Hypercholesterolemia

Hypercholesterolemia is "a condition with abnormally high levels of cholesterol in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population." It should be differentiated from dyslipidemia, where the total cholesterol may not be abnormally high, but the ratios of lipid components are in an unhealthy range.

Prognostication

Non-HDL cholesterol and apolipoprotein B levels may better predict subsequent vascular disease thatn LDL-C levels.According to the Friedewald formula, non-HDL cholesterol is LDL-cholesterol LDL-C and VLDL-C. If LDL-C levels are used as goals of therapy:

"A 'normal' VLDL cholesterol can be defined as that present when triglycerides are <150 mg/dL; this value typically is ≤30 mg/dL. Conversely, when triglyceride levels are >150 mg/dL, VLDL cholesterol usually is >30 mg/dL. Thus, a reasonable goal for non-HDL cholesterol is one that is 30 mg/dL higher than the LDL-cholesterol goal."

Accordingly, the U.S. Preventive Services Task Force states:.

• "The preferred screening tests for dyslipidemia are total cholesterol and HDL-C on non-fasting or fasting samples. There is currently insufficient evidence of the benefit of including TG as a part of the initial tests used to screen routinely for dyslipidemia. Abnormal screening test results should be confirmed by a repeated sample on a separate occasion, and the average of both results should be used for risk assessment."
• "Measuring total cholesterol alone is acceptable for screening if available laboratory services cannot provide reliable measurements of HDL-C; measuring both total cholesterol and HDL-C is more sensitive and specific for assessing coronary heart disease risk than measuring total cholesterol alone. In conjunction with HDL-C, the addition of either LDL-C or total cholesterol would provide comparable information, but measuring LDL-C requires a fasting sample and is more expensive. Direct LDL-C testing, which does not require a fasting sample measurement, is now available; however, calculated LDL (total cholesterol minus HDL minus TG/5) is the validated measurement used in trials for risk assessment and treatment decisions. In patients with dyslipidemia identified by screening, complete lipoprotein analysis is useful."

A more recent study confirms that non-fasting samples may be accurate.

Regarding when to repeat evaluation of risk, "Repeat risk estimation before 8-10 years is not warranted for most people initially not requiring treatment. However, remeasurement within a year seems warranted in those with an initial 15-<20% risk [of cardiovascular disease within ten years]".

Treatment

Antilipemic agents such include:

• Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins)
• Cholesteryl ester transfer protein (CETP) inhibitors (anacetrapib, dalcetrapib , evacetrapib, torcetrapib)
• Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (alirocumab)
• Clofibric acid derivatives

Studies of drugs other than statins show other drugs can lower the cholesterol, but without definite benefit on clinical events. Examples include randomized controlled trials of:

• fenofibrate (fenofibric acid) Fibrates may reduce myocardial infarction, but not mortality according to a meta-analysis. The more recent ACCORD randomized controlled trial of patients with diabetes mellitus type 2 and with triglyceride levels less than 750 mg per deciliter (8.5 mmol per liter) found no reduction in myocardial infarction or mortality. However, among the diabetics with triglycerides about 204 and HDL cholesterol less than 34, there was significant better (primary outcome over 5 years reduced from 17% to 12%). The FIELD randomized controlled trial of patients with diabetes mellitus type 2 also found no reduction in primary outcomes.
• ezetimibe, a cholesterol-absorption inhibitor
• niacin A meta-analysis reported reduce in cardiac events with niacin, but the choice of trails in the meta-analysis is not clear.
• Cholesteryl ester transfer protein (CETP) inhibitors
  • torcetrapib
  • Dalcetrapib
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors
  • Alirocumab
• eicosapentaenoic acid (fish oil)

It is not clear whether to treat to LDL targets. Studies are currently evaluating this.

Clinical practice guidelines

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia.

U.S. Preventive Services Task Force published in 2012 guidelines about screening. .

Clinical practice guidelines by the National Institute for Health and Clinical Excellence in 2008 recommend treatment if the estimated 10 year risk of cardiovascular disease is at least 20%.

The American College of Physicians in 2004 addressed hypercholesterolemia in patients with diabetes . Their recommendations are:

• Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes.
• Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors.
• Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin (the accompanying evidence report states "simvastatin, 40 mg/d; pravastatin, 40 mg/d; lovastatin, 40 mg/d; atorvastatin, 20 mg/d; or an equivalent dose of another statin").
• Recommendation 4: For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

The National Cholesterol Education Program revised their 2001 guidelines in 2004 to include goal LDL values.; however, their 2004 revisions have been criticized for use of nonrandomized, observational data. A decision analysis found that treating to targets is not efficient. However, in this analysis, an older version of the Framingham was used which incorporated EKG findings and included diabetics.

Meta-analyses and trials

In 2012, a meta-analysis of 27 randomized controlled trials of patients, including some at low risk of vascular disease and some with prior vascular disease, reported reduced vascular events, "statins reduced the risks of vascular (RR per 1.0 mmol/L LDL cholesterol reduction 0.85, 95% CI 0.77—0.95) and all-cause mortality (RR 0.91, 95% CI 0.85—0.97)".

Primary prevention

Several meta-analyses, summarizing the randomized controlled trials, have been published.

• In 2011, a meta-analysis of 29 randomized controlled trials, 16 of which examined mortality found reduced mortality (especially among the trials that used high potency statins) and reduced vascular events.
• In 2010, a meta-analysis of 11 randomized controlled trials of patients at increased risk found that overall mortality is insignificantly reduced.
• In 2006, a meta-analysis reported a relative risk reduction in major vascular events of 29.2% in patients treated for 4.3 years. There was no decrease in overall mortality..
• In 2005, a meta-analysis of 10 randomized controlled trials of patients at risk of coronary heart disease found reduced mortality and vascular events.
• In 2005, a meta-analysis by the Cholesterol Treatment Trialists' (CTT) Collaborators of 14 randomized controlled trials found reduction in vascular events and a 19% relative risk reduction in coronary mortality.

Older meta-analyses report similar results:

• In 2001, a meta-analysis estimated that after 5 to 7 years of treatment with statins, the relative risk reduction of coronary heart disease events is decreased by approximately 30%
• In 2000, a meta-analysis concluded "treatment with lipid lowering drugs lasting five to seven years reduces coronary heart disease events but not all cause mortality in people with no known cardiovascular disease."

Treating based on risk factors is probably better than treating to a specific target LDL cholesterol. Using a calculator such as the NIH calculator:

• 5% to 15% risk or coronary heart disease in 5 years, use simvastatin 40 mg
• >15% risk or coronary heart disease in 5 years, use atorvastatin, 40 mg

Important randomized controlled trials included in the meta-analyses are:

• AFCAPS/TexCAPS. The 10 year risk of coronary heart disease among an average patient in this study ((age 57, male, non-smoker, total and HDL cholesterol values of 221 mg/dL and 36 mg/dL, respectively, SBP 138 mm/Hg with medications for hypertension) was 12%.
• JUPITER which found that yreating patients with normal cholesterol level may benefit patients if their high sensitivity c-reactive protein is elevated according to the Jupiter randomized controlled trial. However, the Jupiter trial was stopped early, the subjects had a projected 6.3% risk of coronary events over 5 years and only 17% of patients were taking aspirin.
• Excel studied low risk patients.
• Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study). These subjects had a 3% risk of coronary events in 5 years.

Combination treatment

It is not clear that combination therapy is better than high dose hydroxymethylglutaryl-coenzyme A reductase inhibitors.

If treatment with a hydroxymethylglutaryl-coenzyme A reductase inhibitor does not achieve a desirable cholesterol, other drugs that have been studied include eicosapentaenoic acid which is a metabolite of fish oil. Ezetimibe, a cholesterol-absorption inhibitor, was not clearly beneficial in a study of diabetes mellitus type 2 and a study of mixed primary prevention and secondary prevention. Niacin has been studied with improvements in the LDL and HDL with uncertain effects on carotid intima-media thickness.

Secondary prevention

Clinical practice guidelines by the National Institute for Health and Clinical Excellence recommend a treatment goal of <4 mmol/l (154 mg/dl) for total cholesterol or a low density lipoprotein cholesterol concentration of <2 mmol/l (77 mg/dl). A systematic review summarized randomized controlled trials in secondary prevention.

Combination treatment

If treatment with a hydroxymethylglutaryl-coenzyme A reductase inhibitor does not achieve a desirable cholesterol, other drugs that may be added for additional benefit include niacin and fish oil. Ezetimibe, a cholesterol-absorption inhibitor, was not clearly beneficial in a study of diabetes mellitus type 2 and a study of mixed primary prevention and secondary prevention.

Diabetic patients

Whether diabetes is an equivalent risk factor to having an existing myocardial infarction is debated.

Statin therapy prevents major vascular events in about 1 of every 24 patients with diabetes who use the treatment for 5 years if they are similar to the patients in the meta-analysis by Kearney et al (Number needed to treat is 24).

Treating to a goal of LDL-C < 70 mg/dl and systolic blood pressure to < 115 mm Hg may cause regression of carotid intima-media thickness in a randomized controlled trial.

Complementary and alternative medicine

Preliminary research suggests possible benefit from artichoke leaf.