What medications are used to manage elevated triglycerides and total cholesterol?

Medications for Managing Elevated Triglycerides and Total Cholesterol

Primary Treatment: Statins as First-Line Therapy

For patients with elevated total cholesterol and LDL-cholesterol, statins are the cornerstone of pharmacologic therapy, providing 35-55% LDL-cholesterol reduction and an additional 10-30% dose-dependent triglyceride reduction. 1

Statin Selection and Dosing

• High-intensity statins (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) provide ≥50% LDL-cholesterol reduction and are recommended for patients with established cardiovascular disease or diabetes 1, 2
• Moderate-intensity statins (atorvastatin 10-20 mg, simvastatin 20-40 mg, rosuvastatin 5-10 mg, pravastatin 40-80 mg) provide 30-50% LDL-cholesterol reduction 1
• All statins effectively reduce triglycerides in hypertriglyceridemic patients, with the magnitude of triglyceride reduction proportional to their LDL-lowering potency 3, 4
• Atorvastatin and rosuvastatin have similar dose-response slopes, but rosuvastatin is approximately three-fold more potent 5

Statin Effects on Triglycerides

• In patients with baseline triglycerides >250 mg/dL, statins produce 22-45% triglyceride reductions in a dose-dependent manner 3
• When baseline triglycerides are <150 mg/dL, statins show minimal triglyceride-lowering effect 3
• The triglyceride/LDL-cholesterol reduction ratio is approximately 1.2 for patients with triglycerides >250 mg/dL, 0.5 for triglycerides 150-250 mg/dL, and 0.0 for triglycerides <150 mg/dL 3

Fibrates for Triglyceride-Predominant Dyslipidemia

For severe hypertriglyceridemia (≥500 mg/dL), fibrates are first-line therapy to prevent acute pancreatitis, initiated before addressing LDL-cholesterol. 2

Fibrate Dosing and Efficacy

• Fenofibrate 54-200 mg daily reduces triglycerides by 30-50% and is preferred over gemfibrozil when combining with statins due to lower myopathy risk 1, 2
• Gemfibrozil 600 mg twice daily provides similar triglyceride reduction but has significantly higher myopathy risk when combined with statins and should be avoided 2
• Fibrates provide 5-15% LDL-cholesterol reduction (variable effect) and increase HDL-cholesterol 1
• Evidence shows ~20% cardiovascular disease risk reduction versus placebo, with particular benefit in men with high triglycerides and low HDL-cholesterol 1

When to Use Fibrates

• Immediate initiation for triglycerides ≥500 mg/dL to prevent pancreatitis 1, 2
• Consider after 3 months of optimized lifestyle and statin therapy if triglycerides remain >200 mg/dL 1, 2
• For combined hyperlipidemia with both elevated LDL-cholesterol and triglycerides, optimize statin first, then add fibrate if needed 1

Prescription Omega-3 Fatty Acids

Icosapent ethyl (purified EPA) 2 grams twice daily is indicated as adjunctive therapy to maximally tolerated statins for patients with triglycerides ≥150 mg/dL who have established cardiovascular disease or diabetes with ≥2 additional risk factors, providing a 25% reduction in major adverse cardiovascular events. 2

Omega-3 Formulations and Indications

• Icosapent ethyl (Vascepa®) is the only omega-3 product FDA-approved for cardiovascular risk reduction 2
• Omega-3 carboxylic acid and omega-3-acid ethyl esters (EPA+DHA combinations) are FDA-approved only for severe hypertriglyceridemia (≥500 mg/dL) as adjunct to diet, not for cardiovascular outcomes 2
• Prescription omega-3 fatty acids at 2-4 grams daily provide 20-50% triglyceride reduction 2
• Monitor for increased risk of atrial fibrillation (3.1% vs 2.1% with placebo) 2

Niacin (Limited Role)

Niacin should generally not be used, as it showed no cardiovascular benefit when added to statin therapy in contemporary trials, with increased risk of new-onset diabetes and gastrointestinal disturbances. 2

• Niacin provides 20-25% LDL-cholesterol reduction and raises HDL-cholesterol 1
• Historical evidence versus placebo showed ~20% cardiovascular disease risk reduction, but no incremental benefit when added to statins in well-treated patients 1
• May be considered in select cases at restricted doses (≤2 grams daily) for severe combined hyperlipidemia when other options are exhausted 1

Cholesterol Absorption Inhibitors

• Ezetimibe 10 mg daily provides 18-25% LDL-cholesterol reduction and has proven cardiovascular benefit when added to statins 1
• Strong evidence for modest incremental ~7% cardiovascular risk reduction when added to statin therapy in acute coronary syndrome patients 1
• Minimal effect on triglycerides 1

Bile Acid Sequestrants

• Cholestyramine, colestipol, colesevelam provide 18-25% LDL-cholesterol reduction 1
• Good evidence versus placebo showing ~20% cardiovascular disease risk reduction in primary prevention 1
• Relatively contraindicated when triglycerides >200 mg/dL as they can worsen hypertriglyceridemia 1, 2

PCSK9 Inhibitors

• Evolocumab, alirocumab provide 40-65% LDL-cholesterol reduction 1
• Promising evidence showing ~50% reduction in cardiovascular events when added to statin therapy 1
• Reserved for patients with very high cardiovascular risk or familial hypercholesterolemia who cannot achieve LDL-cholesterol goals with statins and ezetimibe 1

Treatment Algorithm by Clinical Scenario

Elevated LDL-Cholesterol with Normal Triglycerides (<150 mg/dL)

1. Initiate moderate-to-high intensity statin based on cardiovascular risk 1, 2
2. Add ezetimibe if LDL-cholesterol remains above goal after maximizing statin 1
3. Consider PCSK9 inhibitor for very high-risk patients not at goal 1

Moderate Hypertriglyceridemia (200-499 mg/dL) with Elevated LDL-Cholesterol

1. Initiate or optimize statin therapy to achieve LDL-cholesterol goal and provide 10-30% triglyceride reduction 2, 6
2. Target non-HDL-cholesterol <130 mg/dL as secondary goal 1, 2
3. After 3 months of optimized lifestyle and statin, if triglycerides remain >200 mg/dL, add icosapent ethyl 2 grams twice daily (if cardiovascular disease or diabetes with ≥2 risk factors) OR fenofibrate 54-160 mg daily 2

Severe Hypertriglyceridemia (≥500 mg/dL)

1. Immediately initiate fenofibrate 54-200 mg daily to prevent pancreatitis 2
2. Implement extreme dietary fat restriction (10-25% of calories), eliminate all added sugars and alcohol 2
3. Aggressively optimize glycemic control in diabetic patients 1, 2
4. Once triglycerides <500 mg/dL, reassess LDL-cholesterol and add statin if elevated or cardiovascular risk is high 2
5. Consider adding prescription omega-3 fatty acids 2-4 grams daily as adjunctive therapy 2

Combined Hyperlipidemia (Elevated LDL-Cholesterol and Triglycerides)

1. Optimize glycemic control if diabetic (often most effective intervention) 1, 2
2. Initiate high-dose statin as first-line therapy 1
3. If triglycerides ≥500 mg/dL, start fenofibrate before or simultaneously with statin 1
4. If triglycerides 200-499 mg/dL after statin optimization, add fenofibrate or icosapent ethyl 1, 2

Critical Safety Considerations

Statin-Fibrate Combination Therapy

• Use fenofibrate rather than gemfibrozil when combining with statins—fenofibrate does not inhibit statin glucuronidation, resulting in significantly lower myopathy risk 2
• Use lower statin doses (atorvastatin 10-20 mg maximum) when combining with fibrates to minimize myopathy risk 2
• Monitor creatine kinase levels and muscle symptoms, especially in patients >65 years or with renal disease 1, 2
• The ACCORD trial showed no cardiovascular benefit from adding fenofibrate to simvastatin in diabetic patients, so combination therapy should be reserved for specific indications (severe hypertriglyceridemia or pancreatitis prevention) 2

Dose Adjustments for Renal Impairment

• For severe renal impairment (creatinine clearance 15-29 mL/min), start simvastatin at 5 mg daily 7
• Adjust fenofibrate dose based on renal function to minimize myopathy risk 2

Common Adverse Effects

• Statins: myalgia (most common reason for discontinuation at 0.7%), diarrhea, nausea, transaminase elevations 8
• Persistent transaminase elevations (>3× ULN) occur in 0.2-2.3% depending on statin dose, with higher rates at 80 mg doses 8
• Fibrates: gastrointestinal symptoms, increased risk of gallstones, myopathy (especially when combined with statins) 1
• Icosapent ethyl: increased risk of atrial fibrillation, bleeding risk 2

Medications to Avoid or Use with Caution

• Niacin: No proven cardiovascular benefit when added to statins, increases diabetes risk 2
• Gemfibrozil: Significantly higher myopathy risk than fenofibrate when combined with statins; should be avoided 2
• Bile acid sequestrants: Contraindicated when triglycerides >200 mg/dL as they worsen hypertriglyceridemia 1, 2
• Over-the-counter fish oil: Not equivalent to prescription omega-3 formulations and should not be substituted 2