HMG-CoA Reductase Inhibitors Drug-Drug Interaction Table: A Complete Prescriber Reference

What Is the HMG-CoA Reductase Inhibitor Drug Class?

HMG-CoA reductase inhibitors competitively block 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in the mevalonate pathway. Blocking this step cuts hepatic cholesterol synthesis, forces upregulation of LDL receptors, and clears LDL-C from plasma. Eight agents are currently FDA-approved in the United States: atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and the combination product lovastatin/niacin extended-release.

Cardiovascular Outcomes Evidence

The 4S trial (N=4,444) demonstrated that simvastatin 20 to 40 mg reduced major coronary events by 34% over 5.4 years versus placebo in patients with established coronary disease (1). The JUPITER trial (N=17,802) extended this finding to primary prevention: rosuvastatin 20 mg daily cut first major cardiovascular events by 44% (hazard ratio 0.56, 95% CI 0.46 to 0.69, P<0.00001) in patients with elevated hsCRP but LDL-C <130 mg/dL (2). These two trials, separated by 15 years, define the endpoints that statin prescribers are trying to reach.

Intensity Classifications

The 2018 AHA/ACC Guideline on the Management of Blood Cholesterol classifies statins by the LDL-C reduction they produce at standard doses (3):

• High-intensity (LDL-C reduction ≥50%): Atorvastatin 40 to 80 mg, rosuvastatin 20 to 40 mg
• Moderate-intensity (LDL-C reduction 30 to 49%): Atorvastatin 10 to 20 mg, rosuvastatin 5 to 10 mg, simvastatin 20 to 40 mg, pravastatin 40 to 80 mg, lovastatin 40 mg, fluvastatin XL 80 mg, pitavastatin 2 to 4 mg
• Low-intensity (LDL-C reduction <30%): Simvastatin 10 mg, pravastatin 10 to 20 mg, lovastatin 20 mg, fluvastatin 20 to 40 mg, pitavastatin 1 mg

The guideline states: "For patients who are 75 years or younger with clinical ASCVD, high-intensity statin therapy is recommended to reduce LDL-C by at least 50 percent." (3)

Pharmacokinetic Foundations of Statin DDIs

Understanding which statins use which pathways is not optional background knowledge. It is the core of safe prescribing. Every interaction in the table below flows from one of three mechanisms: CYP-mediated metabolism, hepatic uptake transporter inhibition, or efflux transporter inhibition.

CYP3A4-Dependent Statins

Simvastatin, lovastatin, and atorvastatin are all CYP3A4 substrates, but their sensitivity differs considerably. Simvastatin and lovastatin are prodrugs (lactone forms) that undergo near-complete first-pass CYP3A4 metabolism, making them highly sensitive to CYP3A4 inhibition. Atorvastatin is metabolized by CYP3A4 to active hydroxylated metabolites, conferring moderate sensitivity.

Itraconazole 200 mg daily for 4 days increased simvastatin acid AUC by 13.1-fold in a pharmacokinetic crossover study (N=10) (4). That is not a borderline interaction. It is a contraindication in the FDA label for simvastatin.

Clarithromycin 500 mg twice daily for 7 days increased atorvastatin AUC approximately 4.5-fold (5). The simvastatin label caps the dose at 20 mg when clarithromycin cannot be avoided; substituting a non-CYP3A4 statin is usually preferable.

OATP1B1/1B3 Transport

Organic anion-transporting polypeptides 1B1 and 1B3 (encoded by SLCO1B1 and SLCO1B3) mediate hepatic uptake of all statin acids from portal blood into hepatocytes. When these transporters are inhibited, statin concentrations in systemic plasma rise, skeletal muscle exposure increases, and myopathy risk climbs without any corresponding increase in hepatic LDL-receptor upregulation.

Cyclosporine is the archetypal OATP1B1/1B3 inhibitor and also inhibits CYP3A4 and P-glycoprotein. Co-administration with cyclosporine increases rosuvastatin AUC approximately 7-fold, simvastatin acid AUC approximately 8-fold, and atorvastatin AUC approximately 6.8-fold (6). Every statin label contains a specific dose cap or contraindication for cyclosporine co-administration.

Gemfibrozil inhibits OATP1B1 and also inhibits the glucuronidation pathway (UGT1A3) responsible for lactonizing and eliminating certain statin acids. The combination raises cerivastatin AUC by approximately 6-fold, which contributed to cerivastatin's market withdrawal in 2001 after 52 rhabdomyolysis-associated deaths (7). Fenofibrate, by contrast, does not appreciably inhibit OATP1B1 and carries a substantially lower interaction risk with statins.

BCRP and P-Glycoprotein

Breast cancer resistance protein (BCRP, encoded by ABCG2) limits intestinal absorption of rosuvastatin. Eltrombopag, an oral thrombopoietin receptor agonist and BCRP inhibitor, raises rosuvastatin AUC by approximately 55%. BCRP inhibition is especially relevant for newer combination HIV regimens containing cobicistat, which inhibits CYP3A4, P-glycoprotein, and BCRP simultaneously.

The Statin DDI Reference Table

The table below covers clinically significant interactions for each FDA-approved statin. AUC fold-changes reflect data from the FDA drug label or published pharmacokinetic studies. Dose cap = maximum recommended statin dose when co-administration cannot be avoided. "Avoid" = FDA-labeled contraindication or strong avoidance language.

Simvastatin Interactions

| Interacting Drug / Class | Mechanism | AUC Change | FDA Recommendation | |---|---|---|---| | Itraconazole, ketoconazole, posaconazole, voriconazole | CYP3A4 inhibition | Up to 13-fold | Contraindicated (8) | | Clarithromycin, erythromycin, telithromycin | CYP3A4 inhibition | Approx. 3 to 10-fold | Avoid; if unavoidable, cap at 20 mg | | HIV protease inhibitors (nelfinavir, lopinavir/ritonavir, saquinavir) | CYP3A4 inhibition | Up to 12-fold | Contraindicated | | Cobicistat-containing regimens | CYP3A4 + P-gp inhibition | Data limited; expected >5-fold | Contraindicated | | Cyclosporine | OATP1B1 + CYP3A4 | Approx. 8-fold | Contraindicated | | Gemfibrozil | OATP1B1 + UGT inhibition | Approx. 3-fold | Contraindicated | | Danazol, amiodarone | CYP3A4 inhibition | Approx. 2.5 to 3-fold | Cap at 20 mg | | Diltiazem | CYP3A4 inhibition | Approx. 2.7-fold | Cap at 10 mg | | Verapamil | CYP3A4 inhibition | Approx. 2.3-fold | Cap at 20 mg | | Amlodipine | CYP3A4 inhibition (weak) | Approx. 1.6-fold | Cap at 20 mg | | Colchicine | Uncertain; possibly P-gp | Case reports | Use with caution; lowest effective dose | | Large quantities of grapefruit juice (>1 L/day) | CYP3A4 inhibition in gut | Up to 16-fold (case reports) | Avoid |

Atorvastatin Interactions

| Interacting Drug / Class | Mechanism | AUC Change | FDA Recommendation | |---|---|---|---| | Cyclosporine | OATP1B1 + CYP3A4 | Approx. 6.8-fold | Avoid | | Clarithromycin 500 mg BID | CYP3A4 inhibition | Approx. 4.5-fold | Use lowest effective atorvastatin dose; monitor | | Itraconazole 200 mg QD | CYP3A4 inhibition | Approx. 3-fold | Avoid high doses; use lowest dose with monitoring | | Ritonavir + saquinavir | CYP3A4 inhibition | Approx. 3.9-fold | Cap at 40 mg | | Lopinavir + ritonavir | CYP3A4 inhibition | Approx. 5.9-fold | Cap at 20 mg | | Tipranavir + ritonavir | CYP3A4 inhibition | Approx. 9.4-fold | Avoid | | Gemfibrozil | OATP1B1 + UGT | Approx. 1.4-fold | Use with caution; fenofibrate preferred | | Colchicine | Unknown | Case reports | Caution; monitor for myopathy | | Elbasvir/grazoprevir | OATP1B1 | Approx. 1.9-fold | Cap at 20 mg | | Glecaprevir/pibrentasvir | OATP1B1 | Approx. 8.3-fold | Avoid |

Rosuvastatin Interactions

| Interacting Drug / Class | Mechanism | AUC Change | FDA Recommendation | |---|---|---|---| | Cyclosporine | OATP1B1 | Approx. 7-fold | Contraindicated (cap at 5 mg per label) | | Gemfibrozil | OATP1B1 | Approx. 1.9-fold | Cap at 10 mg | | Lopinavir + ritonavir | OATP1B1 + BCRP | Approx. 2.1-fold | Cap at 10 mg | | Atazanavir + ritonavir | OATP1B1 | Approx. 3.1-fold | Cap at 10 mg | | Glecaprevir/pibrentasvir | OATP1B1 + BCRP | Approx. 5.6-fold | Cap at 10 mg | | Elbasvir/grazoprevir | OATP1B1 | Approx. 1.6-fold | Cap at 10 mg | | Sofosbuvir/velpatasvir/voxilaprevir | OATP1B1 + BCRP | Approx. 7.4-fold | Avoid | | Encorafenib | BCRP + OATP1B1 | Approx. 3.2-fold | Avoid or use lowest dose | | Antacids (aluminum/magnesium) | Reduced absorption | Approx. 0.46-fold (54% decrease) | Separate by ≥2 hours | | Colchicine | Unknown | Case reports | Caution |

Pravastatin, Pitavastatin, and Fluvastatin Interactions

| Statin | Interacting Drug | Mechanism | AUC Change | Recommendation | |---|---|---|---|---| | Pravastatin | Cyclosporine | OATP1B1 | Approx. 10-fold | Cap at 20 mg | | Pravastatin | Gemfibrozil | OATP1B1 | Approx. 1.4-fold | Use with caution | | Pravastatin | Clarithromycin | OATP1B1 (minimal CYP) | Approx. 1.0-fold | No dose adjustment needed | | Pitavastatin | Cyclosporine | OATP1B1 | Approx. 4.6-fold | Contraindicated | | Pitavastatin | Gemfibrozil | OATP1B1 + UGT | Approx. 1.4-fold | Cap at 1 mg | | Pitavastatin | Rifampin | OATP1B1 induction then inhibition | Approx. 1.3-fold (induction) | Use with caution | | Fluvastatin | Fluconazole | CYP2C9 inhibition | Approx. 2.4-fold | Cap at 20 mg or use alternate | | Fluvastatin | Cyclosporine | OATP1B1 | Approx. 2-fold | Cap at 20 mg | | Fluvastatin | Gemfibrozil | OATP1B1 + CYP2C9 | Approx. 1.5-fold | Use with caution |

Myopathy Risk: Quantifying the Clinical Consequence

DDI tables only matter if you understand what elevated statin exposure actually does to patients. Statin myopathy exists on a spectrum: myalgia (muscle pain without CK elevation), myositis (muscle pain with CK >10x upper limit of normal), and rhabdomyolysis (CK >10x ULN with myoglobinuria or renal impairment).

Background Rates Without DDIs

In the Heart Protection Study (N=20,536), confirmed myositis occurred in 0.05% of simvastatin 40 mg recipients versus 0.03% of placebo recipients over 5 years, a difference that was not statistically significant (9). Rhabdomyolysis occurred in 5 simvastatin patients (0.05%) and 3 placebo patients (0.03%). These rates are low enough that routine CK monitoring is not recommended in asymptomatic patients by ACC/AHA guidance.

DDI-Amplified Risk

When CYP3A4 inhibitors are added, myopathy risk rises in proportion to AUC increases. The FDA's 2011 simvastatin label revision was triggered by data showing that simvastatin 80 mg had a 0.9% rate of myopathy per year, and that interaction with amiodarone, verapamil, or diltiazem increased that risk further (8). The FDA directed manufacturers to add a new contraindication against initiating simvastatin 80 mg and required dose caps with multiple CYP3A4 inhibitors. Simvastatin 80 mg may only continue in patients already tolerating that dose for 12 months or longer without myopathy.

Pharmacogenomic Modifier: SLCO1B1 c.521T>C

The SEARCH trial (N=12,064) identified the SLCO1B1 c.521T>C variant (rs4149056) as a major determinant of simvastatin-induced myopathy. Carriers of the CC genotype had a 16.9-fold higher risk of myopathy compared to TT homozygotes (OR 16.9, P<0.001 = P<0.001) (10). Patients with this variant are essentially experiencing endogenous OATP1B1 dysfunction, which compounds any exogenous OATP1B1 inhibitor in their regimen.

CPIC (Clinical Pharmacogenomics Implementation Consortium) guidelines recommend considering an alternate statin or dose reduction in SLCO1B1 poor-function phenotypes, particularly when a concurrent OATP1B1 inhibitor cannot be avoided (11).

Managing Unavoidable Statin DDIs in Clinical Practice

Some patients require both a statin and an interacting agent. Transplant recipients on cyclosporine need statin therapy; HIV patients on boosted protease inhibitors have high ASCVD risk. The following framework helps prescribers make defensible choices.

Step 1: Choose the Lowest-Interaction Statin for the Regimen

Pravastatin and pitavastatin do not undergo meaningful CYP3A4 metabolism and have relatively modest OATP1B1 sensitivity compared to simvastatin or lovastatin. For patients on cyclosporine, pravastatin 20 mg is the most commonly used option because cyclosporine raises pravastatin AUC only approximately 10-fold, which is still significant, but the absolute plasma concentrations remain lower than with simvastatin or atorvastatin at equivalent doses.

Rosuvastatin avoids CYP3A4 entirely but is an OATP1B1 and BCRP substrate, which matters in patients on NS5A inhibitor-based HCV regimens (e.g., sofosbuvir/velpatasvir/voxilaprevir raises rosuvastatin AUC 7.4-fold; fluvastatin or pravastatin are preferred alternatives in this setting).

Step 2: Apply the Dose Cap, Not Just a General Warning

The FDA label specifies exact milligram caps, not vague cautions. Prescribers who write "use lowest effective dose" without a specific number are leaving the pharmacist and patient without actionable guidance. For example, simvastatin with diltiazem = 10 mg cap; simvastatin with amiodarone = 20 mg cap; rosuvastatin with lopinavir/ritonavir = 10 mg cap. Write the number.

Step 3: Separate Timing When the Mechanism Is Absorptive

Rosuvastatin absorption decreases by approximately 54% when taken simultaneously with aluminum/magnesium antacids. Separating administration by at least 2 hours restores normal exposure. This is the one major statin DDI where timing, not dose adjustment, is the fix.

Step 4: Counsel on Symptoms and Establish a CK Threshold for Return

Patients on high-risk combinations should know that new muscle pain, weakness, or dark urine warrants same-day contact. The 2022 ACC Expert Consensus Decision Pathway recommends checking CK in symptomatic patients and discontinuing the statin if CK exceeds 10x ULN (12).

Special Populations with Elevated DDI Risk

Post-Transplant Patients

Solid organ transplant recipients on cyclosporine or tacrolimus carry compounded DDI risk. Tacrolimus is a less potent OATP1B1 inhibitor than cyclosporine, but it does inhibit CYP3A4. The combination of calcineurin inhibitor plus azole antifungal prophylaxis (common in the first 3 to 6 months post-transplant) can stack OATP1B1 inhibition onto CYP3A4 inhibition. In this context, fluvastatin (CYP2C9-metabolized, minimal OATP1B1 sensitivity relative to simvastatin) or pravastatin at low doses are preferred by many transplant cardiologists, though dose caps still apply.

HIV-Positive Patients on ART

The REPRIEVE trial (N=7,769) evaluated pitavastatin 4 mg daily in HIV-positive patients on stable ART and found a 35% relative risk reduction in major adverse cardiovascular events versus placebo at a median follow-up of 5.1 years (13). Pitavastatin was chosen partly because it avoids CYP3A4 and has no FDA-labeled dose cap with most current integrase strand transfer inhibitor-based regimens. For patients on boosted protease inhibitors, however, pitavastatin's OATP1B1 sensitivity still requires attention.

The FDA label for pitavastatin contraindicates co-administration with cyclosporine and recommends a 1 mg cap with gemfibrozil. These limits apply regardless of the underlying HIV regimen.

Older Adults

Aging reduces CYP3A4 activity and OATP1B1 expression, effectively pre-loading patients with higher baseline statin exposure. A 75-year-old on simvastatin 40 mg who then receives a 7-day clarithromycin course for community-acquired pneumonia may not tolerate that combination even at labeled doses. Switching to azithromycin (not a CYP3A4 inhibitor) for the antibiotic course is often the simplest solution.

Drug-Drug Interactions with Warfarin and Other Non-Statin Outcomes

Most DDI discussion focuses on myopathy risk, but two other interactions deserve prescriber attention.

Statin-Warfarin

Fluvastatin inhibits CYP2C9, the primary metabolic route for the more potent S-warfarin enantiomer. Co-administration of fluvastatin 40 mg with warfarin raised the S-warfarin AUC by approximately 48% and increased INR in a controlled study (14). Rosuvastatin, despite being a minor CYP2C9 substrate, also raised INR in some patients in case reports. Any statin-warfarin combination warrants INR monitoring within 2 to 4 weeks of initiating, stopping, or dose-adjusting the statin.

Statin-Colchicine

Both statins and colchicine are myotoxic. The interaction mechanism is incompletely characterized but may involve P-glycoprotein competition. Post-marketing case reports document rhabdomyolysis with simvastatin-colchicine and atorvastatin-colchicine combinations, particularly at higher colchicine doses. No FDA-mandated dose cap exists, but prescribers should use the lowest effective colchicine dose, avoid combining with simvastatin >20 mg, and counsel patients on myopathy symptoms.

Summary: Statin Selection by DDI Risk Profile

| Statin | Primary Metabolism | Key Inhibitors to Avoid | Relative Safety With Strong CYP3A4 Inhibitors | |---|---|---|---| | Simvastatin | CYP3A4 (high sensitivity) | Azoles, macrolides, HIV PIs, cyclosporine, gemfibrozil | Lowest (most sensitive) | | Lovastatin | CYP3A4 (high sensitivity) | Same as simvastatin | Lowest (most sensitive) | | Atorvastatin | CYP3A4 (moderate) | Azoles, macrolides, HIV PIs, cyclosporine | Moderate | | Rosuvastatin | Non-CYP3A4; OATP1B1/BCRP | Cyclosporine, NS5A inhibitors, gemfibrozil | High for CYP3A4; moderate for OATP | | Pravastatin | Sulfation; minimal CYP | Cyclosporine (dose cap 20 mg) | High | | Pitavastatin | Glucuronidation; minimal CYP | Cyclosporine (contraindicated), gemfibrozil (1 mg cap) | High | | Fluvastatin | CYP2C9 | Fluconazole, fluvoxamine | High for CYP3A4; moderate for CYP2C9 |

The 2018 AHA/ACC guideline notes: "Statin safety should be assessed on the basis of individual patient characteristics, including... Potential drug-drug interactions." (3) This is not a permission slip to ignore the tables above. It is a directive to use them on every patient.

Prescribers who routinely reconcile the full medication list against the statin DDI profile before writing or renewing a statin prescription will prevent myopathy cases that the trials' background rates never captured, because those trials excluded patients on interacting drugs.

If you are starting a patient on simvastatin and their current regimen includes any CYP3A4 inhibitor, OATP1B1 inhibitor, or gemfibrozil, select a different statin first. Check the label for the interacting drug, not just the statin, because both labels may carry the warning and both updates may not occur simultaneously.