Sleeper Strategies for Cholesterol and Triglycerides

In the 1973 Woody Allen movie Sleeper, the main character, Miles Monroe is cryogenically frozen. He awakens 200 years later in a new world, filled with wondrous new technology, such as robot butlers, self-driving cars, video chatting, and personal hovercrafts. However, one of the most surprising things about this strange new world occurs when Miles sits for breakfast. The former health food storeowner asks for wheat germ and granola only to be told that steak, eggs, cream pies, hot fudge and other high cholesterol, high fat foods were now thought to be healthy.  A few years prior to the release of Sleeper, the groundbreaking Framingham Heart Study first implicated high cholesterol levels in the blood as a risk factor for heart artery disease, setting off a national frenzy towards low fat low cholesterol diets.  While many of the technological advances predicted by Sleeper have already come to pass, high cholesterol and high triglycerides in the blood are still associated with heart disease. 

In 2013, the American College of Cardiology and the American Heart Association published an updated guideline on treating high cholesterol to reduce the risk of heart artery disease.  The guideline identified four categories of patients who should be treated. The first category includes patients with a heart attack, a heart stent, a stroke or blockage in the leg arteries. Treating this group, who already has established disease, aims to prevent another event in someone who has disease; this is called secondary prevention.  The next three categories aim to reduce risk for those who have not yet demonstrated heart disease; called primary prevention. These patients include: 1) patients with low density lipoprotein (LDL) levels > 190, 2) diabetic patients with LDL levels between 70 and 189 and 3) patients whose 10 year estimated risk for heart disease is greater than 7.5%, based on a risk calculator (www.cvriskcalculator.com).

For treatment, the guideline recommends statins. Statins have a clearly demonstrated benefit in each of the four categories, with those benefits outweighing the risks of the medication. Other medications (niacin, fibrates, omega 3 fatty acids, for example) can lower cholesterol, but do not reduce heart attacks, stroke and death. So statins clearly are the medications to use to lower cholesterol, but how to use them is not as clear. Prior to this guideline, doctors were expected to lower a patient’s LDL to under 100 for primary prevention or under 70 in those who already had heart disease. Patients were started on low doses of statins and their dose increased based on the their blood tests until they met the goal. These numbers, 100 and 70, were not based on data from trials but rather from the opinion of experts. The guideline authors found that there was absolutely no data supporting titration of medications to a specific LDL goal (ie, increasing statin dosage until a prespecified target was achieved).  Therefore, the 2013 guideline controversially recommended shifting away from treating to an LDL target to treating with a fixed dose of a statin (where there is supporting data) and using the highest tolerated dose of a statin. For example, a heart attack patient may be started on a high-intensity statin (such as Lipitor or Crestor) and subsequent blood tests are used only to see if there are side effects or to see if the patient is taking the medication. The medical community did not embrace this recommendation as patients (and doctors) are very goal oriented and like to see their cholesterol numbers go down and hit a target.  A reasonable hybrid approach would be to start a moderate or high dose of a statin, and then check blood work. If the patient is at goal and tolerating the medication, then no change is made. If the patient is not at goal, then the statin dose can be increased and labs repeated.

Even the idea of lowering cholesterol itself is controversial; does lowering cholesterol reduce the risk of heart disease, stroke and heart death?  This is the called the cholesterol lowering hypothesis. Statins lower cholesterol, but so do a number of other medications. Statins have been shown to reduce the risk for heart attack and stroke, while other medications have not.  The reason may be that statins have other properties (for example, anti-inflammatory effects) that may be a factor in their ability to lower risk.  At the time the 2013 guideline was published, there was no data showing that adding a non-statin drug to a statin further reduced cardiac risk. Since then the IMPROVE-IT trial showed that adding ezetimibe (Zetia) to simvastatin (Zocor) reduced cardiac events to a modest degree.  This was the first non-statin to show a benefit and the trial seemed to validate the cholesterol-lowering hypothesis. Given this data, it would be reasonable to add Zetia to patient who is on a maximally tolerated statin but whose LDL is still high. Even more recently, newer injectable agents have been developed which dramatically lower cholesterol and LDL levels.  Trials are ongoing to see if these agents reduce the risk for heart disease and heart deaths, providing further confirmation of the cholesterol lowering hypothesis.

It has been known for years that a high level of triglycerides is associated with heart disease.  A recent study looked at 15,000 heart patients and found that high triglyceride levels increased the risk of death over 22 years, even after adjusting for cholesterol levels.  The higher the triglycerides, the higher the risk for death. Another study showed that patients with a genetic mutation that produced low triglyceride levels had a low risk for heart disease.  Unfortunately, how to treat triglycerides is not clear as there is no evidence that lowering triglycerides lowers the risk for heart events. There is no data showing that lowering triglycerides above and beyond lowering LDL levels with statins reduces heart attack and strokes. Triglycerides can be reduced by watching carbohydrates, losing weight, exercising, increasing fish consumption and treating diabetes.  Recently, the Food and Drug Administration (FDA) took the unusual step of withdrawing approval for niacin and fenofibrate combinations with statins stating, “scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels…in statin-treated patients results in a reduction in the risk of cardiovascular events”.

Much is known about cholesterol and triglycerides and the role they play in heart disease. However, there is a lot to be learned about which medications should be used and how to best use them. Stay tuned; hopefully it won’t take another 157 years to find the answers. Until then, both the art and the science of medicine should be used to achieve the best outcome for each individual patient.