at TSRI.

"This exciting new discovery represents a significant advance in our ability to transform simple organic molecules and to rapidly build complex structures from readily available materials—we expect to use it in both the discovery and development of biologically active compounds that help patients prevail over serious disease," said co-author Martin D. Eastgate, a Director in Chemical and Synthetic Development at Bristol-Myers Squibb, who participated in the study as part of a long-standing research collaboration between Bristol-Myers Squibb and TSRI.

The new method is a modification of what is already one of the most widely used sets of chemical reactions: amide bond-forming reactions. These occur naturally in cells to stitch together amino-acids into proteins, for example. Since the 1940s, when they became a popular tool for laboratory chemists, they have been instrumental in the discovery of many new compounds as well as new methods for synthesizing compounds.

Amide bond-forming reactions couple carbon atoms on carboxylic acids to nitrogen atoms on another broad class of compounds called amines. The reactions are relatively safe and easy, and produce water, H2O, as a co-product. Chemists have long dreamed of using similarly cheap and easy techniques to make carbon-to-carbon couplings. That would enable them to synthesize, and potentially turn into drugs and other useful products, an enormous number of organic molecules that have previously been inaccessible.

Carbon to Carbon

The method devised by Baran and his team essentially repurposes the traditional amide bond-forming strategy to achieve carbon-carbon couplings. The new reactions again involve easy, safe conditions—the co-product now is carbon dioxide, CO2—and the same inexpensive and widely available starting materials, carboxylic acids. This time the reaction partners are not nitrogen-containing amines but organic compounds containing carbon and zinc, which are also relatively easy to buy or make.

The path to the new invention began with a long-known reaction called the Barton decarboxylation. "We started by asking ourselves what would happen if we could use a metal to trap a radical [a highly reactive charged molecule] generated in the Barton decarboxylation," said TSRI Research Associate Josep Cornella. "We realized that if we could do that, it would open up a totally new approach to organic synthesis and carbon-carbon coupling."

The method the team ultimately developed employs an inexpensive and commercially available activating agent that primes the chosen carboxylic acid for the reaction. A metal catalyst—inexpensive nickel—then facilitates the reaction between the carboxylic acid and its carbon-zinc partner compound.

A key ingredient turned out to be a "ligand" compound that helps the metal catalyst do its job. "We found that common, readily available bipyridine ligands work best—these help to stabilize the nickel so it can catalyze the reaction," said TSRI Research Associate Tian Qin.

Evolocumab could be more effective than ezetimibe in lowering cholesterol in statin-intolerant patients

 

Ezetimibe                                                                                                           atorvastatin

In the first major trial of its kind, Cleveland Clinic researchers used a blinded rechallenge with atorvastatin or placebo to objectively confirm the presence of muscle-related symptoms in patients with a history of intolerance to multiple statins and found that evolocumab (a PCSK9 inhibitor) was a more effective option to lower cholesterol than ezetimibe in these patients.

The double-blinded, placebo-controlled clinical trial was designed with two stages:

• In Phase A, patients were assigned to two groups. Each group was treated for 10 weeks with atorvastatin or placebo in a blinded fashion, then crossed over to the alternate therapy for another 10 weeks. Patients were asked to report any muscle pain or weakness.
• Patients who reported intolerable muscle symptoms on atorvastatin, but not placebo, moved to Phase B. In this 24-week phase, patients with confirmed statin intolerance were administered two alternative non-statin therapies, ezetimibe vs. evolocumab.
• The research is being presented at the American College of Cardiology's 65th Annual Scientific Session and simultaneously published online in the Journal of the American Medical Association.
  "Statin intolerance has been a very challenging clinical problem," said Steven Nissen, M.D., chairman of Cardiovascular Medicine at Cleveland Clinic. "The study showed that PCSK9 inhibitors can significantly lower cholesterol in patients with documented statin intolerance, providing an effective treatment for these difficult to manage patients."
  The GAUSS-3 trial enrolled 511 patients with very high levels of LDL cholesterol - averaging more than 210 mg/dL ¬¬- and with a history of muscle-related statin intolerance. More than 80% of participants had previously reported intolerance to three or more statins. The study showed that 42.6 percent of these patients reported muscle pain or weakness on atorvastatin, but not placebo, and 26.5 percent on the placebo, but not atorvastatin.

Evolocumab could be more effective than ezetimibe in lowering cholesterol in statin-intolerant patients

PCSK9-inhibitor drugs: A game-changer for individuals with extremely high cholesterol levels

A 59-year-old heart patient with dangerously high levels of cholesterol that could not be adequately reduced by statin drugs now has near-normal cholesterol levels, thanks to a new class of drugs that grew out of work done by UT Southwestern Medical Center researchers.

Two of these drugs, in a category known as PCSK9 inhibitors, were approved by the Food and Drug Administration last summer for use by some individuals with extremely high cholesterol levels.

"If you take the core patients who are at highest risk, it makes you appreciate how important this drug class is," said Dr. Amit Khera, Director of the Preventive Cardiology Program and Associate Professor of Internal Medicine at UT Southwestern.

Frank Brown of Dallas, grandfather of six and the owner of Frank's Wrecker Service in Dallas, has familial hypercholesterolemia, an inherited condition that causes high levels of cholesterol, especially low-density lipoprotein (LDL) cholesterol or "bad cholesterol." High levels of LDL cholesterol are strongly associated with heart disease.

Mr. Brown, with a history of two heart attacks, had been aggressively treated with multiple drugs to reduce his cholesterol levels, but they remained stubbornly high.

"When I first met Mr. Brown, he had a strong family history of heart disease, he had a cholesterol level that was ridiculously high with an LDL of 384, and he was having chest pains," said Dr. Amit Khera, who is Mr. Brown's cardiologist.

Dr. Khera, who holds the Dallas Heart Ball Chair in Hypertension and Heart Disease at UT Southwestern, was treating Mr. Brown with three cholesterol-lowering medications: a statin, which is a class of drugs that works by blocking a substance the body needs to make cholesterol; ezetimibe, a drug that blocks absorption of cholesterol in the intestine; and colesevelam, which sequesters bile acids. Even with this trio of medicines, Mr. Brown's LDL cholesterol level hovered around 200.

PCSK9-inhibitor drugs: A game-changer for individuals with extremely high cholesterol levels

Cholesterol-lowering statin drugs could delay prostate cancer growth in patients receiving ADT

In a study published online today by JAMA Oncology, the researchers report that men who had been taking statins since the start of androgen deprivation therapy (ADT) went a median of 27.5 months before their disease began to worsen, compared to 17.4 months for men who didn't take statins. The trial involved 926 patients, 70 percent of whom had their disease progress during a six-year period.

"This median 10-month benefit in delaying disease progression suggests that statins could be a valuable addition to our current therapies for prostate cancer," says the study's first author, Lauren Harshman, MD, medical oncologist at the Lank Center for Genitourinary Oncology at Dana-Farber. "These results are supported by multiple prior epidemiologic studies demonstrating that statin use may be associated with improved outcomes in prostate cancer, but require validation."

The trial grew out of laboratory studies that suggested statins could delay prostate cancer growth in patients receiving ADT. (ADT reduces the amount of androgen in the body, preventing prostate cancer cells from using it to fuel their growth. For many years, it has been the frontline treatment for patients with hormone-sensitive prostate cancer that has spread beyond the prostate gland.)

The laboratory phase of the research focused on a protein called SLCO2B1, which helps a variety of drugs and hormones enter cells. One of these immigrants to the cell is dehydro-epiandrosterone  sulfate (DHEAS), a precursor of testosterone, the hormone that spurs prostate cancer cell growth. Statin drugs, too, rely on SLCO2B1 to gain entry to cells.

More : http://oncology.jamanetwork.com/article.aspx?articleid=2288665

Cholesterol-lowering statin drugs could delay prostate cancer growth in patients receiving ADT

Cholesterol Drug Vytorin Linked to Reduced Heart Attack Risk

We know that, Ezetimibe/simvastatin  is a drug combination used for the treatment of dyslipidemia. It is a combination of ezetimibe (known as Zetia in the United States and Ezetrol elsewhere) and the statin drug simvastatin (known as Zocor in the U.S.). The combination preparation is marketed by Merck & Co. under the trade names Vytorin and Inegy. Ezetimibe reduces blood cholesterol by acting at the brush border of the small intestine and inhibiting the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver.

Simvastatin is an HMG-CoA reductase inhibitor or statin. It works by blocking an enzyme that is necessary for the body to make cholesterol.