Statins (HMG-CoA Reductase Inhibitors)

What This Medicine Does

Statins are one of the most studied and prescribed medicines in the world. They work by:

1. Blocking cholesterol production - Your liver makes less cholesterol
2. Increasing cholesterol removal - Your liver removes more LDL from your blood
3. Stabilizing plaque - Helps make cholesterol deposits in arteries less likely to rupture
4. Reducing inflammation - Calms inflammation in your blood vessels

The result: Lower LDL cholesterol and significantly reduced risk of heart attack and stroke.

---

Understanding Cholesterol & Statins

Why Lower LDL?

LDL ("bad" cholesterol) builds up in your artery walls, forming plaque. Over time, this plaque can:

• Narrow your arteries (reducing blood flow)
• Rupture suddenly (causing heart attack or stroke)
• Make arteries stiff and less flexible

Statins help prevent and partially reverse this process.

How Much Benefit?

For every 39 mg/dL (1 mmol/L) reduction in LDL:

• Heart attack risk drops by ~20%
• Stroke risk drops by ~15-20%
• Benefits start within the first year and continue long-term

---

What to Expect: A Timeline

Week 2-4: First Results

• Cholesterol levels start dropping
• Your doctor may check levels at this point

Month 2-3: Full Effect

• Maximum cholesterol-lowering effect achieved
• Your doctor will check if the dose is working

Long-Term: Ongoing Protection

• Heart and blood vessel benefits continue as long as you take it
• Risk reduction accumulates over years

---

Common Things You Might Notice

Muscle Symptoms (Most Common Concern)

What people report:

• Mild muscle aches
• Soreness or stiffness
• Weakness (rare)
• Cramps (rare)

Important context:

• True statin-related muscle problems occur in about 5-10 people out of 100
• Many people blame statins for muscle aches that have other causes
• Exercise, aging, and vitamin D deficiency can cause similar symptoms

What to do:

• Tell your doctor about muscle symptoms
• Don't stop on your own - your doctor can check if it's really the statin

Other Common Effects

• Mild digestive upset (nausea, gas, constipation)
• Headache (usually mild)
• Slight fatigue or weakness (rare)
• Sleep problems (very rare)

---

Muscle Symptoms: What's Really Happening?

True Statin Muscle Problems

• Myalgia: Muscle aches without lab abnormalities (most common)
• Myopathy: Muscle symptoms with elevated CK (blood test)
• Rhabdomyolysis: Severe muscle breakdown (very rare, ~1 in 100,000)

The "Nocebo" Effect

Studies show an interesting pattern:

• When people know they're taking a statin, muscle symptoms are common
• When people don't know (blinded studies), muscle symptoms are similar to placebo
• This doesn't mean symptoms aren't real - just that the cause may not be the medicine

If you have muscle symptoms, don't stop abruptly. Your doctor can:

1. Check a blood test (CK) to see if muscle damage is occurring
2. Try a lower dose
3. Switch to a different statin
4. Try alternate-day dosing

---

When to Call Your Doctor

Seek Immediate Care For:

• Dark, cola-colored urine - May indicate severe muscle breakdown
• Severe, unexplained muscle pain - Especially with weakness
• Yellowing of skin or eyes - Possible liver problem (rare)
• Severe abdominal pain - With nausea and vomiting

Contact Your Doctor Soon For:

• New or worsening muscle symptoms
• Muscle weakness that affects daily activities
• Unusual fatigue or weakness
• Scheduled surgery (may need to hold statin)

---

Daily Practical Tips

1. Take it consistently - Same time each day helps you remember

2. Evening dosing optional - For atorvastatin and rosuvastatin, any time works. For others, evening may be slightly more effective (your liver makes more cholesterol at night)

3. Avoid grapefruit juice - If taking simvastatin, atorvastatin, or lovastatin, grapefruit can increase blood levels (rosuvastatin and pravastatin are fine with grapefruit)

4. Report all muscle symptoms - Let your doctor know about any muscle pain, but don't stop on your own

5. Exercise is safe - Physical activity doesn't increase risk of muscle problems

6. Stay consistent - Don't skip doses; cholesterol-lowering effect depends on regular use

---

Pregnancy & Breastfeeding

Important: Statins should generally NOT be taken during pregnancy or breastfeeding.

• Stop statins before trying to become pregnant
• Use effective contraception if taking statins and of childbearing age
• If you become pregnant while taking a statin, contact your doctor immediately

---

Food & Medicine Interactions

Grapefruit Juice

• Affects: Simvastatin, atorvastatin, lovastatin
• Why: Grapefruit blocks breakdown of these statins, increasing blood levels
• Safe with: Rosuvastatin, pravastatin, pitavastatin, fluvastatin

Other Important Interactions

---

For Healthcare Professionals

Clinical Information

Pharmacology & Mechanism

Statins competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. This reduces hepatic cholesterol, upregulates LDL receptors, and increases LDL clearance from plasma. Additional pleiotropic effects include plaque stabilization, anti-inflammatory properties, and improved endothelial function.

Statin Intensity Classification

Dosing & Administration

Starting Dose Selection:

• High ASCVD risk: High-intensity statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg)
• Moderate risk: Moderate-intensity statin
• Lower risk: Consider moderate-intensity based on risk-benefit discussion
• Age ＞75: Start moderate-intensity; consider high-intensity if tolerated

Administration:

• Can be taken any time of day for atorvastatin/rosuvastatin
• Evening dosing preferred for simvastatin, lovastatin, fluvastatin (liver cholesterol synthesis peaks nocturnally)
• May be taken with or without food

Monitoring

Baseline:

• Fasting lipid panel (LDL-C, non-HDL-C, ApoB optional)
• ALT, AST
• CK baseline if high risk for myopathy or symptoms present

Follow-up:

• Recheck lipids 4-12 weeks after initiation or dose change
• Repeat liver enzymes only if symptomatic or dose escalation to high-intensity
• Routine CK monitoring not recommended (check only if symptoms present)
• Once stable, lipids every 3-12 months

Expected Lipid Response:

• LDL-C reduction: High intensity 50%, Moderate intensity 30-50%
• Triglycerides: 7-30% reduction
• HDL-C: 5-10% increase

Contraindications & Warnings

Contraindications:

• Active liver disease or unexplained persistent ALT elevation ＞3x ULN
• Pregnancy (Category X)
• Breastfeeding
• Hypersensitivity to statin components

Warnings & Precautions:

• Myopathy - Risk factors: advanced age, female, Asian ancestry, renal/hepatic impairment, interacting medications, high statin dose
• Rhabdomyolysis - Rare but serious; monitor CK with muscle symptoms
• Liver enzyme elevation - Routine monitoring not required; check if symptomatic
• Cognitive effects - Reports of memory loss/confusion; causal relationship not established; benefits generally outweigh risks
• New-onset diabetes - Small increase in risk (9-12%); higher with intensive statin therapy
• Hemorrhagic stroke - Possible increased risk in those with prior hemorrhagic stroke

Drug Interactions

CYP3A4 Interactions (affect atorvastatin, simvastatin, lovastatin):

Non-CYP3A4 Statins (rosuvastatin, pravastatin, pitavastatin):

• Fewer drug interactions
• Preferred when polypharmacy necessary
• Note: Rosuvastatin levels increased by gemfibrozil and cyclosporine despite non-CYP metabolism

Muscle Symptom Management

Algorithm for Muscle Symptoms:

1. Assess CK - If symptoms present
2. If CK normal - Continue statin, monitor, or try lower dose/alternate statin
3. If CK ＞4x ULN - Discontinue statin, recheck CK in 2-4 weeks
4. If CK ＞10x ULN - Discontinue statin, monitor for rhabdomyolysis
5. Rechallenge - If symptoms improve, may try lower dose or different statin

Statin-Associated Muscle Symptoms (SAMS):

• True SAMS: ~5-10% incidence
• Many "statin intolerant" patients can tolerate:
  • Lower dose
  • Alternate-day dosing (especially with long half-life statins)
  • Different statin
  • Non-statin alternatives (ezetimibe, PCSK9 inhibitors, bempedoic acid)

Special Populations

Pregnancy: Category X - discontinue prior to conception; alternatives include bile acid sequestrants

Breastfeeding: Contraindicated

Geriatric: Start moderate-intensity; monitor for drug interactions and polypharmacy

Renal Impairment:

• Atorvastatin: No adjustment needed
• Rosuvastatin: Max 10 mg if CrCl ＜30 mL/min
• Pravastatin: No adjustment needed
• Simvastatin: Avoid if CrCl ＜30 mL/min

Asian Ancestry: Higher rosuvastatin blood levels; start at 5 mg, max 20 mg

Efficacy & Outcomes

Primary Prevention:

• 21% relative risk reduction in major ASCVD events per 1 mmol/L (39 mg/dL) LDL reduction

Secondary Prevention:

• 22% relative risk reduction in major ASCVD events
• All-cause mortality reduction ~10%
• Stroke risk reduction ~20%

High-Intensity vs Moderate-Intensity:

• Additional 15% relative risk reduction with high-intensity
• Absolute benefit depends on baseline risk

---

---

References

1. FDA Statin Prescribing Information (atorvastatin, rosuvastatin, simvastatin, pravastatin). U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/
2. Grundy SM, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Journal of the American College of Cardiology. 2019;73:e285-e350. https://www.acc.org/guidelines
3. Ference BA, et al. Variations in PCSK9 and HMGCR and Cardiovascular Events. Journal of the American College of Cardiology. 2019;73:2349-2359. https://pubmed.ncbi.nlm.nih.gov/
4. Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and Safety of Statin Therapy. The Lancet. 2015;385:1549-1555. https://pubmed.ncbi.nlm.nih.gov/
5. NIH National Heart, Lung, and Blood Institute. Cholesterol Management. https://www.nih.gov/
6. American Heart Association. Statins and Cardiovascular Prevention. https://www.heart.org/

---

Medical Disclaimer: This content is for educational purposes only and is not a substitute for professional medical advice. Always consult your healthcare provider before starting, stopping, or changing any medication.