Considering Drug Therapy
Healthy lifestyle changes are recommended for all adults to reduce cardiovascular risk. Whether or not to supplement drug therapy to lower cholesterol levels is the next consideration for patients.
The 2013 ACC/AHA guideline recommends initiating statins—the cornerstone of evidence-based lipid medications—in patients belonging to one of these Four Statin Benefit Groups:
| Patient Benefit Groups | Statin Therapy Intensity | Strength of Recommendation |
|---|---|---|
| Individuals with clinical ASCVD | High | A (strong) |
| Individuals with primary elevations of LDL-C > 190 mg/dL | High | B (moderate) |
| Individuals 40 to 75 years of age with diabetes with LDL-C 70-189 mg/dL:10 year ASCVD risk <7.5% 10 year ASCVD risk >7.5% |
Moderate |
E (expert opinion) |
Individuals without clinical ASCVD or diabetes with all of the following:
|
Moderate to High | A (strong) |
Important considerations:
- The 2013 guidelines did not provide recommendations for initiation of statin therapy in patients with congestive heart failure (Class II, III, or IV) or a need for hemodialysis, due to insufficient RCT evidence.
- In persons with diabetes <40 or >75 years of age, statin therapy should be individualized based on considerations of ASCVD risk reduction benefits, the potential for adverse effects, drug-drug interactions and patient preferences (Grade E).
| Statin Therapy Intensity | |||
|---|---|---|---|
| High | Moderate | Low | |
| Approximate LDL lowering | ≥50% | <50% to 30% | <30% |
| Example Medication/Dosage (from RCTs) | Atorvastatin ≥40mg | Atorvastatin 10 mg Simvastatin 20-40 mg Pravastatin 40 mg Lovastatin 40mg |
Pravastatin 10-20 mg Lovastatin 20 mg |
Statins are the cornerstone of lipid therapy, although there are other drugs to be aware of because they are still used at times in practice.
| Drugs Affecting Lipoprotein Metabolism* | ||||
|---|---|---|---|---|
| Drug Class and Agents | Lipid/Lipoprotein Effects | Side Effects | Contraindications | Clinical Trial Results |
HMG-CoA reductase inhibitors (statins)
|
LDL ↓ 18%-55% HDL ↑ 5% – 15% TG ↓ 7%-30% |
Myopathy; increased liver enzymes | Absolute: active or chronic liver disease Avoid mixing with grapefruit juice. Relative: concomitant use of certain drugs§ |
Reduced major coronary events, CHD deaths, need for coronary procedures, stroke, and total mortality |
Bile acid sequestrants
|
LDL ↓ 15%-30% HDL ↑ 3% – 5% TG No change or increase |
Gastrointestinal distress; constipation; decreased absorption of other drugs | Absolute: dysbetalipoproteinemia; TG>400 mg/dL Relative: TG>200 mg/dL |
Reduced major coronary events and CHD deaths |
Nicotinic acid
|
LDL ↓ 5%-25% HDL ↑ 15%-35% TG ↓ 20%-50% |
Flushing; hyperglycemia; hyperuricemia (or gout); upper gastrointestinal distress; hepatotoxicity | Absolute: chronic liver disease; severe gout Relative: diabetes; hyperuricemia; peptic ulcer disease |
Reduced major coronary events, and possibility total mortality |
Bile acid sequestrants
|
LDL ↓ 15%-30% HDL ↑ 3% – 5% TG No change or increase |
Gastrointestinal distress; constipation; decreased absorption of other drugs | Absolute: dysbetalipoproteinemia; TG>400 mg/dL Relative: TG>200 mg/dL |
Reduced major coronary events and CHD deaths |
Fibric acids
|
LDL ↓ 5%-20% (may be increased in patients with high TG) HDL ↑ 10%-20% TG ↓ 20%-50% |
Dyspepsia; gallstones; myopathy; unexplained non-CHD deaths in WHO study | Absolute: severe renal disease; severe hepatic disease | Reduced major coronary events |
| * HMG-CoA indicates 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglycerides; ↓, decrease; ↑, increase; and CHD, coronary heart disease. § Cyclosporine, macrolide antibiotics, various antifungal agents, and cytochrome P-450 inhibitors (fibrates and niacin should be used with appropriate caution).Table from Adult Treatment Panel III. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA, May 16, 2001 |
||||
Ezetimibe
Ezetimibe is an anti-lipidemic drug. It is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. It is used when statins are not tolerated or are contraindicated in a patient. A study published in the New England Journal of Medicine surprisingly found that despite a remarkable drop in LDL and C-reactive protein levels when ezetimibe is used in conjunction with a statin in patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima media thickness, as compared with simvastatin alone (NEJM, 2008). The full article is located in the library: Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia. Read about recent (2014) RCT data on ezetimibe on the section of this module titled,“Evolving Evidence, Conflicting Interpretations.”
Omega-3 Fatty Acids
Some clinical trials suggest that relatively high intakes of n-3 fatty acids in the form of fish, fish oils, or high-linolenic acid oils may reduce risk for major coronary events in persons with established CHD (secondary prevention). More clinical evidence is needed to make recommendations on higher doses for primary prevention.
Evidence of Effectiveness of Combination Lipid-lowering Medications
After lifestyle modifications, statins are the first line of treatment. The 2013 ACC/AHA guidelines suggest that (1) statins are the only evidence-based treatment for cholesterol; (2) medium- or high-intensity fixed-dose statin therapy is recommended based on cardiovascular risk (low-dose only in cases of tolerability concerns); and (3) combination drugs are no longer recommended.
The systematic review entitled “Comparative Effectiveness of Lipid Modifying Agents” (2009), by the University of Ottawa Evidence-based Practice Center, and funded by the United States Agency for Healthcare Research and Quality (AHRQ) compared the following medication combinations with statin monotherapy:
- Statin plus a bile acid sequestrant
- Statin plus ezetimibe
- Statin plus a fibrate
- Statin plus niacin
- Statin plus Omega-3 fatty acids
According to the review:
- The evidence is insufficient to conclude that combination therapy leads to lower rates of clinical events and death (myocardial infarctions, strokes, and the need for invasive vascular procedures) than statin monotherapy. In these studies, clinical events included myocardial infarctions, strokes, and the need for invasive vascular procedures.
- The evidence is insufficient to assess whether any combination regimen provides greater reduction in LDL cholesterol than statin monotherapy. Evidence is also insufficient for other intermediate outcomes, including total cholesterol, HDL cholesterol, and coronary artery and carotid intima thickening.
- The evidence is insufficient to draw conclusions about the rates of adverse events of combination therapy compared with statin monotherapy. The adverse events assessed in these studies included elevation of liver enzymes, myalgia, rhabdomyolysis, and cancer.
Adverse Effects of Statins
Some patients are reluctant to initiate treatment with statins because of concerns regarding possible side effects. The most frequently cited reasons are fear of liver and muscle damage.
The most common adverse effects reported by people taking statins are skeletal muscle symptoms (weakness, fatigue, cramping and pain; Mlodinow 2014). Clinical studies have reported the incidence of statin-related myalgia from <1% to 20%. This wide discrepancy has been attributed to the differences in the clinical trials’ patient exclusion criteria and in how muscular disorders were defined in the studies. According to the ACC/AHA guideline report, there is only one additional case of myopathy per 10,000 statin users compared with those on placebo. The depletion of coenzyme Q10 (CoQ10) has been postulated as the mechanism for statin-induced myopathy, and a large study is currently under way to compare placebo and CoQ10 in patients with myopathy.
Rhabdomyolysis is a rare, but very serious, complication of statin use and is characterized by severe muscle pain, muscle weakness, increased serum creatinine and a ten-fold increase in creatine kinase (CK). Rhabdomyolysis has a fatality rate of 10%. Fortunately, its occurrence rate < 0.06% over five years. In patients taking both gemfibrozil and a statin, the incidence was ten times higher. Studies have also shown an increased risk of myopathy and rhabdomyolysis in patients taking the high dose of simvastatin (80 mg), but not other statins. At lower doses, simvastatin appears to be safe and well tolerated and had the lowest discontinuation rates (along with pravastatin) due to adverse effects among statins in clinical studies.
Despite the widespread belief among the public that statins can cause liver toxicity, studies have shown that statins are not associated with acute or chronic liver failure. The incidence of statin-related hepatotoxicity is very small (< 1.5% over five years in patients with coronary heart disease) and appears to be dose dependent. The ACC/AHA guidelines and the FDA still recommend checking baseline transaminase levels prior to statin therapy, but routine monitoring is not indicated.
There may be a small increase in new-onset Type 2 Diabetes Mellitus in patients who take statins. For patients on high intensity therapy, the ACC/AHA guideline has reported an excess rate of diabetes of 3 per 1000 patient years. For patients on moderate intensity therapy, the excess rate was 1 per 1000 patient years.
Other serious adverse effects have been reported with statin use. A major prospective study has shown that statins increased the risk for a recurrence of bleeding in patients with a previous history of intracerebral hemorrhage (ICH). Patients with a history of ICH need to have a very high 10-year cardiovascular event risk (>40%) for the statin benefit to outweigh the risk. A recent analysis has shown that statins increased the risk of developing cataracts. Numerous meta-analyses and reviews have shown no link between statin use and malignancy. No causal association has been found between statin use and peripheral neuropathy.
The following factors may increase the risk for statin-induced adverse effects:
- Multiple and/or serious comorbidities
- Unexplained ALT elevation > 3 times the upper limit of normal
- Prior statin intolerance
- Concomitant use of drugs that affect statin metabolism
- Age > 75 years
- Pre-existing muscle disorders
- Low Vitamin D levels
Statins are safe and effective for children and adolescents with familial hyperlipidemia. They are contraindicated in women who are pregnant, breastfeeding or trying to conceive.
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