Best Med #3: statins
Next up on my list of “Best Meds,” let’s talk about statins.
Lipidology is an amazingly complex and ever-evolving field that is way beyond the bounds of what one article can accomplish. But it is clear that high levels of low-density lipoprotein (LDL)-cholesterol can promote the accumulation of plaque in the arteries and raise your risk for heart attack and stroke. Therefore, it seems practical and prudent to focus on LDL as the target for cardiovascular risk reduction.
Statins are a class of drugs that work to stop the body from producing LDL-cholesterol and reabsorb existing LDL. Statins work by competitively inhibiting HMG-CoA reductase, the rate limiting enzyme in the cholesterol synthesis pathway. When there is less LDL cholesterol in the blood, the liver senses this and produces more LDL receptors to increase uptake, thereby further reducing the LDL in the blood. And this works to reduce the risk of what we call atherosclerotic cardiovascular disease (ASCVD) events, defined as a nonfatal myocardial infarction (heart attack), death from coronary heart disease, or stroke. Each 1 mmol/L (approximately 39 mg/dl) reduction in LDL levels in the blood reduces the risk of ASCVD events by 22% after 5 years.
Like metformin, evidence indicates that statins also have these “pleiotropic” effects and may prevent cardiovascular disease by improving the health of blood vessels, modulating the body’s inflammatory response, maintaining the stability of plaques in the arteries (plaque rupture is what causes the badness), and preventing blood clot formation.
Lovastatin, isolated from the fungus Aspergillus terreus, was the first statin brought to market in 1987 after nearly two decades of searching and research. Now there are many statins on the market including fermentation-derived types like pravastatin and simvastatin and synthetic types like atorvastatin and rosuvastatin. They differ in intensity—the amount by why they lower LDL in the blood.
Statins should unquestionably be used for secondary prevention—reducing the impact of a disease or injury that has already occurred. There is irrefutable evidence that statins decrease mortality in people with known cardiovascular disease, which includes prior stroke, unstable or stable angina, and vascular disease. Few drugs have had such a dramatic effect on health outcomes. Greater benefit is seen with higher intensity statin therapy. In other words, once a patient has a heart attack or stroke, we get them on high intensity statin therapy immediately.
Statin use becomes a bit more complicated and controversial when we are talking about primary prevention—preventing disease or injury before it occurs. Guidelines by the American College of Cardiology and the American Heart Association recommend statin treatment for primary prevention of cardiovascular disease in adults with LDL cholesterol ≥ 190 mg/dL and/or those with diabetes. These guidelines also recommend statins for those who have at least one risk factor for coronary heart disease, are between ages 40 and 75 years old, and have at least 10% ten-year risk of heart disease. This risk calculation uses a pooled cohort algorithm that includes risk factors such as abnormal lipid levels in the blood, diabetes, high blood pressure, and smoking. For those with a 10-year cardiovascular disease event risk of 7.5-10% or greater, we consider using a low-to-moderate intensity statin. This decision to initiate statin therapy for those on the borderline is a matter of shared decision making between a physician and a patient. Additional information such as a family history, blood tests for specific molecules like ApoB and Lipoprotein(a), and a coronary calcium score can all help to inform the decision.
There is a storm of controversy around these recent guidelines with critics saying that they vastly overestimate the risk and therefore put many patients on statins who will not benefit. Critics also lament the absence of a clear LDL treatment target. And most unfortunately, outsized media attention on the potential adverse consequences—muscle pains, liver toxicity, elevated blood sugar, cognitive impairment, etc.—has caused significant misinformation about the side effects of statin therapy. Here is some information to help clear the muddy waters.
Statin associated muscle symptoms (SAMS) are the most commonly reported adverse effects of statins. Randomized control trials, the gold standard of drug research, actually report minimal differences in the rates of muscle symptoms between statin-treated and placebo-treated groups. Despite this, the reported incidence of SAMS in patients taking statins ranges from 10-29% and is one of the major reasons that patients stop therapy. Thankfully, the incidence of actual muscle breakdown is extremely low. Given the risk reduction benefits of statins, it is worthwhile to try a lower dose of the same statin or use a different statin before discontinuing therapy altogether.
Data do indicate that statin therapy increases the relative risk of developing new onset diabetes. While not insignificant, the ability of statins to dramatically reduce the risk of cardiovascular events far outweighs the risk of new-onset diabetes. The strongest predictors of diabetes, regardless of whether patients have received statins, include older age, higher baseline fasting glucose levels, and other features of the metabolic syndrome—all of which can be addressed through proper lifestyle behaviors. The risk appears to be greatest among people in whom diabetes is most likely to develop anyway — at which point they would be treated with statins as part of their routine care.
Statins are metabolized in the liver and were once thought to be a cause of liver toxicity. However, rates of liver injury are quite rare and now we do not even check liver enzymes routinely except for once, just prior to the initiation of statin therapy. The most common reason for elevated liver enzymes here in the U.S. is nonalcoholic fatty liver disease (NAFLD) which is related to obesity. Statin use in patients with NAFLD is associated with a reduction in liver enzymes and improved liver health.
Observational studies on the association between statin therapy and cognitive function have shown mixed results. Despite initial concerns, higher quality evidence—meta analyses and randomized controlled trials—show no association between statin use and cognitive dysfunction.
Here is a helpful image that summarizes the clinical benefits and potential adverse effects of statin therapy.
My final take: Overwhelming evidence suggests that the benefits of statin therapy far outweigh any real or perceived risks. This has been shown time and again in clinical trial after clinical trial. Indeed, statins rank amongst the most studies drug classes. However, the effectiveness of statins has mostly been studies in middle aged and older individuals during relatively short treatment periods. To what extent these results can be extrapolated to younger individuals remains unclear.
While an abundance of data may not yet exist, there is no reason to believe that statins are not effective in younger patients, even those who do not technically qualify for therapy based on current guidelines. And it seems reasonable to start communicating the benefit of statins not solely in terms of ASCVD risk reduction, but as gains in life expectancy.
While we generate more data on the efficacy of statins in a younger demographic, we must identify young individuals at increased risk of ASCVD on a case by case basis. A comprehensive risk assessment digs deeper that standard lipid profiles and risk scores to include a detailed family history, cholesterol subdivisions particle numbers, novel biomarkers of vascular inflammation, and coronary calcium scoring. We have the tools and tests to get a more robust picture for each patient.
Statins appear to be a potent ingredient for a long, healthy life. We should be positioning them as such for both younger and older people alike.