DRUG OPTIONS FOR TREATING CHOLESTEROL AND REDUCING CARDIOVASCULAR RISK

A subject I’ve blogged about several times is cholesterol. The biochemistry of cholesterol, it’s clinical significance, and guidelines for treatment can all be found by searching Dr G Opines, and more specifically, DrGOpines.com.

Many times I’ve also said I think statin drugs should be in the water. They are so safe and so effective there is no reason they shouldn’t be. Recently reported information states that statin therapy leads to a 20% to 60% reduction in LDL-C (the bad cholesterol) levels which is the goal, and to a “consistent relative ASCVD risk reduction of 20% to 25%, which is the real purpose.” That means statins do what they’re supposed to do. Two things that have impacted cardiovascular disease the most are smoking cessation and statins!

The safety of statins is not an issue, either. Only “5% to 10% of patients experience statin-associated myalgias or other skeletal muscle adverse effects…” The major catastrophic adverse events the media likes to over-report occur so rarely they’re no longer mentioned.

If you have the slightest elevation of your total cholesterol, especially your LDL-C, you should take a statin. If a parent or sibling died at a young age (under 60) of a heart attack, you should take a statin. If you, personally, have had any cardiovascular event at any age, you should take a statin. If you’re diabetic, you should take a statin. If you fit one of these categories and you’re not taking a statin, shame on you because you’re missing out on a chance to prevent severe cardiovascular events.

Although prevention of first-time cardiovascular events by statins is still a debatable issue, there’s no question statins lessen the incidence of second events. But in Dr. G’s opinion, the prevention of first-time events IS reduced by statins, and anyone in the categories listed in the previous paragraph should be taking one. 

A July 20, 2021, article in JAMA discusses the current options available for lipid-lowering therapy and gives specifics on the nuances of each. Five drugs are currently available for treatment with one promising additional drug awaiting FDA approval. These drugs are:

     HMG-CoA REDUCTASE INHIBITORS—STATINS (there are 7)

     EZETIMIBE—ZETIA

     PCSK-9 INHIBITORS

     BEMPEDOIC ACID

     ICOSAPENT ETHYL—OMEGA-3 FATTY ACID IN FISH OIL

     INCLISIRAN—Not yet available for clinical use-awaiting FDA approval

You’re probably on one or more of these drugs. Having this many options gives physicians a realistic chance to improve cardiovascular outcomes; even better than what we’ve seen with statins alone. 

Statins are the “first-line agents.” They form the base to which other treatments are added. The goal is to lower the LDL-C to less than 70 mg/dL and in most patients that goal is reached. Some patients don’t reach the goal with maximal doses of a statin, or they are unable to tolerate high doses. These patients are candidates for the addition of another drug.

The first, cheapest, and safest option is Ezetimibe (Zetia). This drug lowers cholesterol by  blocking its absorption in the gastrointestinal tract. When added to a statin, it will lower the LDL-C an additional 10% to 20%. Most patients tolerate it very well, and it’s low cost is appealing.

For most patient’s, cholesterol will be controlled by the statin-ezetimibe combination, and nothing stronger will ever be needed. However, for those folks who don’t get to goal, the other  three drugs, and soon a fourth, are available. The problem, if you can call it that, is that  PCSK-9 Inhibitors are injectable drugs (every 2-4 weeks) and Bempedoic acid is very expensive ($360/month on average). 

PCSK-9 inhibitors are very effective at lowering LDL-C. A 50% to 60% reduction, when prescribed alone, or added to a statin, is common. The statin-PCSK-9 combination has shown a 15% reduction in ASCVD risk beyond that of a statin alone. However, it is an injection that is given every 2-4 weeks. Cost ranges from $450 to $550 per month. Those two factors are somewhat of a deterrent.

Icosapent Ethyl is orally administered and is a synthetic form of omega-3 fatty acids found in fish oil. Adding it to a statin further reduces ASCVD risk by 25%.

Bempedoic acid is given orally and lowers LDL-C by about 20%. For patients who cannot tolerate a statin, Bempedoic acid is an ideal substitution. No study has yet proven this drug improves ASCVD outcomes, though.

The new kid on the block, Inclisiran, is awaiting FDA approval. It is injectable, but is given only once every six months after a 1-3 injection loading period. Adverse events are rare to date. It’s anticipated INCLISIRAN with improve medication adherence rates and lead to more consistent lowering of LDL-C. 

So, in a nutshell, this is the current cholesterol-lowering armamentarium—A Statin baseline, followed by adding ezetimibe, then, if necessary, Bempedoic acid, Icosapent Ethyl, or PCSK-9 Inhibitor, and when approved, injections of Inclisiran. Lowering the LDL-C to below 70 mg/dL and elevating the HDL-C to 60 mg/dL or higher are the goals that ultimately lead to reducing the risk of arteriosclerotic cardiovascular disease. More studies are being conducted to clarify this outcome, but results have already shown improvement and great promise.  

Dr. G’s Opinion: I’m a very vocal statin advocate. Started at an early age, statins can neutralize the chronic “dietary sins of our youth and adulthood,” and reverse a genetically-generated high cholesterol. In my opinion, you’re never too old to start. N.B. rjwatercolors. As recently as 8 years ago, the last four drugs did not exist, or at least I was unaware of them. Now that they are available and seem to be quite safe, there is good reason to expect every patient’s cholesterol to be at goal. Hopefully, that will translate to a far lower incidence of ASCVD, the real goal. 

Reference: JAMA Insights/Clinical Update. Wilkins JT, Lloyd-Jones DM  Novel Lipid-Lowering Therapies to Reduce Cardiovascular Risk JAMA 2021 July 20;326(3):266-267.