Tags Posts tagged with "Cholesterol"


Lower triglycerides may reduce cardiovascular risk

By David Dunaief, M.D.

Dr. David Dunaief

The lipid, or cholesterol, profile is one of the most common batteries of blood tests. Why? Abnormal cholesterol levels may have an integral role in exacerbating a number of chronic diseases. These diseases are some of the most common, including atherosclerosis (hardening of the arteries), cardiovascular disease (heart disease and stroke) and vascular dementia. It’s even thought to be a component of age-related macular degeneration, the number one cause of vision loss in those who are at least age 60 in industrialized countries (1).

Let’s delve into the components that make up the cholesterol profile. The lipid panel is made up of several components. These include total cholesterol, HDL or “good cholesterol,” LDL or “bad cholesterol” and triglycerides. Many people focus more on total cholesterol, HDL, and LDL and less on triglycerides. We worry about whether the levels are high enough for HDL and are low enough for total cholesterol and LDL. Is this the proper focus? With total cholesterol and LDL, this seems to be appropriate.

However, with HDL it is becoming more complicated; it is less about how high the levels are and more about the functionality of HDL. There are drugs that increase HDL levels, such as niacin and the fibrates, without significantly reducing cardiovascular events. This was demonstrated in the AIM-HIGH trial (2). In this trial, niacin added to a statin drug increased HDL levels and decreased triglyceride levels without a change in the primary end point of cardiovascular outcomes. Thus, they were deemed less than satisfactory and the trial was abruptly ended. However, triglycerides get the short end of the stick. Just look at the lack of coverage in the mainstream media. In this article, we will explore the different components of the lipid panel and the supposed roles they play in our health. Let’s look at the research.

HDL — the good cholesterol that may not be so good

Eating one-and-a-half cups of oatmeal each day can lower your cholesterol by 5 to 8 percent.

For years, when patients were told their total cholesterol and LDL are high, they asked if their HDL levels compensated for this. Of course, we in the medical community are partially to blame for fueling this thinking. More and more studies point to the importance of HDL functionality rather than the level.

In a study investigating a specific gene variant, or mutation, those who had very high levels of HDL, a mean of 106 mg/dL, and two copies of a P376L mutation, had an increased risk of heart disease (3). In a population of 300 participants with this very high level of HDL, only one had this mutation.

When the investigators broadened the number to 1,282 participants, the results were the same. Results were consistent when they looked at a meta-analysis of 300,000 participants with high HDL.

Carriers of the gene mutation, meaning they had one copy instead of two, were at a 79 percent increased risk of heart disease. Those who had this gene mutation were mostly Ashkenazi Jews of European descent. The good news is that this gene mutation is rare. However, it does show that in certain circumstances, HDL is not always good.

Lest you become too relaxed about this study, since the occurrence was uncommon, another study’s results showed that there is a U-shaped curve when it comes to HDL levels (4). In other words, those on the lowest and the highest ends of HDL levels had higher risk of death from both cardiovascular and noncardiovascular death. There were associations among HDL and other factors, like vegetable and fruit consumption, high blood pressure, diabetes, age and sex. Thus, HDL may not by itself be an indicator of heart disease death risk as suggested by the investigators in the trial. This was a large population-based study with over 600,000 participants.

In a third study, results showed that functionality is more important than HDL level (5). What is called the cholesterol-efflux capacity may be central to HDL functionality. This technique calibrates the reverse transport of cholesterol. Cholesterol is removed from a type of white blood cell in the wall of the artery, put back into the bloodstream and removed by the liver. The importance of the functionality is that a higher cholesterol-efflux capacity results in a lower risk of cardiovascular disease. In other words, you may not be able to rely on HDL levels to determine cardioprotective effects.

Triglycerides should get their due

Triglycerides need their 15 minutes of fame, just like the rest of the cholesterol profile. Triglycerides may be an independent risk factor for cardiovascular disease. In a study, results showed that triglycerides are an independent risk factor for all-cause mortality in those with heart disease (6). But even more interesting is that those with high normal levels, those between 100 and 150 mg/dL, have a significantly increased risk of cardiovascular death. In other words, those who are still within normal limits, but at the upper end, should consider reducing their levels.

The results also showed a dose-dependent curve; the higher the levels of triglycerides, the higher the risk of death from cardiovascular disease. Measurements used included borderline high of 150-199 mg/dL, moderately high of 200-499 mg/dL and very high of >500 mg/dL. This was a secondary prevention trial, meaning the patients already had heart disease. Unfortunately, a disproportionate number of patients were men, 81 percent. However, this study had a strong duration of 22 years with data based on 15,000 patients. The weakness of this trial was its inability to control for confounders such as sickness, treatments and cause of death. Still, this signifies that triglycerides have an important role in our health.

Triglycerides are affected by diet. The elements in the diet that raise levels include sugars, grains — for some even whole grains — and starchy vegetables as well as saturated fats and trans fats.

What about whole eggs? Good, bad or neutral?

Today, the debates in the medical community over eggs’ merits, detriments or neutrality continue. In an observational trial from Finland, results show that one egg a day did not increase the risk of heart disease (7). Whew, now we can put that debate behind us and eat eggs, right? NOT SO FAST!

While the strength of the trial was its very impressive duration of 21 years, the weaknesses of the trial were huge. First, participants were asked for a four-day dietary history at the start of the trial and then never again. It was assumed that they were eating the same foods over this long time period. Second, there were no blood tests taken specifically for the study. In other words, there are no cholesterol levels for the trial. So we don’t know if one egg a day — and remember we’re making a gigantic assumption that they did eat one egg a day — had any negative impact on cholesterol levels. Third, this study population did not include women. There were 1,032 men involved. Having said all this, you could try an egg a day. However, I would highly recommend a physician’s supervision.

In my practice, I had several patients eat two eggs a day, and their total cholesterol levels went up by approximately 100 mg/dL in one month. But this is anecdotal data from my clinical experience.

In conclusion, don’t think you’re safe if you have a high HDL level. It is best to lower your triglycerides to below 100 mg/dL, and an effective way to do this is by reducing sugars, grains, starchy vegetables and saturated fat in your diet. However, there is subset data suggesting that the fibrate class of drugs may have benefit in those who have triglycerides of at least 500 mg/dL (6).

References: (1) www.nlm.nih.gov. (2) N Engl J Med 2011; 365:2255-2267. (3) Science 2016; 351:1166-1171. (4) AHA 2015 Scientific Sessions; Nov. 10, 2015. (5) N Engl J Med. 2014;371(25):2383-2393. (6) Circ Cardiovasc Qual Outcomes 2016;9:100-108. (7) Am J Clin Nutr. 2016;103(3):895-901.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, visit www.medicalcompassmd.com or consult your personal physician.

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High cholesterol is a problem that affects a countless number of people in the United States. One of the challenges is that it has no noticeable symptoms but may result in an increased risk of cardiovascular disease, including heart attacks and strokes. So what do we do about it?

Currently, the standard medical treatments for high cholesterol are statins. Statins include rosuvastatin (Crestor), atorvastatin (Lipitor), simvastatin (Zocor) and pravastatin (Pravachol). But now a new drug has been approved by the FDA, and it is the first drug in a new class, proprotein convertase subtilisin/kexin type 9 inhibitors or, more affectionately and easier to say, PCSK9 inhibitors.

The first medication approved in this class was Praluent (alirocumab) on Friday, July 24, 2015 (1). PCSK9 inhibitors are monoclonal antibodies that turn off specific proteins in the liver, reducing the levels of LDL, the “bad” cholesterol (2). Right behind, Repatha (evolocumab), another PCSK9 inhibitor, was just recommended by the FDA advisory board. Usually the FDA follows advisory board recommendations.

Therefore, we will likely have two drugs from this class approved and on the market.

Will PCSK9 inhibitors take the place of statins?
Hardly, at this point. The FDA has taken a conservative and narrow approach when it comes to indications for alirocumab (1). Patients who have either heterozygous familial hypercholesterolemia (FH), a genetic disease that affects about 1 in 500 Americans, or those who have atherosclerotic cardiovascular disease (ASCVD), meaning they have had heart attacks, strokes or chest pain due to plaque buildup in the arteries, are presently candidates for treatment. And then, only if both lifestyle modifications and the highest tolerated dose of statins are not sufficient to produce the desired effects. Then, PCSK9 inhibitors may be added to lower LDL further. Patients who are intolerant of statins and who do not have cardiovascular disease are not currently candidates. This may change, but not at the moment.

Class effectiveness of alirocumab and PCSK9
These drugs have been shown to significantly reduce the LDL levels. In five randomized controlled trials, the gold standard of studies, alirocumab was shown to reduce LDL levels by between 36 and 59 percent over placebo (3).

Ironically, though it lowers the LDL considerably, 10-year risk assessment calculator for cardiovascular disease based on the Framingham Heart Study does not include LDL as a consideration (4).

Caveats for this new drug class
There are two significant limitations. One is the outcomes data, and one is the cost. Oh yeah, and I forgot to mention that you need to inject the drug every two weeks.

While this class has shown impressive results in reducing LDL levels, especially compared to statins, it is still in trials to determine whether the reduction in bad cholesterol actually translates into a reduction in cardiovascular events. Trials are not expected to be finished until 2018 (5). This may be one reason for the FDA’s limited treatment population.

Already, drug costs seem to be soaring. Just when we thought they were getting better for statins, since most of them now are generic, here comes a new class of cholesterol-lowering drugs with an even higher price tag. The annual cost for treatment is expected to be around $14,600 (3). This does not help. According to Sanofi and Regeneron Pharmaceuticals, the companies involved, this is a low price for the type of drug, monoclonal antibodies, and the savings from preventing cardiovascular events will be worth the price.

Ironically, the drugs have yet to demonstrate this outcome.

The side effect profile
Unfortunately, with just about every medication there is the dreaded side effect profile. Presently, it seems that alirocumab has a mild side effect profile. These include itchiness, bruising, swelling and pain in the site of injection, flu symptoms and nasopharyngitis (inflammation of the mucous membranes of the nasal passages and pharynx) (3). There were also some allergic reactions that involved hospitalization. As a class, monoclonal antibodies are known to potentially precipitate significant infection. We will have to wait and see whether or not this is the case with PCSK9 inhibitors. Remember, it took a number of years before we knew some of statins’ adverse reactions and the extent of their side effects.

The role of statins
With the recent ACC/AHA guidelines for statin use, published in 2013, these drugs continue to be prescribed for a broader audience of patients. They recommend that those who have LDL levels between 70 and 189 mg/dL and at least a 7.5 percent risk of a cardiovascular event over 10 years are candidates for statins for primary prevention, and this is cost-effective (6). That does not mean these patients necessarily need to have elevated total cholesterol nor elevated bad cholesterol.

In an even broader recommendation, a recent study suggested that people between the ages of 75 and 94 could be on a generic statin for primary prevention of a heart attack or death as a result of coronary heart disease (7). These results were based on using two studies and then forecasting from those results. The authors suggested that this may be both clinically and financially effective. However, they did acknowledge that this would exclude those with adverse reactions to statins.

Have we gone too far with this recommendation? According to an editorial in the same journal, harm from modest side effects would most likely limit the use of these drugs in this population (8).

Impending triglycerides
In two trials, results show that patients who have acute coronary syndrome (ACS) and who are treated with statins have a 50 to 61 percent increased risk of a cardiovascular event in the short term and long term if their triglyceride levels are mildly elevated, either greater than 175 or 195 mg/dL depending on which of the two studies is considered (9). ACS is defined as reduced blood flow to the heart resulting in unstable angina (chest pain), heart attack or cardiac arrest. In one of the two trials, the long-term effects of high triglycerides >175 mg/dL were compared to triglycerides <80 mg/dL. Almost all of the patients were on statins and had LDL levels that were near optimal (<70 mg/dL) with a mean of 73 mg/dL. By the way, “normal” triglycerides, according to most labs, are <150 mg/dL.

Move over bones — vitamin D for healthy cholesterol
In a non-drug-related study, it turns out that high vitamin D levels in children are associated with lower total cholesterol levels, non-HDL “bad” cholesterol levels and triglyceride levels overall (10). The authors note that higher non-HDL levels in children may result in a greater risk of cardiovascular disease in later life.

Though it is exciting to have more options in the arsenal for medical treatment, the moral of the story is that those who do not fit the FDA’s criteria for usage should most likely watch and wait to see how longer term side effects and outcomes play out. Statins are beneficial, as we know, but we may be overreaching in terms of the patient population for treatment. In my clinical experience, lifestyle changes including diet and exercise are important for reducing triglycerides to normal levels. And finally, it is never too early to start mild prevention for cardiovascular disease, such as by managing vitamin D levels.

(1) FDA.gov. (2) health.harvard.edu. (3) medpagetoday.com. (4) cvdrisk.nhlbi.nih.gov. (5) J Am Coll Cardiol. 2015:23;65(24):2638-2651. (6) JAMA 2015; 314:134-141. (7) Ann Intern Med 2015; 162:533-541. (8) Ann Intern Med 2015; 162:590-591. (9) J Am Coll Cardiol 2015; 65:2267-2275. (10) PLoS One. 2015 Jul 15;10(7):e0131938.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com or consult your personal physician.

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Triglycerides is a term that most of us recognize. This substance is part of the lipid (cholesterol) profile. However, this may be the extent of our understanding. Compared to the other substances, HDL (“good” cholesterol) and LDL (“bad” cholesterol), triglycerides are not covered much in the lay press and medical research tends to be less robust than for the other components. If I were to use a baseball analogy, triglycerides are the Mets, who get far less attention than their crosstown rivals, the Yankees.

But are triglycerides any less important? It is unclear whether a high triglyceride level is a biomarker for cardiovascular disease – heart disease and stroke – or an independent risk in its own right (1) (2). This debate has been going on for over 30 years. However, this does not mean it is any less important.

What are triglycerides? The most rudimentary explanation is that they are a kind of fat in the blood. Alcohol, sugars and excess calorie consumption may be converted into triglycerides.

Risk factors for high triglycerides include obesity, smoking, a high carbohydrate diet, uncontrolled diabetes, hypothyroidism (underactive thyroid), cirrhosis (liver disease), excessive alcohol consumption and some medications (3).

What levels are normal and what are considered elevated? According to the American Heart Association, optimal levels are <100 mg/dL; however, less than 150 mg/dL is considered within normal range. Borderline triglycerides are 150-199 mg/dL, high levels are 200-499 mg/dL and very high are >500 mg/dL (3).

While medicines that focus on triglycerides, fibrates and niacin, have the ability to lower them significantly, it is questionable whether this reduction results in clinical benefits, like reducing the risk of cardiovascular events. The ACCORD Study, a randomized controlled trial, questioned the effectiveness of medication; when these therapies were added to statins in type 2 diabetes patients, they did not further reduce the risk of cardiovascular disease and events (4). Instead, it seems that lifestyle modifications may be the best way to control triglyceride levels.

Let’s look at the evidence.

If you need a reason to exercise, here is really good one. I frequently see questions pertaining to optimal exercise timing and intensity. Most of the answers are vague, and the research is not specific. However, hold on to your hats, because a recent study may give the timing and intensity answer, at least in terms of triglycerides.

Study results showed that walking a modest distance with alacrity and light weight training approximately an hour after eating (postprandial) reduced triglyceride levels by 72 percent (5). However, if patients did the same workout prior to eating, then postprandial triglycerides were reduced by 25 percent. This is still good, but not as impressive. Participants walked a modest distance of just over one mile (2 kilometers). This was a small pilot study of 10 young healthy adults for a very short duration. The results are intriguing nonetheless, since there are few data that give specifics on optimal amount and timing of exercise.

There is good news for those who want to lower their triglycerides: calorie restriction may not the best answer. In other words, you don’t have to torture yourself by cutting calories down to some ridiculously low level to get an effect. We probably should be looking at exercise and carbohydrate intake instead.

In a well-controlled trial, results showed that those who walked and maintained 60 percent of their maximum heart rate, which is a modest level, showed an almost one-third reduction in triglycerides compared to the control group (maintain caloric intake and no exercise expenditure) (6). Those who restricted their calorie intake saw no difference compared to the control. This was a small study of 11 young adult women.Thus, calorie restriction was trumped by exercise as a way to potentially reduce triglyceride levels.

In addition, when calorie restriction was compared to carbohydrate reduction, results showed that carbohydrate reduction was more effective at lowering triglycerides (7). In this small but well-designed study, patients with nonalcoholic fatty liver disease were randomized to either a lower calorie (1200-1500 kcal/day) or lower carbohydrate (20 g/day) diet. Both groups significantly reduced triglycerides, but the lower carbohydrate group reduced triglycerides by 55 percent versus 28 percent for the lower calorie group. The reason for this difference may have to do with oxidation in the liver and the body as a whole. Both groups lost similar amounts of weight, so weight could not be considered a confounding or complicating factor. However, the weakness of this study was its duration of only two weeks.

The paradigm has been that, when cholesterol levels are drawn, fasting levels provide a more accurate reading. Except this may not be true.

In a new analysis, fasting may not be necessary when it comes to cholesterol levels. NHANES III data suggests that nonfasting and fasting levels yield similar results related to all-cause mortality and cardiovascular mortality risk. The LDL levels were similarly predictive regardless of whether a patient had fasted or not. The researchers used 4,299 pairs of fasting and nonfasting cholesterol levels. The duration of follow-up was strong, with a mean of 14 years (8).

Why is this relevant? Triglycerides are an intricate part of a cholesterol profile. With regards to stroke risk assessment, nonfasting triglycerides possibly may be more valuable than fasting. In a study involving 13,596 participants, results showed that, as nonfasting triglycerides rose, the risk of stroke also rose significantly (9).

Compared to those who had levels below 89 mg/dL (the control), those with 89-176 mg/dL had a 1.3-fold increased risk of cardiovascular events, whereas those within the range of 177-265 mg/dL had a twofold increase, and women in the highest group (>443 mg/dL) had an almost fourfold increase. The results were similar for men, but not quite as robust at the higher end with a threefold increase.

The benefit of nonfasting is that it is more realistic and, according to the authors, also involves remnants of VLDL and chylomicrons, other components of the cholesterol profile that interact with triglycerides and may affect the inner part (endothelium) of the arteries.

What have we learned? Triglycerides need to be discussed, just as we review HDL and LDL levels regularly. Elevated triglycerides may result in heart disease or stroke. The higher the levels, the more likely there will be increased risk of mortality – both all-cause and cardiovascular. Therefore, we ideally should reduce levels to less than 100 mg/dL.

Lifestyle modifications using carbohydrate restriction and modest levels of exercise after a meal may be the way to go to the best results, though the studies are small and need more research. Nonfasting levels may be as important as fasting levels when it comes to triglycerides and the cholesterol profile as a whole; they potentially give a more realistic view of cardiovascular risk, since we don’t live in a vacuum and fast all day.

(1) Circulation. 2011;123:2292-2333. (2) N Engl J Med. 1980;302:1383–1389. (3) nlm.nih.gov. (4) N Engl J Med. 2010;362:1563-1574. (5) Med Sci Sports Exerc. 2013;45(2):245-252. (6) Med Sci Sports Exerc. 2013;45(3):455-461. (7) Am J Clin Nutr. 2011;93(5):1048-1052. (8) Circulation Online. 2014 July 11. (9) JAMA 2008;300:2142-2152.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.