7.2 Dyslipidemia & Atherosclerotic Cardiovascular Disease (CCS Guidelines & Statin Therapy)

Dyslipidemia & Atherosclerotic Cardiovascular Disease (CCS Guidelines & Statin Therapy)

Atherosclerotic Cardiovascular Disease (ASCVD)—encompassing coronary artery disease, ischemic stroke, transient ischemic attack (TIA), and peripheral arterial disease—remains a principal cause of morbidity, hospitalization, and mortality in Canada. Elevated levels of circulating atherogenic apolipoprotein B-containing lipoproteins, predominantly Low-Density Lipoprotein Cholesterol (LDL-C), drive the initiation, progression, and rupture of arterial plaques. In Canadian pharmacy practice, managing dyslipidemia is governed by the evidence-based clinical practice guidelines of the Canadian Cardiovascular Society (CCS).

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Cardiovascular Risk Stratification & Screening Principles

The CCS guidelines emphasize that lipid-lowering pharmacotherapy must be guided by total 10-year cardiovascular risk rather than isolated lipid concentrations alone.

                         CCS CARDIOVASCULAR RISK TIERS (FRS)
                                          │
         ┌────────────────────────────────┼────────────────────────────────┐
         ▼                                ▼                                ▼
     LOW RISK                     INTERMEDIATE RISK                    HIGH RISK
• 10-year FRS < 10%              • 10-year FRS 10%–19.9%          • 10-year FRS ≥ 20%
• Lifestyle modifications        • Assess LDL-C & Risk Modifiers  • Statin indicated for all
• Pharmacotherapy rarely needed  • Statin if LDL-C ≥ 3.5 mmol/L   • Goal: ≥ 50% LDL-C reduction
  unless LDL-C ≥ 5.0 mmol/L        or ApoB ≥ 1.05 g/L               • Add ezetimibe if LDL-C ≥ 2.0

1. The Framingham Risk Score (FRS)

The modified Framingham Risk Score is the recommended cardiovascular risk assessment tool for primary prevention in Canada. It estimates the 10-year probability of total cardiovascular events (coronary death, myocardial infarction, coronary insufficiency, angina, ischemic stroke, TIA, peripheral arterial disease, and heart failure):

• Low Risk: 10-year FRS < 10%
• Intermediate Risk: 10-year FRS 10% to 19.9%
• High Risk: 10-year FRS ≥ 20%

2. Universal Screening Criteria

The CCS guidelines recommend screening with a complete fasting or non-fasting lipid profile (total cholesterol, HDL-C, triglycerides, calculated LDL-C, and non-HDL-C) for:

• All individuals aged ≥ 40 years, regardless of baseline health status;
• All postmenopausal women, regardless of chronological age;
• Individuals of any age possessing any of the following clinical risk factors:
  • Diabetes mellitus (type 1 or type 2);
  • Current cigarette smoking;
  • Arterial hypertension;
  • Chronic kidney disease (eGFR < 60 mL/min/1.73m² or persistent urinary albumin-to-creatinine ratio [ACR] ≥ 3.0 mg/mmol);
  • Documented atherosclerosis (clinical ASCVD);
  • Family history of premature cardiovascular disease;
  • Chronic inflammatory systemic diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis, inflammatory bowel disease);
  • HIV infection receiving antiretroviral therapy;
  • Chronic obstructive pulmonary disease (COPD);
  • Erectile dysfunction;
  • History of hypertensive disorders of pregnancy (preeclampsia, gestational hypertension) or gestational diabetes.

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Statin-Indicated Conditions (Treatment Without Risk Score Calculation)

A core concept in Canadian dyslipidemia management is the Statin-Indicated Condition. Patients presenting with any of the following high-risk clinical conditions do not require Framingham Risk Score calculation—they are automatically categorized as high cardiovascular risk, and statin therapy is recommended regardless of their baseline LDL-C level:

                            STATIN-INDICATED CONDITIONS
                                         │
         ┌───────────────────────────────┼───────────────────────────────┐
         ▼                               ▼                               ▼
   CLINICAL ASCVD                 ABDOMINAL AORTIC              DIABETES MELLITUS
• Prior MI, ACS, angina              ANEURYSM (AAA)          • Age ≥ 40 years, OR
• Coronary revascularization      • Infrarenal ≥ 3.0 cm, or  • Age ≥ 30 with duration ≥ 15y,
• Ischemic stroke, TIA               prior surgical repair     OR microvascular complications
• Peripheral artery disease
         ┌───────────────────────────────┼───────────────────────────────┐
         ▼                               ▼                               ▼
 CHRONIC KIDNEY DISEASE       SEVERE HYPERCHOLESTEROLEMIA      HIGH FRS (≥ 20%)
• Age ≥ 50 years with:        • Documented baseline          • 10-year Framingham Risk
  - eGFR < 60 mL/min/1.73m²     LDL-C ≥ 5.0 mmol/L, or         Score ≥ 20%
  - or ACR ≥ 3.0 mg/mmol        Familial Hypercholesterolemia

1. Clinical ASCVD: Established coronary artery disease (prior myocardial infarction, acute coronary syndromes, stable angina, coronary artery bypass graft [CABG], percutaneous coronary intervention [PCI]), cerebrovascular disease (ischemic stroke, TIA), or documented peripheral arterial disease.
2. Abdominal Aortic Aneurysm (AAA): Documented infrarenal aortic diameter ≥ 3.0 cm or prior surgical/endovascular repair.
3. Diabetes Mellitus: Any patient with type 1 or type 2 diabetes who meets at least one of:
   • Age ≥ 40 years;
   • Age ≥ 30 years with a diabetes disease duration ≥ 15 years;
   • Presence of microvascular complications (diabetic nephropathy with ACR ≥ 3.0 mg/mmol, retinopathy, or autonomic/peripheral neuropathy).
4. Chronic Kidney Disease (CKD): Non-dialysis patients aged ≥ 50 years with an eGFR < 60 mL/min/1.73m² or urinary ACR ≥ 3.0 mg/mmol (supported by the landmark SHARP trial). Note: Statins are generally not initiated in patients maintained on chronic maintenance hemodialysis or peritoneal dialysis unless an independent ASCVD indication exists, as 4D and AURORA trials showed no cardiovascular benefit.
5. Severe Hypercholesterolemia: Confirmed baseline LDL-C ≥ 5.0 mmol/L or genetically confirmed Familial Hypercholesterolemia (FH).

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Primary Prevention in Intermediate Risk (FRS 10%–19.9%)

In intermediate-risk individuals, statin therapy is recommended if:

• LDL-C ≥ 3.5 mmol/L, OR
• Apolipoprotein B (ApoB) ≥ 1.05 g/L, OR
• Non-HDL-C ≥ 4.2 mmol/L.

If the baseline LDL-C is < 3.5 mmol/L, statin therapy should still be considered if "risk modifiers" are present:

• High-sensitivity C-reactive protein (hs-CRP) ≥ 2.0 mg/L in men ≥ 50 or women ≥ 60 years (JUPITER trial);
• Coronary Artery Calcium (CAC) score > 0 Agatston units (especially CAC > 100 or > 75th percentile for age and sex);
• Confirmed family history of premature ASCVD;
• Lipoprotein(a) [Lp(a)] ≥ 100 nmol/L (or ≥ 50 mg/dL).

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CCS 2021: Treatment Thresholds for Intensification (Not "Targets")

The 2021 CCS dyslipidemia guideline replaced fixed LDL-C targets with thresholds for intensifying therapy. Start a maximally tolerated statin. Recheck lipids, and add a non-statin drug when the level on statin therapy stays at or above the threshold for the patient's risk group:

                    CCS 2021 INTENSIFICATION LOGIC

      Maximally tolerated statin  ──>  recheck lipids in 4–12 weeks
                                              │
            Is LDL-C at or above the threshold for this risk group?
               (ASCVD 1.8 | primary prevention 2.0 | FH 2.5 mmol/L)
                                              │
                          ┌───────────────────┴───────────────────┐
                          ▼                                       ▼
                         NO                                      YES
                  Continue, adherence                 Add ezetimibe (all groups)
                  and lifestyle support               ASCVD: ezetimibe and/or PCSK9i

• Worked contrast: a patient after MI on atorvastatin 80 mg has LDL-C 1.9 mmol/L. That is at or above 1.8, so intensification is recommended even though the value is below the old 2.0 "target". A patient with diabetes and no ASCVD whose LDL-C fell from 3.6 to 1.9 mmol/L (47% reduction) is below the 2.0 threshold, so continuing the statin with adherence support is reasonable.
• Why thresholds: the outcome trials of add-on therapy (IMPROVE-IT, FOURIER, ODYSSEY OUTCOMES) enrolled patients above specific LDL-C levels. The CCS adopted those entry levels as the points at which adding therapy has proven benefit.

Non-HDL-C and ApoB as Alternatives

When serum triglycerides are elevated (about 1.5 mmol/L or more), calculated LDL-C becomes less accurate and underestimates the atherogenic particle burden. The 2021 CCS guideline suggests the NIH (Sampson) equation rather than the older Friedewald formula for calculating LDL-C. CCS therefore accepts non-HDL-C or ApoB in place of LDL-C at every decision point:

• ApoB: every atherogenic particle (LDL, VLDL, IDL, Lp(a)) carries one ApoB molecule, so ApoB counts particles directly and does not depend on fasting.
• Non-HDL-C (total cholesterol minus HDL-C): measures cholesterol in all atherogenic particles, can be taken non-fasting, and costs nothing extra.
• Lipoprotein(a): measure once in a lifetime as part of initial screening. A level of 50 mg/dL (100 nmol/L) or more is a risk modifier that favours earlier or more intensive therapy.

Statin Pharmacology, Potencies & Pharmacokinetics

Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are the foundational first-line pharmacotherapy for dyslipidemia. Statins competitively inhibit the rate-limiting step in hepatic de novo cholesterol biosynthesis, depleting intracellular cholesterol stores. This triggers upregulation of cell-surface LDL receptors on hepatocytes, profoundly increasing receptor-mediated endocytosis and clearance of circulating LDL and VLDL remnants from plasma.

Statin Potency Categories

Pharmacokinetic & Physicochemical Distinctions

                           STATIN PHYSICOCHEMICAL PROPERTIES

          LIPOPHILIC STATINS                                HYDROPHILIC STATINS
    (Atorvastatin, Simvastatin, Lovastatin)              (Rosuvastatin, Pravastatin)
    ┌────────────────────────────────────┐       ┌────────────────────────────────────┐
    │ • Passive diffusion into tissues   │       │ • Active uptake via hepatic OATP1B1│
    │ • High extrahepatic penetration    │  vs   │ • Minimal extrahepatic penetration │
    │ • Metabolized by CYP3A4            │       │ • Rosuvastatin: minor CYP2C9;      │
    │   (Except: fluvastatin = CYP2C9)   │       │   Pravastatin: non-CYP sulfation   │
    │ • High interaction risk with       │       │ • Low interaction liability        │
    │   macrolides, azoles, protease inb │       │ • Longer half-life (Rosuva ~19 hrs)│
    └────────────────────────────────────┘       └────────────────────────────────────┘

• Lipophilic Statins (Atorvastatin, Simvastatin, Lovastatin): Cross biological membranes readily via passive diffusion. They undergo extensive phase I hepatic oxidation via CYP3A4. Concurrent administration of potent CYP3A4 inhibitors (clarithromycin, erythromycin, ketoconazole, itraconazole, posaconazole, ritonavir, cobicistat, diltiazem, verapamil, amiodarone, and large quantities of grapefruit juice) dramatically elevates statin serum concentrations, increasing myopathy risk.
• Hydrophilic Statins (Rosuvastatin, Pravastatin): Highly hepatoselective; require active transport via organic anion-transporting polypeptide 1B1 (OATP1B1) for hepatic entry. Rosuvastatin undergoes minimal metabolism via CYP2C9; pravastatin is metabolized non-enzymatically and cleared by sulfation. They exhibit virtually zero CYP3A4 drug-drug interactions.
• Timing of Administration: Statins with short elimination half-lives (simvastatin, lovastatin, pravastatin: t½ ~ 1–3 hours) must be administered in the evening or at bedtime to coincide with nocturnal peak hepatic cholesterol synthesis. In contrast, atorvastatin (t½ ~ 14 hours) and rosuvastatin (t½ ~ 19 hours) have prolonged terminal elimination half-lives and active circulating metabolites, permitting administration at any time of day, with or without food.

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Statin-Associated Muscle Symptoms (SAMS) & Safety Monitoring

While statins are generally exceptionally well-tolerated, adverse musculoskeletal complaints are the leading cause of non-adherence and premature drug discontinuation.

                            THE SPECTRUM OF SAMS
                                     │
         ┌───────────────────────────┼───────────────────────────┐
         ▼                           ▼                           ▼
      MYALGIA                    MYOSITIS                 RHABDOMYOLYSIS
• Muscle aches, stiffness,   • Muscle symptoms WITH       • Extreme muscle breakdown
  weakness                     CK elevation (> ULN to     • CK > 10× to 40× ULN
• Normal Serum CK              < 10× ULN)                 • Dark brown urine (myoglobin)
• Incidence: 5%–10%          • Less common                • Acute renal failure
• Often bilateral, proximal  • Requires drug hold until   • Medical emergency;
  large muscle groups          symptoms & CK normalize      immediate hospitalization

1. Diagnostic Classifications of SAMS

• Myalgia: Muscle pain, soreness, tenderness, stiffness, or cramping (typically bilateral, involving large proximal muscle groups such as the thighs, calves, and buttocks) occurring without serum creatine kinase (CK) elevation.
• Myositis / Myopathy: Musculoskeletal symptoms accompanied by confirmed elevation in serum CK (> upper limit of normal [ULN] up to 10 × ULN).
• Rhabdomyolysis: Severe, acute muscle necrosis characterized by marked CK elevations (typically > 10 × ULN, frequently > 40 × ULN), myoglobinuria (tea-colored or brown urine), electrolyte derangements (hyperkalemia, hyperphosphatemia), and acute renal failure. Rhabdomyolysis is rare (< 1 in 100,000 patient-years) but life-threatening.

2. Baseline Laboratory Testing & Routine Monitoring Rules

• Baseline Testing: Many clinicians measure ALT, and CK in patients at higher risk of muscle symptoms, before starting a statin, so that later values have a reference point.
• Prohibition on Routine Surveillance: Routine periodic monitoring of CK or ALT in asymptomatic patients is explicitly NOT recommended. Measuring CK or transaminases routinely generates false alarms, unnecessary dose reductions, and inappropriate statin discontinuation. Repeat CK and ALT testing is indicated only if the patient develops unexplained muscle pain, fatigue, tenderness, brown urine, or symptoms of jaundice.

3. Structured Clinical Algorithm for Managing SAMS

                           SAMS CLINICAL RECHALLENGE ALGORITHM
                                           │
                   Patient presents with new, unexplained muscle aches
                                           │
                                    Check Serum CK
                                           │
                     ┌─────────────────────┴─────────────────────┐
                     ▼                                           ▼
              CK > 10× ULN or                             CK < 5×–10× ULN
             Brown Urine (Rhabdo)                        (or Normal CK)
                     │                                           │
         • STOP statin immediately                   • Discontinue statin for
         • Hospitalize for aggressive IV               "statin holiday" (2–4 weeks)
           hydration & renal protection              • Confirm symptom resolution
         • DO NOT rechallenge with same statin       • Screen for secondary triggers:
                                                       hypothyroidism, vitamin D def,
                                                       strenuous exercise, CYP interactions
                                                                 │
                                                    ┌────────────┴────────────┐
                                                    ▼                         ▼
                                            Symptoms Resolve          Symptoms Persist
                                                    │                         │
                                        • RECHALLENGE with lower      • Muscle pain not
                                          dose of alternate statin      statin-related
                                          (e.g., switch to rosuvastatin)• Investigate other
                                        • Or use INTERMITTENT DOSING    rheumatologic / ortho
                                          (e.g., rosuvastatin 5–10 mg   etiologies
                                          once or twice weekly)
                                        • Add ezetimibe to reach target

1. Evaluate Baseline & Secondary Triggers: Before declaring true statin intolerance, rule out predisposing factors: untreated hypothyroidism (elevated TSH increases myopathy risk tenfold), severe vitamin D deficiency, intense unaccustomed physical exercise, and concurrent interacting medications.
2. The Statin Holiday: If symptoms are bothersome, temporarily hold the statin for 2 to 4 weeks until symptoms completely resolve. If symptoms do not resolve after 4 weeks of cessation, the muscle pain is unlikely to be statin-induced.
3. Statin Rechallenge: Once asymptomatic, rechallenge the patient. More than 70% of patients reporting SAMS can successfully tolerate a statin upon rechallenge. Strategies include:
   • Switching from a lipophilic statin (atorvastatin) to a hydrophilic statin (rosuvastatin or pravastatin);
   • Reducing the dose to the lowest available tablet size;
   • Utilizing intermittent non-daily dosing: Rosuvastatin has a prolonged half-life of 19 hours and long-lasting hepatic receptor upregulation. Dosing rosuvastatin 5 to 10 mg once, twice, or three times weekly achieves significant LDL-C reductions (20% to 35%) while maintaining excellent musculoskeletal tolerability.

Non-Statin Pharmacotherapies & Pivotal Cardiovascular Outcome Trials

When LDL-C stays at or above the CCS intensification threshold on maximally tolerated statin therapy (1.8 mmol/L in ASCVD, 2.0 mmol/L in statin-indicated primary prevention), or when a patient cannot tolerate statins, evidence-based non-statin therapies are added.

                           CCS ESCALATION ALGORITHM (POST-ACS / ASCVD)

                       ┌───────────────────────────────────────────┐
                       │     MAXIMALLY TOLERATED STATIN THERAPY    │
                       │     (Atorvastatin 80 mg or Rosuva 40 mg)  │
                       └─────────────────────┬─────────────────────┘
                                             │
                                   Re-check LDL-C in 6–8 weeks
                                             │
                        Is LDL-C still ≥ 1.8 mmol/L (ASCVD)?
                                             │
                              ┌──────────────┴──────────────┐
                              ▼                             ▼
                             NO                            YES
                       Maintain Therapy             STEP 1: ADD EZETIMIBE
                                                    (10 mg PO daily; IMPROVE-IT)
                                                            │
                                                Re-check LDL-C in 4–12 weeks
                                                            │
                                             Is LDL-C still ≥ 1.8 mmol/L?
                                                            │
                                             ┌──────────────┴──────────────┐
                                             ▼                             ▼
                                            YES                            NO
                                  STEP 2: ADD PCSK9 INHIBITOR       Maintain Therapy
                                  (Evolocumab or Alirocumab SC;     (Statin + Ezetimibe)
                                   FOURIER / ODYSSEY OUTCOMES)

1. Ezetimibe (IMPROVE-IT Trial)

• Mechanism: Selectively binds to and inhibits the Niemann-Pick C1-Like 1 (NPC1L1) sterol transporter protein located in the brush border of the jejunal enterocyte. It selectively blocks intestinal absorption of both dietary and biliary cholesterol without inhibiting the absorption of triglycerides, fat-soluble vitamins, or bile acids. Hepatic cholesterol delivery decreases, upregulating hepatic LDL receptors.
• Efficacy: Prescribed at a fixed dose of 10 mg daily. As monotherapy, it lowers LDL-C by 15% to 20%. When added to background statin therapy, it provides an incremental 15% to 20% additional reduction in LDL-C.
• Pivotal Trial (IMPROVE-IT): Enrolled 18,144 post-ACS patients randomized to simvastatin 40 mg alone versus simvastatin 40 mg plus ezetimibe 10 mg. The addition of ezetimibe lowered median LDL-C from 1.8 to 1.4 mmol/L and demonstrated a statistically significant reduction in major adverse cardiovascular events (cardiovascular death, MI, or stroke). Ezetimibe is the usual first add-on to a statin because it is oral, inexpensive and well tolerated. In ASCVD, CCS allows a PCSK9 inhibitor first, or both, when LDL-C is far above threshold or risk is very high.

2. PCSK9 Inhibitors (Evolocumab & Alirocumab)

• Mechanism: Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is an enzyme produced by hepatocytes that binds to the LDL receptor complex on the cell surface, directing the receptor toward lysosomal degradation rather than recycling back to the cell surface. Evolocumab (Repatha) and Alirocumab (Praluent) are fully human monoclonal antibodies (IgG2 and IgG1, respectively) that bind circulating PCSK9 with high affinity, preventing LDL receptor degradation. Hepatic LDL receptor recycling increases up to tenfold, dramatically clearing circulating LDL-C.
• Administration & Efficacy: Administered by subcutaneous injection via prefilled auto-injector pens (evolocumab 140 mg SC every 2 weeks or 420 mg SC monthly; alirocumab 75–150 mg SC every 2 weeks or 300 mg monthly). They produce profound, dose-dependent reductions in LDL-C of 50% to 60%, and reduce ApoB, non-HDL-C, and Lipoprotein(a).
• Landmark Cardiovascular Outcome Trials:
  • FOURIER Trial (Evolocumab): 27,564 patients with established ASCVD on background statin. Adding evolocumab reduced median LDL-C from 2.4 to 0.78 mmol/L and achieved a 15% relative risk reduction in major cardiovascular events.
  • ODYSSEY OUTCOMES (Alirocumab): 18,924 patients with recent ACS. Adding alirocumab reduced MACE by 15% and was associated with lower all-cause mortality in patients with baseline LDL-C ≥ 2.6 mmol/L.
• CCS Indication: Patients with established ASCVD whose LDL-C remains ≥ 1.8 mmol/L (or non-HDL-C ≥ 2.4 mmol/L, or ApoB ≥ 0.70 g/L) on maximally tolerated statin therapy, with or without ezetimibe. Patients with heterozygous familial hypercholesterolemia remain candidates when LDL-C stays ≥ 2.5 mmol/L on statin plus ezetimibe.

3. Icosapent Ethyl (IPE / Vascepa) — The REDUCE-IT Trial

• Mechanism: A highly purified ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Its mechanism is distinct from conventional triglyceride lowering; EPA integrates into cellular membranes, stabilizing atherosclerotic plaque membranes, blunting endothelial inflammation, inhibiting platelet aggregation, and reducing macrophage infiltration.
• Pivotal Trial (REDUCE-IT): Evaluated 8,179 statin-treated patients with established ASCVD or diabetes with ≥ 1 additional risk factor, who had well-controlled LDL-C (1.06–2.59 mmol/L) but persistently elevated fasting triglycerides (1.52 to 5.63 mmol/L). Patients were randomized to icosapent ethyl 2 g PO BID with meals (4 g/day) or mineral oil placebo.
• Results: Icosapent ethyl achieved a striking 25% relative risk reduction (ARR 4.8%, NNT = 21 over 4.9 years) in the primary composite endpoint of cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina.
• Safety Warnings: Icosapent ethyl is associated with a statistically significant increase in hospitalized atrial fibrillation or flutter (3.1% vs 2.1%) and a modest increase in minor bleeding events (11.8% vs 9.9%), though fatal bleeding was not increased.
• Critical Practice Distinction: Over-the-counter fish oil supplements contain unpurified mixtures of EPA and docosahexaenoic acid (DHA). Trials evaluating DHA/EPA mixtures (e.g., STRENGTH trial) failed to demonstrate cardiovascular benefit, and DHA raises circulating LDL-C. Pharmacists must never substitute dietary fish oil capsules for prescription icosapent ethyl.

4. Fibrates (Fenofibrate vs. Gemfibrozil)

• Mechanism: Peroxisome proliferator-activated receptor-alpha (PPAR-α) agonists. Upregulate lipoprotein lipase (LPL) synthesis, increasing triglyceride catabolism and reducing hepatic VLDL production. Lower triglycerides by 30% to 50% and raise HDL-C by 10% to 20%.
• Clinical Role: Indicated primarily as first-line therapy to prevent acute pancreatitis when serum triglycerides are severely elevated (≥ 10.0 mmol/L).
• The ACCORD-Lipid Trial: Adding fenofibrate to simvastatin in patients with type 2 diabetes did not reduce cardiovascular events compared to statin monotherapy.
• Gemfibrozil-Statin Prohibition: Gemfibrozil is strictly contraindicated in combination with any statin. Gemfibrozil potently inhibits statin glucuronidation (via UGT1A1 and UGT1A3) and blocks OATP1B1 hepatic uptake, causing a massive, unpredictable 5- to 15-fold increase in statin plasma concentrations, triggering severe rhabdomyolysis and acute renal failure. If a fibrate must be combined with a statin for severe hypertriglyceridemia, fenofibrate is the only acceptable option, as it does not inhibit statin glucuronidation.

5. Bile Acid Sequestrants (Cholestyramine, Colesevelam)

• Mechanism: Non-absorbable anion-exchange resins that bind negatively charged bile acids in the intestinal lumen, preventing enterohepatic recycling and promoting fecal bile acid excretion. The liver depletes intrahepatic cholesterol to synthesize replacement bile acids, upregulating LDL receptors.
• Clinical Considerations: Lowers LDL-C by 15% to 30%, but can paradoxically increase serum triglycerides by stimulating hepatic VLDL synthesis. Contraindicated if baseline triglycerides > 3.4 to 4.5 mmol/L.
• Drug Binding Interactions: Binds co-administered acidic medications (warfarin, levothyroxine, digoxin, thiazides, beta-blockers). Other oral medications must be administered at least 1 to 2 hours before or 4 to 6 hours after the bile acid sequestrant.