Treating High Cholesterol: Lifestyle, Statins, and the New Generation of Powerful Cholesterol Drugs
In part 1, we walked through screening and testing for high cholesterol and coronary artery disease, in part 2, we review treatment. Once we know your numbers and your risk, how low should we aim, and what tools – lifestyle and medications – do we have to get there?
We now have:
Better clarity from AHA/ACC guidelines on treatment targets
Multiple classes of cholesterol-lowering medications
Extremely potent newer drugs like PCSK9 inhibitors that can drop LDL by 50–60% on top of statins.
This is how I think about treating and optimizing cholesterol levels (and atherosclerotic risk) in practice. As always, this is general education, not personal medical advice.
What are we actually aiming for?
The most recent 2018 AHA/ACC Cholesterol Guideline focuses on how much we lower LDL cholesterol, and in higher-risk patients, the actual LDL number we land on.
Broadly:
For primary prevention (no prior heart attack or stroke), the goal is often at least a 30–50% LDL reduction, depending on your baseline risk.
For very high-risk patients the guideline aims for:
≥50% LDL reduction and
LDL <70 mg/dL, with some experts pushing even lower in the highest-risk patients.
Large trials (ex: IMPROVE-IT, FOURIER, ODYSSEY Outcomes) consistently show:
as LDL gets lower – even well below 70 mg/dL – cardiovascular events continue to fall, without clear safety signals at very low LDL levels.
So I usually frame the goal this way:
Low to moderate risk: Aim for at least a 30% reduction, little reason not to target LDL below 70 mg/dL if possible, though <100 mg/dL is reasonable depending on the risk.
High or very high risk: LDL well below 70 mg/dL, ideally <55 mg/dL and ≥50% reduction
Lifestyle: still the foundation of cholesterol treatment
Nutrition
Patterns consistently linked to lower LDL and lower event rates:
Mediterranean-style eating
Vegetables, fruits, whole grains, beans, lentils, nuts, seeds, olive oil, and fish.
Less saturated fat, minimal trans fat
Moderate red/processed meats, butter, cream, coconut oil; avoid foods with “partially hydrogenated oils.”
More soluble fiber
Oats, barley, beans, lentils, apples, citrus, flax and chia seeds can all help pull LDL down.
Fewer ultra-processed foods and sugary drinks
These worsen insulin resistance and weight which increase risk of heart attack and stroke independent of cholesterol levels.
Movement and weight
≥150 minutes/week of moderate aerobic activity (50-70% max HR), or 75 minutes vigorous (70%+)
2+ strength sessions/week
Other levers
Stop smoking / nicotine
Keep alcohol modest; it’s no longer recommended as a “heart-protective” strategy
Optimize sleep and stress (both influence blood pressure, weight, and inflammation)
Statins: the workhorse medications
Statins (atorvastatin, rosuvastatin, simvastatin, etc.) are still the backbone of cholesterol treatment, with decades of evidence.
High-intensity statins
Atorvastatin 40–80 mg, Rosuvastatin 20–40 mg ≈50% or more LDL reduction
Moderate-intensity statins
Atorvastatin 10–20 mg, Rosuvastatin 5–10 mg ≈30–49% LDL reduction
Low-intensity statins
Older, small-dose regimens (e.g., simvastatin 10 mg) <30% LDL reduction
What about statin side effects?
The vast majority of people tolerate statins well.
Muscle aches do occur for some, and this often resolves spontaneously. True severe muscle injury is rare.
If someone struggles with side effects, we can: change statin type or dose, add non-statin drugs to achieve targets with lower statin doses.
Non-statins: ezetimibe, bempedoic acid, and more
When statins alone aren’t enough—or aren’t tolerated—we layer other medications.
Ezetimibe
Oral, once-daily, blocks cholesterol absorption in the gut.
Adds roughly 15–25% more LDL reduction on top of a statin.
The IMPROVE-IT trial showed incremental event reduction when ezetimibe was added to statin therapy in high-risk patients.
Bempedoic acid
Oral medication that inhibits ATP-citrate lyase, an enzyme upstream of HMG-CoA reductase (the statin target).
Lowers LDL by roughly 17–28% in trials, particularly in statin-intolerant or incompletely treated patients.
The CLEAR Outcomes trial (2023) showed that in statin-intolerant patients at high risk, bempedoic acid reduced LDL and cardiovascular events vs placebo.
PCSK9 inhibitors: extremely powerful LDL-lowering
PCSK9 (proprotein convertase subtilisin/kexin type 9) is a protein that causes LDL receptors on liver cells to be broken down. More PCSK9 → fewer LDL receptors → higher LDL.
Blocking PCSK9 keeps LDL receptors alive longer, dramatically lowering LDL levels.
Injectable monoclonal antibodies: evolocumab & alirocumab
Evolocumab (Repatha) and alirocumab (Praluent) are subcutaneous injections given every 2–4 weeks.
In large trials (FOURIER for evolocumab; ODYSSEY Outcomes for alirocumab):
~50–60% further LDL reduction on top of statins
Significant reductions in major cardiovascular events.
Real-world data confirm that many patients see 50% or greater LDL reductions, though individual responses vary.
Guidelines generally reserve PCSK9 monoclonal antibodies for:
Very high-risk ASCVD patients whose LDL remains ≥70 mg/dL despite maximally tolerated statin + ezetimibe
Familial hypercholesterolemia (genetic very high LDL)
Selected statin-intolerant patients with high risk and high LDL
Inclisiran: twice-yearly PCSK9-silencing injection
Inclisiran is a small interfering RNA (siRNA) that turns down PCSK9 production in the liver.
In the ORION-10 and ORION-11 trials, twice-yearly inclisiran injections (after initial doses) led to about 50% sustained LDL reductions compared with placebo, on top of background therapy.
The appeal is durable LDL lowering with just two maintenance injections per year.
Emerging oral PCSK9 inhibitors
Several oral PCSK9 inhibitors are now in late-stage development.
Merck’s investigational oral agent enlicitide has shown ≈55–60% LDL reductions vs placebo in phase 3 trials, similar to injectable PCSK9 antibodies, with results recently presented at the American Heart Association meeting in November, 2025.
How I think about “optimizing” cholesterol in practice
Putting it all together, a simplified stepwise approach based on AHA/ACC guidance looks like this:
Step 1: Establish baseline risk and treatment goals
Do you have diabetes? Familial hypercholesterolemia? Smoking?
What is your 10-year risk (using the pooled cohort equations)?
What is your current LDL, and do you have risk-enhancing factors (e.g., high Lp[a])?
Step 2: Maximize lifestyle
Dial in nutrition, movement, weight, sleep, stress, and nicotine cessation.
For some people, this alone is enough to bring LDL into a reasonable range.
Step 3: Initiate or optimize statin therapy
Choose statin intensity based on risk.
Check LDL response after ~6–12 weeks.
Step 4: Add additional meds if needed
If LDL is still above target or statins are limited by side effects: ezetimibe, bempedoic acid, PCSK9i
