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Introduction

Before we move on through the quagmire of the pharmaceutical drug industry, I wanted to mention one other drug that has been added to the arsenal of cholesterol lowering drugs called PCSK9 Inhibitors. In addition I would like to discuss anti-diabetic drugs, their mechanism of action and their devastating side effects that affect some.


Cholesterol lowering with  PCSK9 Inhibitors

Drug companies are not satisfied with Statin drugs lowering your cholesterol low enough so now they are pushing for you to take a Statin and a PCSK9 inhibitor which together will probably lower cholesterol to such a level that if has never been seen in nature.  What is the problem with these drug companies, Statins work, they do lower cholesterol but it’s the aftermath destruction that patients have to pay the price,for something that does not need lowering in the first place. These PCSK9 inhibitors are expensive at $50/month. The website Healthline state:

Adverse events were reported in 69 percent of people taking evolocumab in the clinical trials. Injection-site swelling or rash, limb pain, and fatigue were some of the reported side effects.  In the alirocumab trials, adverse events were reported in 81 percent of participants taking the drug. These included injection-site reactions, muscle pain, and eye-related events. Long-term side effects and risks are not yet known

And Wikipedia continue to say that the side effects were severe enough so:

Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.


Fixing a Mutant Gene can also Lower Cholesterol

 

So what are these new drugs (actually I found an article in the NCBI database discussing the function and physiology of this gene dated 2008, however they begin the article saying “In the past few years..”since it dates back to 2003) PCSK9. This acronym stands for Proprotein Convertase Subtilisin/Kexin type 9 gene.  It is a gene that helps create an enzyme that binds to a receptor for LDL. The gene actually provides instructions to make a protein to regulate the amount of cholesterol produced by controlling the number of LDL receptors on the cell. It appears that this GOI (gene of interest) became just that, as a means to ‘fix’ people with a genetic mutation of this gene that causes hypercholesterolemia..so how many people have this condition???

Well the numbers in the population are not going to add up to much, certainly not to warrant all of the research money necessary to bring it market and get its approval, so we will just add it to the existing prescriptions of Statins.  How wonderful so all of our devoted patients that take statins can get a double basinful so we can really kick cholesterol to the kerb. This is out and out lunacy.  What researchers discovered was that statins actually upregulate PCSK9 putting the brakes on their principal mode of action which is to increase LDL receptors in the liver thus diminishing LDL particles in the blood, therefore PCSK9 inhibition should potentiate(increase) the effects of statins.


Risk of cognitive disorder with the new cholesterol lowering drug

In 2014 due to early trial evidence the FDA requested drug developers of these inhibitors to assess any Cognitive adverse effects and in following trails like the OSLER trail (Open Label study of long term evaluation against LDL Cholesterol) reported that out of 1,104 hypercholesterolemia patients who received 420 mg of ‘Evolocumab’ ( Brand of PCSK9 inhibitor ) for over 1 year, 3 reported amnesia and 5 with memory or mental impairment <1%. In 2015 an 11 month follow up study to OSLER showed an increase from 4,465 participants reporting delirium,cognitive,and attention disorders, disturbances, dementia and mental impairment. In the words of the drug developers it is early days yet but clearly a risk exists concerning cognitive disorder.

*If you want to read more about cholesterol lowering drug I would direct you to a website called THINCS (The International Network of Cholesterol Skeptics)


Lowering Blood Sugar

The body is quite capable of managing biological processes including blood sugar levels.  As we explained in the previous article The secretion of insulin from the Pancreatic Beta cells (Islet cells) are regulated by the existence of glucose in the bloodstream, however the molecular and cellular mechanisms involved in insulin secretion are Islet cell signaling proteins called G Protein coupled receptors (GPCR) that regulate communications within the cells and outside of the cells. The secretion of insulin is stimulated by glucose (GSIS – Glucose stimulated insulin secretion) that is received by a glucose transporter GLUT2 which in turn activates ATP that changes the Potential difference (PD) of the cell.  This PD depolarizes the cell closing the potassium channels and opening the calcium channels and it is the accumulation of calcium that activates the insulin secretion.  The purpose of the insulin signal is to notify the cells to uptake the glucose in the blood.  What interferes with this process is excessive refined sugar intake and chronic nutrient deficiency (such as Chromium, Vanadium and Zinc) which requires a simple dietary change and that should be the only treatment advice.  But that’s too simple..it can’t possibly work.

Diabetes is Destroying the Social Fabric of Society including the Next Generation

Civilizations that either do not have access, nor the money to buy from supermarkets and fast food outlets, but live off the land, generally do not suffer from diabetes. I remember watching a documentary where a family originally from Mexico living in the US, both the husband and wife earning meager salaries, would try to buy some vegetables from the supermarket but because of time constraints they would eat fast food most of the week and feed their teenager son and daughter with the same food.  The main reason that they could not afford real food every day because the husband had raging diabetes, that he was trying to control buying expensive drugs.  So on one hand he was trying to lower his blood glucose, and on the other he was raising it. The WHO reports that  diabetes is the leading cause of death in Mexico affecting 24% of men and 21% of women over the age of 35.  Mexican children have the world’s highest rate of childhood obesity, clocking in at more than 28% between the ages of 5 and 9, and 38% between the ages 10-19, Mexican population is about 130 million.  These are Nov 2011 figures, so what is it now ?.  In the US diabetes rates are 29 million people, and in the UK 3.8 million.

Soda Plants are Dehydrating Communities

Swigging sugar packed soda drinks simply fuels the diabetic crisis, and on top of that soda companies set up their bottling plants in various countries and use up precious water to produce their product (typically 1 litre of soda requires 3 litres of water to produce), depriving farmers that need the water to cultivate and irrigate their growing lands.  This dehydration of whole communities occurring in 1999 in North east India in Kaladera where before the arrival of the soda company’s (Coca- Cola) bottling plant  farmers could easily draw water from 40 foot wells, but in 2003 the farmers had to bore wells 200 feet deep to draw water.  In Plachimada, southern India the same soda company was kicked out in March 2004 because the village council refused to renew their licence because it had dehydrated the community and contaminated the water supply.  I remember watching a documentary where this soda company had set up bottling operations in a small mexican community, dehydrated it and everybody was drinking soda, even the small infants were being bottle fed with coca-cola.

Rosiglitazone the anti-diabetic drug that kills

 

The infamous anti-diabetic drug that was introduced in 1999 was Rosiglitazone, at the same time when Pioglitazone was around which was another Thiazolidinedione class of drug. The result of a drug trial conducted in 1999 by its maker SmithKline Beecham (Glaxo) found that the drug had a nasty side effect in some…Heart failure…whoopee, the blood sugar has been lowered but I suffered a heart attack for my troubles..the regulatory agencies should have immediately requested withdrawal of such a dangerous drug..did they?

In 2004 the WHO sent Glaxo a caution about the cardiac events associated with drug, and after a meta analysis (extrapolating results from a combination of studies) they confirmed it..wait a minute..so the drug must have been approved..yes it was on May 22 1999 the drug was approved despite the fact that 36 out of 2902 trial participants suffered ischaemic cardiovascular events (Coronary heart disease).  You must appreciate that these communications between drug company, the FDA and WHO were unknown to the public..why would they need to know?   They just risk their lives taking the stuff.

Approving a Potential Killer

 

It was also discovered that this drug also increased LDL by 19%, but this was dismissed saying that the LDL particles were big and fluffy and posed no risk..well the Statinator is going to say something about this. As the years passed review articles began voicing their concerns about the cardiovascular association with Rosiglitazone, reports of water retention and Congestive heart failure began to surface within the first 2 years of drug launch. But the FDA did their job with a fake fix and modified the drug packet labelling to reflect these rare risks.  One diabetes expert came forward praising the cardiovascular safety of the drug..what ???..either there is a risk or there is not..which is it?  It turns out that our physician, the diabetes expert was paid a visit from a delegation of ‘heavies’ from the makers of rosiglitazone and told basically to shut his mouth or be sued because of a perceived stock price loss of $4 billion.  As the reports of CHF began accumulating, the FDA ‘came to the rescue’ and put the CHF risks in the warning section of the package inserts..now this is laughable since 95% of drug takers nor the prescribing physician ever read them.


The Truth is Revealed

By 2006 sales of Rosiglitazone were $3.3 billion annually..oh I forgot about the other drug Pioglitazone whose sales were $2.8 billion/year. which by the way reported less CHF events but it was associated with Bladder cancer.  Other studies followed including ADOPT, Avandia (brand name for Rosiglitazone)  in daily practice (seeding trial) and DREAM, all of which focused on how good this drug lowered blood glucose..and the CHF…well maybe later, in another trial. However 75 cardiac events were recorded during the DREAM trial and 55 in the placebo group.  Fortuitously GSK the makers of Rosiglitazone were being sued by the state of New York pertaining to an antidepressant drug and as a result of that lawsuit GSK agreed to establish a ‘clinical trial register’ revealing the results of all clinical trials conducted after December 2000. The actual results from the trials of Rosiglitazone would now be revealed since 35 of the 42 randomized trials were never published. The meta analysis carried out by Steven Nissen of the Cleveland Clinic foundation in 2007 uncovered around 30-43% increase of Cardiac events associated with this drug (quite a difference from the 36 out of 2902 reported earlier). Anti diabetes drugs are supposed to lower the risk of Cardiovascular mortality not increase it so in 2007 this was shocking news for all except the drug maker who knew all along but chose to keep it quiet.  The editorial of the Lancet writes:

“The story of Rosiglitazone is one of death,greed and corruption…The trust between doctor patient , researcher and participant, or author and editor is undermined when the foundations on which evidence is built are treated with such casual contempt.”

From the book ‘Deadly medicines and Organized crime’ Peter Gotzsche

This is what’s written on the Drugs.com website for the Anti-diabetic Rosiglitazone

“Thiazolidinedione antidiabetics such as rosiglitazone may cause or worsen heart failure in some patients. Tell your doctor if you have a history of heart failure. Rosiglitazone should not be used to treat patients who have heart failure with symptoms, or moderate to severe heart failure. You will be monitored for signs of heart failure when you start rosiglitazone and if your dose increases. Contact your doctor at once if you develop symptoms of heart failure (eg, swelling of the hands, ankles, legs, or feet; shortness of breath; sudden unexplained weight gain). Your doctor may need to stop your medicine or change your dose.”

Rosiglitazone is withdrawn in Europe, but still available in the US

Rosiglitazone was withdrawn in Europe on September 2010, but the FDA decided to keep it approved in the US, and in 2009 began the TIDE trail which was scheduled to finish in 2015. The purpose of this trial was to compare Rosiglitazone against Pioglitazone in terms of cardiovascular safety, but as we stated before we know the answer and so did the drug maker. Since the US and Europe refused to supply trial participants  GSK went to India..plenty of people there to exploit. In 2010, the Indian drug regulator halted the trial (2 FDA officers also suggested to stop the trial..wow..talk about closing the barn door after the horse has bolted) because by then all and sundry knew that the drug was causing 500 heart attacks and 300 cases of heart failure every month in the US. Even after all that had occurred the FDA still refused to withdraw the drug but only to issue a warning:

Rosiglitazone should only be used in patients already being treated with the drug, and in those patients whose blood sugar cannot be controlled with other drugs, and who after consulting with their healthcare professional,do not wish to use  Rosiglitazone.

So, if you want to lower your blood sugar what risk do you chose Coronary heart failure or Bladder cancer?

Why is there an association of Congestive heart failure (CHF) and Rosiglitazone?

By all accounts this drug does a wonderful job in treating insulin resistance as well as hypertension which is positive side effect, but it also increases HDL and increases LDL (but not small particle). The mechanism of action involves Peroxisome Proliferator Activated Receptors (PPARs).  What the hell are PPARs ?.  These are nuclear proteins (protein class that sense steroid and thyroid hormones) receptors that regulate specific gene expression. Since they can directly bind to DNA and regulate adjacent genes they are classified as transcription factors (to produce mRNA ‘DNA ‘Xerox’ copies). Activation is initiated by the binding of a Ligand, a substance that forms a complex for a biological purpose, in this case it results in up/down regulation of gene expression, to control the organism, including  development and homeostasis.  PPARs γ (gamma) are expressed in all tissues, the heart, muscle, colon, kidney,pancreas and spleen, and activation ligands are generally Prostaglandin E2 (fatty acids and eicosanoids, which we covered in the Metabolic typing series of articles).

Since adipocytes (Fat cells that make up the adipose or fat tissue of the body) are involved in the pathogenesis of insulin resistance ( there are obvious associations between obesity and diabetes since they run together symptomatically). PPARgamma are predominant in adipose tissue specifically in the skeletal muscle and these are the targets to re-regulate (fancy word for interfere with..lol) the gene expression.  These Thiazolidinedione antidiabetics stimulate adipocyte differentiation, producing smaller adipocytes that are more insulin sensitive. So here is the catch, a very serious side effect is that these drugs cause serious fluid retention, found to be as much as 7% in a monotherapy scenario and 15% when combined with insulin.  The fluid retention begins with a peripheral edema (swelling in the lower part of the body caused by excess fluid) that progresses to a pulmonary edema (fluid in the lungs causing breathing problems) and congestive heart failure ( heart weakening, it does not mean the heart stops, but the body becomes congested with excess fluid and the heart has to work harder).

So the question is, what is fluid retention, and what causes it?  First of all each kidney is made up of about a million filtering units called nephrons that are made of a filter (called the Glomerulus and a tiny tubule, that filter small amounts of blood.  The glomerulus permits fluid and waste products to pass through it, and block the flow of  blood cells and large molecules (mostly proteins). The filtered fluid then passes through the tubule, sending minerals into the bloodstream and removing waste. The final product is excreted as urine. The kidney is also responsible for fluid balance and s electrolyte balance of sodium and potassium so renal physiology includes sodium re absorption.

Evidence suggests that the  Thiazolidinedione antidiabetics induces an edema associated with reduced urinary sodium and water excretion directly affecting the tubular transport and vascular hyperpermeability, excessive leakage of fluid and proteins from blood vessels to the interstitial space (space between cells). In other words the drug interferes with the fluid balance responsibility of the kidney.   Two bodies of evidence indicated that the activation of sodium transport processes in the distal nephron (Convoluted tubule) may underlie the drug-induced fluid retention. First, within the kidney, PPARγ is highly expressed in the renal medullary collecting duct, with lower expression levels in glomeruli, proximal tubules, and microvasculature (smallest system of blood vessels).  Second, in a cultured human cortical collecting duct (CCD) cell line, PPARγ agonists increased levels of cell surface α-ENaC. which are epithelial sodium channels that are involved in the reabsorption of sodium ions at the collecting ducts of the nephrons. These channels are critical for the maintenance of body salt and water homeostasis.  In essence the drug interferes with the fluid balance of the kidneys, causing the build up of bodily fluid.


Conclusion

Can you imagine if alternative medicine prescribed natural substances that interfered with human physiology to this extent, it would be like the ‘Blacklist’ where a special task force would be assembled to shut down every health food store and close every naturopath practice until they were no more.  All alternative practitioners would be on the FBI/Interpol’s most wanted list.  In the next article we’ll look at the regulatory agencies and their role in protecting us citizens….lol.

According to the surgeon general, obesity today is officially an epidemic; it is arguably the most pressing public health problem we face, costing the healthcare system an estimated $90 billion a year. Three of every five Americans are overweight; one of every five is obese. The disease formerly known as adult-onset diabetes has had to be renamed Type II diabetes since it now occurs so frequently in children. A recent study in the Journal of the American Medical Association predicts that a child born in 2000 has a one-in-three chance of developing diabetes. (An African American child’s chances are two in five.) Because of diabetes and all the other health problems that accompany obesity, today’s children may turn out to be the first generation of Americans whose life expectancy will actually be shorter than that of their parents. The problem is not limited to America: The United Nations reported that in 2000 the number of people suffering from overnutrition–a billion–had officially surpassed the number suffering from malnutrition–800 million.”

Michael Pollan, The Omnivore’s Dilemma: A Natural History of Four Meals 2007


References/Acknowledgments:

  1. Destroy Chronic pain Dr Russell Schierling Chiropractor 2016
  2.  PCSK9 function and Physiology A.Petersen, L.Fong, S.Young NCBI 2008
  3. The rise and fall of rosiglitazone Steven Nissen European Heart journal 2010  
  4. Unravelling the mechanism of action of Thiazolidinediones C.Khan, L.Chen,    S.Cohen Journal of clinical Investigation Dec 2000 
  5. Deadly Medicines and Organized crime Book Peter Gotzsche 2013
  6. Rosiglitazone  Drugs.com
  7. Renal & Vascular mechanism of  Thiazolidinediones-Induced fluid retention      T.Young, S.Soodvilai NCBI 2008
  8. Epithelial sodium channel,   α-ENaC, renal medullary collecting duct, Distal         nephron, Wikipedia
  9.  Glomerular Filtration rate (GFR) The National Kidney Foundation
  10. Mexico diabetes rates contend for world’s worst ZDNET Lauren Villagran Nov 2011
  11.  Coca-Cola Drinking the world dry Waron Want  Nov 2007

Author:  Eric Malouin

 

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