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

Atorvastatin drug plus zoledronic acid may help treat toxoplasmosis

In continuation of my update on Atorvastatin and Zoledronic acid

Researchers at the University of Georgia have discovered that a combination of two commonly prescribed drugs used to treat high cholesterol and osteoporosis may serve as the foundation of a new treatment for toxoplasmosis, a parasitic infection caused by the protozoan Toxoplasma gondii. They published their findings recently in PLOS Pathogens.

Toxoplasma gondii is a parasite capable of infecting nearly all warm-blooded animals. While healthy human adults usually suffer no lasting ill effects from infection, it can be harmful or fatal to unborn fetuses or those with weakened immune systems.

"For many years, therapies for toxoplasmosis have focused on drugs that target only the parasite," said Silvia Moreno, senior author of the article and professor of cellular biology in UGA's Franklin College of Arts and Sciences. "But in this paper, we show how we can hit the parasite with two drugs simultaneously, one that affects body chemistry in the host and one that affects the parasite."

The UGA researchers discovered that a combination of the cholesterol lowering drugatorvastatin and osteoporosis medication zoledronic acid, both more commonly known by their respective trade names, Lipitor and Zometa, produce changes in the mammalian host and in the parasite that ultimately block parasite replication and spread of the infection.

"These two drugs have a strong synergy," said Moreno, who is also a member of UG

A's Center for Tropical and Emerging Global Diseases. "The mice we treated were cured from a lethal infection using this combination approach."

Moreno and her colleagues began working on this drug combination following a series of experiments with unexpected results. They created a genetically modified version of the parasite in the laboratory that lacked a specific enzyme essential for one of the organism's most basic functions.

Atorvastatin drug plus zoledronic acid may help treat toxoplasmosis

FDA Approves Merck’s Liptruzet (ezetimibe and atorvastatin), a New Product That Can Help Lower LDL Cholesterol

In continuation of my update on ezetimibe and atorvastatin
FDA Approves Merck’s Liptruzet (ezetimibe and atorvastatin), a New Product That Can Help Lower LDL Cholesterol

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

How statins harm muscles—and how to stop it

In continuation of my update  on statin 

Statins have transformed heart health, saving millions of lives by lowering cholesterol and reducing the risk of heart attacks and strokes. But for many patients, these drugs come with a troubling downside: muscle pain, weakness and, in rare cases, severe muscle breakdown that can lead to kidney failure.

University of British Columbia researchers and their collaborators at the University of Wisconsin-Madison have now pinpointed the cause. Their findings, published last week in Nature Communications, could pave the way for a new generation of statins without these side effects.

How statins affect muscle cells

The team used cryo-electron microscopy, a powerful imaging technique that reveals proteins at near-atomic detail, to capture how statins interact with a critical muscle protein called the ryanodine receptor (RyR1). This protein acts like a gatekeeper for calcium inside muscle cells, opening only when muscles need to contract. When statins bind to it, they force the gate open, causing calcium to leak continuously—a toxic effect that can damage muscle tissue.

"We were able to see, almost atom by atom, how statins latch onto this channel," said lead author Dr. Steven Molinarolo, a postdoctoral researcher in UBC's department of biochemistry and molecular biology. "That leak of calcium explains why some patients experience muscle pain or, in extreme cases, life-threatening complications."

Implications for future statin development

The study focused on atorvastatin, one of the most widely prescribed statins, but the findings suggest the effect may be common across the drug class. The researchers discovered that statins bind in a highly unusual way: Three molecules cluster together inside a pocket of the protein. The first molecule attaches when the channel is closed, priming it to open. Two more molecules then wedge in, forcing the channel wide open.

"This is the first time we've had a clear picture of how statins activate this channel," said Dr. Filip Van Petegem, senior author and professor at UBC's Life Sciences Institute. "It's a big step forward because it gives us a roadmap for designing statins that don't interact with muscle tissue."

By adjusting only those parts of the statin molecule that are responsible for the negative effects, scientists could preserve the part that lowers cholesterol while reducing the risk.

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

How statins harm muscles—and how to stop it

FDA Approves Juxtapid - New Orphan Drug for Rare Cholesterol Disorder

In continuation of my update on Juxtapid (lomitapide) 

We know that, Lomitapide (INN) is an investigational drug for the treatment of familial hypercholesterolemia, developed by Aegerion Pharmaceuticals.  It has been tested in several Phase II clinical trials as single treatment and in combinations with atorvastatin, ezetimibe and fenofibrate. 

The US Food and Drug Administration approved lomitapide on December 21, 2012 as anorphan drug to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non-high-density lipoprotein (non-HDL) cholesterol in patients with homozygous familial hypercholesterolemia (HoFH).

FDA Approves Juxtapid - New Orphan Drug for Rare Cholesterol Disorder