What is mixed hypercholesterolemia?

Mixed Hypercholesterolemia: Definition, Types, and Management

Mixed hypercholesterolemia (also called mixed dyslipidemia) is characterized by elevations in both cholesterol and triglyceride levels, often with low HDL cholesterol, which significantly increases cardiovascular disease risk and requires targeted treatment based on the specific subtype. 1

Definition and Characteristics

• Mixed hypercholesterolemia presents with elevations in total cholesterol, LDL cholesterol, and triglycerides, often accompanied by decreased HDL cholesterol levels 1
• The lipid profile typically shows both LDL-C ≥130 mg/dL and triglycerides ≥150 mg/dL, creating an atherogenic pattern that increases cardiovascular risk 1
• This condition can be either primary (genetic) or secondary (due to underlying conditions like diabetes, obesity, or metabolic syndrome) 1

Types of Mixed Hypercholesterolemia

Familial Combined Hyperlipidemia (FCHL)

• Most common primary dyslipidemia with a population prevalence of 5-10% 1
• Characterized by multiple lipoprotein abnormalities due to hepatic overproduction of apoB-containing lipoproteins (VLDL, IDL, LDL) 1
• Strongly associated with premature cardiovascular disease, especially in those under 40 years of age 1, 2
• Diagnosis is made when elevated levels of cholesterol, triglycerides, or apoB are found in a patient and at least two of these abnormalities also appear in first-degree relatives 1

Type III Dysbetalipoproteinemia (Familial Dysbetalipoproteinemia)

• Characterized by elevations of both cholesterol and triglycerides with a cholesterol-to-triglyceride ratio of approximately 1:1 1
• Associated with homozygosity for apolipoprotein E2 or other polymorphisms 1
• May present with distinctive palmar xanthomas and tuberous/eruptive xanthomata 1
• Moderately increases risk of cardiovascular disease 1

Familial Hypercholesterolemia with Secondary Hypertriglyceridemia

• Patients with underlying familial hypercholesterolemia who develop hypertriglyceridemia due to another cause 3
• Can present with very high total and LDL cholesterol with moderately elevated triglycerides 3
• Requires direct measurement of LDL-C for accurate diagnosis 3

Clinical Significance and Cardiovascular Risk

• Mixed hyperlipidemia significantly increases cardiovascular disease risk through multiple mechanisms 1
• Triglyceride-rich lipoproteins (TRLs) contribute to atherogenesis by:
  • Increasing expression of inflammatory proteins and adhesion molecules 1
  • Impairing endothelial cell-dependent vasodilation 1
  • Enhancing recruitment of monocytes to endothelium 1
  • Interfering with HDL's anti-inflammatory functions 1
• The combination of elevated triglycerides and low HDL creates small, dense, highly atherogenic LDL particles 1

Diagnosis

• Diagnosis requires a complete lipid profile showing elevated LDL-C, total cholesterol, and triglycerides 1
• When triglycerides are >400 mg/dL, calculated LDL-C becomes inaccurate; direct LDL-C measurement is recommended 1, 3
• Non-HDL cholesterol (total cholesterol minus HDL cholesterol) is a valuable marker in mixed dyslipidemia 1
• Apolipoprotein B levels can be useful as they reflect the total number of atherogenic particles 1
• Family history assessment is crucial to identify genetic forms 1, 2

Management Approach

Lifestyle Modifications

• First-line approach includes therapeutic lifestyle changes:
  • Fat and cholesterol-restricted diet 1
  • Weight reduction for those with excess weight 1
  • Physical exercise as an important ancillary measure 4
  • Limiting alcohol intake, especially in hypertriglyceridemia 4

Pharmacological Treatment

• For mixed dyslipidemia, statins are the first-line therapy at maximally tolerated effective doses, with consideration of adding fibrates, niacin, or omega-3 fatty acids based on residual lipid abnormalities 4, 5
• Fenofibrate is specifically indicated for mixed dyslipidemia to reduce elevated LDL-C, total cholesterol, triglycerides, and apoB, while increasing HDL-C 4
• Combination therapy considerations:
  • Fenofibrate is preferred over gemfibrozil when combining with statins due to lower risk of rhabdomyolysis 6
  • Niacin can be added to target both low HDL and elevated triglycerides 5
  • Omega-3 fatty acids may be considered for persistent hypertriglyceridemia 5
• Newer therapies for refractory cases include bempedoic acid, PCSK9 inhibitors, and agents targeting apolipoprotein CIII and angiopoietin-like 3 7

Special Considerations

• In patients with diabetes and mixed dyslipidemia, aggressive lipid management is crucial as 50% of mortality is from coronary artery disease 1
• When triglycerides are severely elevated (>1000 mg/dL), the immediate priority shifts to preventing pancreatitis 1
• Patients with mixed dyslipidemia often have comorbid conditions like metabolic syndrome, non-alcoholic fatty liver disease, or diabetes that require simultaneous management 2

Monitoring

• Lipid levels should be monitored periodically after initiating therapy 4
• Consider dose adjustments if lipid levels fall significantly below target range 4
• Treatment should be withdrawn if inadequate response after two months at maximum recommended doses 4