Tag Archives: triglycerides

Has REDUCE-IT Resurrected Fish OIl Supplements (And Saved Amarin)?

The answers are no and yes.

There is still no reason to take over the counter fish oil supplements.

In fact, a study published Saturday found that fish oil supplementation (1 g per day as a fish-oil capsule containing 840 mg of n−3 fatty acids, including 460 mg of eicosapentaenoic acid [EPA] and 380 mg of docosahexaenoic acid [DHA]

did not result in a lower incidence than placebo of the primary end points of major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type.

However, another study  published Saturday (REDUCE-IT) and presented at the annual American Heart Association Scientific Sessions to great fanfare found that an ethyl-ester formulation (icosapent ethyl) of eicosapentanoic acid (EPA, one of the two main marine n-3 fish oils)  reduced major cardiovascular events by 25% in comparison to placebo.

When I wrote about Icosapent ethyl (brand name Vascepa) in a previous blog post in 2015 there was no data supporting its use:

A fish oil preparation, VASCEPA,  available only by prescription, was approved by the FDA in 2012.

Like the first prescription fish oil available in the US, Lovaza, VASCEPA is only approved by the FDA for treatment of very high triglycerides(>500 mg/dl).

This is a very small market compared to the millions of individuals taking fish oil thinking that  it is preventing heart disease.

The company that makes Vascepa (Amrin;$AMRN)would also like to have physicians prescribe it to their patients who have mildly or moderatelyelevated triglycerides between 200 and 500 which some estimate as up to 1/3 of the population.

The company has a study that shows that Vascepa lowers triglycerides in patients with such mildly to moderately elevated triglycerides but the FDA did not approve it for that indication.

Given the huge numbers of patients with trigs slightly above normal, before approving an expensive new drug, the FDA thought, it would be nice to know that the drug is actually helping prevent heart attacks and strokes or prolonging life.

After all, we don’t really care about high triglycerides unless they are causing problems and we don’t care about lowering them unless we can show we are reducing the frequency of those problems.

Data do not exist to say that lowering triglycerides in the mild to moderate range  by any drug lowers heart attack risk.

In the past if a company promoted their drug for off-label usage they could be fined by the FDA but Amarin went to court and obtained the right to promote Vascepa to physicians for triglycerides between 200 and 500.

Consequently, you may find your doctor prescribing this drug to you. If you do, I suggest you ask him if he recently had a free lunch or dinner provided by Amarin, has stock in the company (Vascepa is the sole drug made by Amarin and its stock price fluctuates wildly depending on sales and news about Vascepa) or gives talks for Amarin.

If he answers no to all of the above then, hopefully, your triglycerides are over 500.

And although elevated triglycerides confer an elevated CV risk nearly all prior trials evaluating different kinds  of triglyceride-lowering therapies, including extended-release niacin, fibrates, cholesteryl ester transfer protein inhibitors, and omega-3 fatty acids have failed to show reductions in cardiovascular events

REDUCE-IT, Amarin trumpeted widely in September (before the actual data was published)  now provides impressive proof that it prevents cardiovascular disease. Has the skeptical cardiologist changed his mind about fish oil?

Vascepa Is Not Natural Fish Oil

Although Amarin’s marking material states “VASCEPA is obtained naturally from wild deep-water Pacific Ocean fish” the active ingredient is an ethyl ester form of eicosapentoic acid (EPA) which has been industrially processed and distilled and separated out from the other main omega-3 fatty acid in fish oil (DHA or docosohexanoieic acid).

Natural fish oil contains a balance of EPA and DHA combined with triacylglycerols (TAGS).

So even if the REDUCE-IT trial results can be believed they do not support the routine consumption of  over the counter fish oil supplements for prevention of cardiovascular disease.

Does REDUCE-IT  Prove The Benefit of Purified High Dose EPA?

REDUCE-IT was a large (8179 patients) randomized, double-blind placebo controlled trial

Eligible patients had a fasting triglyceride level of 150 to 499 mg per deciliter  and a low-density lipoprotein (LDL) cholesterol level of 41 to 100 mg per deciliter  and had been receiving a stable dose of a statin for at least 4 weeks. In 2013 the protocol was changed and required a triglyceride level>200 mg/dl.

Participants were randomized to icosapent ethyl (2 g twice daily with food [total daily dose, 4 g]) or a placebo that contained mineral oil to mimic the color and consistency of icosapent ethyl and were followed for a median of 4.9 years. A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group.

More importantly, the hard end-points of CV death, nonfatal stroke and heart attack were also significantly lower in the Vascepa arm compared to the “placebo” arm.

These results are almost unbelievably good and they are far better than one would have predicted given only a 17% reduction in triglycerides.

This makes me strongly consider prescribing Vascepa (something I heretofore have never done) to my higher risk patients with triglycerides over 200 after we’ve addressed lifestyle and dietary contributors.

Perhaps the high dose of EPA (4 grams versus the 1 gram utilized in most trials) is beneficial in stabilizing cell membranes, reducing inflammation and thrombotic events as experimental data has suggested.

Lingering Concerns About The Study

Despite these great results I have some concerns:

  1. The placebo contained mineral oil which may not have been neutral in its effects. In fact, the placebo arm had a significant rise in the LDL cholesterol.
  2. Enrolled patients were predominantly male and white. No benefit was seen in women.
  3. Higher rates of serious bleeding were noted in patients taking Vascepa
  4. Atrial fibrillation developed significantly more often in Vascepa patients (3.1%) versus the mineral oil patients (2.1%)

Finally, the trial was sponsored by Amarin Pharma. This is an aggressive company that I don’t trust.  The steering committee consisted of academic physicians (see the Supplementary Appendix), and representatives of the sponsor developed the protocol,  and were responsible for the conduct and oversight of the study, as well as the interpretation of the data. The sponsor was responsible for the collection and management of the data. All the data analyses were performed by the sponsor,

After i wrote my negative piece on Vascepa in 2015 a number of Amarin investors attacked me because Vascepa is the only product Amarin has and any news on the drug dramatically influences its stock price. Here is the price of Amarin stock in the last year.

The dramatic uptick in September corresponds to the company’s announcement of the topline results of REDUCE-IT. Since the actual results have been published and analyzed the stock has dropped 20%.

High Dose Purified and Esterified EPA-Yay or Nay?

I would love to see another trial of high dose EPA that wasn’t totally under the control of Amarin and such trials are in the pipeline.

Until then, I’ll consider prescribing Amarin’s pills to appropriate patients* who can afford it and who appear to have significant residual risk after statin therapy*.

But, I will continue to tell my patients to stop paying money for useless OTC fish oil supplements.

Megaskeptically Yours,-

ACP

N.B.* Appropriate patients will fit the entry criteria for REDUCE-IT described below.

Patients could be enrolled if they were 45 years of age or older and had established cardiovascular disease or were 50 years of age or older and had diabetes mellitus and at least one additional risk factor. Eligible patients had a fasting triglyceride level of 150 to 499 mg per deciliter (1.69 to 5.63 mmol per liter) and a low-density lipoprotein (LDL) cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter) and had been receiving a stable dose of a statin for at least 4 weeks;

So either secondary prevention (prior heart attack or stroke) or primary prevention in patients with diabetes and another risk factor.

 

 

What Happens To Cholesterol Levels When You Switch To Low Or Non Fat Dairy

When individuals  discover that they have abnormal  cholesterol readings they are often told to initiate  lifestyle changes to try to correct them.

Based on what physicians and patients have been taught  over the last twenty years, the likely dietary change recommended and the easy , first step is likely  to be to cut back on dairy fat.

IMG_6135
Yoplait Original-25% Less Sugar.(but still with 18 grams per 6 oz serving). A typical supermarket/doctor’s lounge yogurt with lots of ingredients added in (sugar, modified corn starch, Vitamin A Acetate, Vitamin D3)to replace the natural good taste and nutrients found in dairy fat.
IMG_6272 (1)
Traders Point Creamery plain yogurt. Ingredients= milk and cultures. Taste =fantastic. Grams of sugar=zero.

After all, it’s a pretty easy transition to start using skim milk and non fat yogurt because these line the supermarket shelves and have been filled with chocolate or added sugar to taste more palatable.

You might miss the great taste that butter adds to bread or cooking but for your health you would be willing to switch to non butter spreads and cut down on the cheese in your diet because  based on what you have heard from numerous media sources this is a giant step toward reducing your cholesterol numbers.

 

 

 

 


 

Unfortunately, it is a horribly misguided  step.

Although, the switch to low or non fat dairy lowers your cholesterol numbers, it is  not lower cholesterol numbers that you want: what you want is a lower risk of developing stroke or heart attack or the other complications of atherosclerosis.

Let me repeat: Don’t worry about your cholesterol numbers, worry about your overall risk of developing heart attack or stroke.

Due to 30 years of misinformation, the concept that lowering your cholesterol means lower risk of heart disease has become firmly entrenched in the public’s consciousness-but in the case of dietary intervention this has never been documented.

I take care of a 69 year old woman who has an abnormal heart rhythm and chest pain. As part of her evaluation for chest pain we performed a coronary CT angiogram (CCTA) which showed advanced but not obstructive atherosclerotic plaque in her right and left anterior descending coronary arteries.

This lady was not overweight, followed a healthy diet and exercised regularly. Her mother, a sedentary, heavy smoker, suffered a heart attack at age 54.

Her PCP had obtained lipid values on her 6 months before I saw her which were abnormal but the patient had been reluctant to start the recommended statin drug because of concerns about side effects.

After seeing her CCTA I advised that she begin atorvastastin 10 mg daily and aspirin to help reduce her long term risk of heart attack, stroke.

She decided without telling me not to take the statin, again due to side effect concerns, but started the aspirin, and began to pursue what she felt were healthy dietary changes.

When I saw her back in the office she told me  “I don’t eat butter or cheese anymore and I’ve switched to skim milk.” She had substituted olive oil for butter.

Here are her lipid values before and after her dietary changes (TC=total cholesterol, LDL= bad cholesterol, HDL=good cholesterol, trigs=triglycerides)

Date              TC             LDL       HDL   trigs            ASCVd 10 year risk

3/2015         275          173       72       149                         7.9%

10/2015      220           122       43      274                         8.3%

At first glance, and especially if we focus only on the total and bad cholesterol, this appears to be a successful response to dietary changes:  a 29% reduction in the bad cholesterol and a 25% drop in the total cholesterol.

However, although the LDL or bad cholesterol has dropped a lot, the HDL or good cholesterol has dropped by  more: 40%!

This is the typical change when patients cut out dairy fat-the overall ratio of bad  to good cholesterol actually rises.

In addition, the pattern she has now, with a low HDL and high triglycerides is typical of the metabolic syndrome which is recognized as likely to contribute to early  atherosclerosis: so-called “atherogenic dyslipidemia.”

When I plugged both sets of numbers into the ASCVD 10 year risk calculator app (see here) her estimated 10 year risk of heart attack and stroke had actually increased from 7.9% to 8.3%.

Hopefully, this anecdote will reinforce what population studies show:

  • There is NO evidence that dairy fat consumption increases risk of cardiovascular disease (see here)
  • Current recommendations to consume non or low fat dairy (often  accompanied by increase in added sugars) are not supported by scientific studies.

Finally, my patient is another example of an inherited tendency to development of premature atherosclerosis: her diet, exercise, body weight were all optimal and could not be tweaked to lower her risk.

Such patients must deal with the cardiovascular cards they have been dealt. If they have advanced atherosclerosis, as much as they may dislike taking medications, statins are by far the most effective means of reducing their long term risk of heart attack and stroke.