Introduction
Atheromatous plaque in arterial wall is the pathologic substrate for myocardial infarction and ischemic stroke and is intimately related to the deposition of oxidized lipids from the circulation into the subintimal space, initiating a vicious cycle of local inflammation, macrophage foam cell formation, and smooth muscle recruitment. The measurement of circulating lipids has led to significant improvements not only in understanding the pathophysiology of atherosclerotic cardiovascular disease (ASCVD) but also in improving risk prediction and management of ASCVD.
Traditional Lipoprotein Measurements
The three major classes of lipoproteins are low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL). Apolipoprotein B (apoB) is the main protein constituent of atherogenic lipoproteins, including LDL, VLDL, intermediate-density lipoprotein (IDL), lipoprotein(a), and chylomicrons, and it serves as the primary ligand for the LDL receptor and scavenger receptors in arterial macrophages and other tissues types. LDL cholesterol (LDL-C) is the most abundant apoB-containing lipid, accounting for 60% to 70% of the total serum cholesterol. VLDL consists of triglycerides and most of the remaining atherogenic apoB-containing cholesterol. IDL is similar to LDL and also contains apoB and triglycerides. Chylomicrons are very large particles that carry dietary cholesterol and triglycerides from the intestine to the liver. In contrast, HDL cholesterol (HDL-C) contains apolipoprotein A-I (apoA-I), which is considered atheroprotective, and makes up approximately 20% to 30% of the total serum cholesterol pool. Total cholesterol, HDL-C, and triglycerides are directly measured enzymatically, and LDL-C is typically calculated using the Friedewald formula ( Fig. 8.1 ). The overall burden of atherogenic lipoproteins can be assessed as non-HDL-C, calculated by simply subtracting HDL-C from total cholesterol (see Fig. 8.1 ).
Total and Low-Density Lipoprotein Cholesterol
Genetic and intervention studies in humans reveal an overwhelming consistency in the relationship between LDL-C (or total cholesterol) levels and both incident ASCVD in those free of ASCVD and recurrent events in those with established ischemic heart disease ( Fig. 8.2 ). Studies have revealed an absence of atheromatous plaques and clinically evident coronary disease in populations where LDL-C is maintained under 100 mg/dL (2.6 mmol/L) (or total cholesterol < 150 mg/dL [3.9 mmol/L]). LDL-C levels above 190 mg/dL (4.9 mmol/L) suggest a genetic disorder such as familial hypercholesterolemia and increased short-term ASCVD risk. Total cholesterol is directly measured and was the primary lipid studied in the original cholesterol investigations. Current American and European ASCVD risk algorithms use total cholesterol as the measure of atherogenic lipoprotein. Total and LDL-C levels can be lowered by a variety of interventions, including reduced dietary intake of trans and saturated fats, increased dietary intake of soluble fiber, and pharmacotherapies such as statins, bile acid sequestrants, nicotinic acid, cholesterol absorption inhibitors, and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors ( Table 8.1 ).
| Lipid-Modifying Therapies | LDL-C | NON-HDL-C | HDL-C | Triglycerides | Lp(a) |
|---|---|---|---|---|---|
| Statins | ↓ 18–55% | ↓ 15–51% | ↑ 5–15% | ↓ 7–30% | ↔ |
| Bile-acid sequestrants | ↓ 15–30% | ↓ 4–16% | ↑ 3–5% | ↑ 0–10% | |
| Cholesterol absorption inhibitors | ↓ 13–20% | ↓ 14–19% | ↑ 3–5% | ↓ 5–11% | |
| PCSK9 inhibitors | ↓ 61–62% | ↓ 52% | ↑ 5–7% | ↓ 12–17% | ↓ 25% |
| ApoB antisense | ↓ 25–37% | ↑ 2–15% | ↓ 9–26% | ↓ 21–33% | |
| MTP inhibitor | ↓ 44–50% | ↓ 44–50% | ↓ 12–↑1% | ↓ 29–45% | ↓ 15–19% |
| Nicotinic acid | ↓ 5–25% | ↓ 8–23% | ↑ 15–35% | ↓ 20–50% | ↓ 20–40% |
| Fibric acids | ↓ 5–↑20% | ↓ 5–19% | ↑ 10–20% | ↓ 20–50% | |
| Long-chain omega-3 fatty acids | ↓6–↑25% | ↓5–14% | ↓ 5–↑7% | ↓ 19–44% |
High-Density Lipoprotein Cholesterol
HDL-C is the other major lipid used in validated risk scoring algorithms. Observational studies show consistent relationships between low HDL-C (< 40 mg/dL) (1 mmol/L) and increased ASCVD risk ( Fig. 8.3 ). HDL-C levels have a significant inherited component and are typically higher in women and in those of African descent. Low HDL-C levels are associated with smoking, insulin resistance, hypertriglyceridemia, and physical inactivity. Low HDL-C is one of the five components of the metabolic syndrome and is often part of a lipid triad that includes high triglycerides and small dense LDL particles. HDL-C levels below 40 mg/dL (1 mmol/L) in men and below 50 mg/dL (1.3 mmol/L) in women are considered major ASCVD risk markers; however there is insufficient evidence to support raising HDL-C as a treatment target. Lifestyle interventions that are associated with increases in HDL-C include smoking cessation, weight loss, reduced carbohydrate consumption, increased physical activity, and moderate alcohol consumption. Nicotinic acid is the most potent clinically available pharmacotherapy that raises HDL-C levels, with differential and weaker effects seen after administration of fibrates and statins (see Table 8.1 ). However, as noted above, raising HDL-C has not been proven to be a valid therapeutic approach to improve ASCVD outcomes.
Triglycerides
Triglycerides are fatty acids that contain most of the fat stored by the body and are derived from dietary sources and metabolism of fat depots. A fasting triglyceride level above 150 mg/dL (1.7 mmol/L) is considered dyslipidemia and is a component of the metabolic syndrome. Hypertriglyceridemia is defined as a fasting level above 200 mg/dL (2.3 mmol/L) and is associated with increased ASCVD risk. Increasing triglyceride levels reflect enrichment of circulating levels of triglyceride-rich lipoproteins; of which VLDL is the most common, followed by IDL and chylomicrons.
The relationship between hypertriglyceridemia and ASCVD risk has been controversial. Adjustment for HDL-C and non-HDL-C levels partially attenuates the association between triglyceride levels and incident events in some but not all studies. In contrast, Mendelian randomization studies suggest that triglyceride-rich lipoproteins or their remnants are causally related to increased risk of ischemic heart disease. Elevated triglyceride levels are associated with an atherogenic dyslipidemia comprised of cholesterol enrichment of triglyceride-rich lipoproteins, increased small dense LDL particles, and low HDL-C, which may also contribute to the increased risk seen with hypertriglyceridemia, especially among those with metabolic syndrome or diabetes. Lastly, the increased ASCVD risk seen with elevated triglycerides seems to be disproportionately higher in women than in men.
Triglyceride levels can rise significantly following a fatty meal; therefore it is usually recommended to measure fasting triglyceride levels; however nonfasting triglyceride levels above 200 mg/dL (2.3 mmol/L) are also associated with increased risk and may be a better predictor than fasting levels ( Fig. 8.4 ). In fact, several of the Mendelian randomization studies mentioned above assessed nonfasting triglyceride levels and demonstrated causality with incident ischemic heart disease. Elevations in nonfasting triglycerides reflect increased exposure to atherogenic triglyceride-rich lipoproteins in the circulation.
Hypertriglyceridemia, like low HDL-C, is also seen with hyperglycemia and increased insulin resistance, obesity, alcohol intake, physical inactivity, and carbohydrate intake. When triglyceride levels are above 400 mg/dL (4.5 mmol/L), the levels of triglyceride-rich lipoproteins such as VLDL and IDL are elevated and the calculated LDL-C is not valid. Therefore, non-HDL-C should be calculated (see the section on non-HDL-C) when triglycerides are above 200 to 400 mg/dL (2.3 to 4.5 mmol/L).
Fibrates, high-dose nicotinic acid, and high-dose omega-3 fatty acids are the most potent triglyceride-lowering agents (see Table 8.1 ). Most other lipid-lowering drug classes modestly lower triglyceride levels, with the exception of bile acid sequestrants, which can raise levels. The evidence to support targeting triglyceride levels to reduce ASCVD risk is inconsistent. In two randomized controlled trials, adding fenofibrate to statin therapy did not improve outcomes compared with statin alone in the overall trial populations, but did show a benefit in the subgroups defined by high triglyceride and low HDL-C at baseline. Monotherapy with gemfibrozil in high-risk patients improved outcomes, but a meta-analysis of all fibrate trials revealed no improvement in cardiovascular mortality and a nonsignificant trend toward increased noncardiovascular deaths. The evidence for nicotinic acid is remarkably similar to that of fibrates: older studies without statin background therapy suggested benefit but more contemporary trials with background statin therapy have been negative. Similar to the fibrate trials, subgroups defined by high triglyceride and low HDL-C seemed to benefit from high-dose nicotinic acid. Omega-3 fatty acids have been studied using various formulations and various doses of the active ingredients. A randomized controlled trial in Japanese patients showed improvement in a composite ASCVD endpoint in those allocated to pure ethyl ester in addition to background statin therapy, with a magnified effect in those with high triglyceride and low HDL-C. However, a subsequent meta-analysis of omega-3 fatty acids failed to show a consistent improvement in any cardiovascular endpoint. Ongoing randomized trials of high-dose omega-3 fatty acids among those with elevated triglycerides and ASCVD risk will provide more direct guidance on the role of omega-3 therapies in reducing triglycerides to reduce ASCVD risk. Regardless of ASCVD risk, triglyceride levels should be kept below 500 mg/dL (5.6 mmol/L) to avoid the risk of pancreatitis.
Causes of Secondary Dyslipidemia
Traditional lipids are routinely measured and abnormal values (dyslipidemia) are often acted upon directly with the goal of reducing ASCVD risk. However, there are common conditions that can lead to dyslipidemia that should be evaluated ( Table 8.2 ). In addition to diets enriched in trans and saturated fats, the most common conditions leading to increased LDL-C levels include hypothyroidism, kidney disease, menopause, and medications including thiazide diuretics, fibrates, and glucocorticoids. With respect to triglycerides, in addition to diets with high glycemic loads, other common conditions leading to elevated levels include excess alcohol intake, diabetes, nephrotic syndrome, β-blockers, hormone replacement therapy, atypical antipsychotic drugs, and other conditions that also raise LDL-C levels (see Table 8.2 ). Addressing these causes first can often lead to improvements or resolution of the dyslipidemias without lipid-modifying therapies.
| Elevated LDL-C | Elevated Triglycerides | Low HDL-C | |
|---|---|---|---|
| Diseases | |||
| Hypothyroidism | + | + | + |
| Chronic kidney disease | + | + | + |
| Nephrotic syndrome | + | + | + |
| Autoimmune disorders | + | + | + |
| Menopause | + | + | + |
| Polycystic ovary syndrome | + | + | |
| Pregnancy | + | + | |
| HIV infection | + | + | + |
| Obstructive liver disease | + | ||
| Diabetes | + | + | |
| Metabolic syndrome | + | + | |
| Excessive alcohol intake | + | ||
| Drugs | |||
| Thiazide diuretics | + | + | |
| Glucocorticoids | + | + | |
| Anabolic steroids | + | + | |
| Fibric acids | + | ||
| Omega-3 fatty acids containing docosahexanoic acid | + | ||
| Thiazolidinediones | + | + (rosiglitazone only) | |
| Immunosuppressive drugs | + | + | |
| Oral estrogens | + | ||
| Tamoxifen | + | ||
| Raloxifene | + | ||
| Retinoids | + | ||
| β-blockers | + | + | |
| Atypical antipsychotics | + | ||
| Protease inhibitors | + | ||
| Bile acid sequestrants | + | ||
| Cyclophosphamide | + | ||
Non-High-Density Lipoprotein Cholesterol
Non-HDL-C is calculated easily by subtracting HDL-C from total cholesterol and represents the cholesterol in all apoB-containing atherogenic lipoproteins, including LDL, VLDL, and IDL (see Fig. 8.1 ). Typically, thresholds for defining treatment and goals for non-HDL-C are 30 mg/dL (0.77 mmol/L) higher than those for LDL-C; therefore ideal non-HDL-C levels are below 130 mg/dL (3.3 mmol/L) for primary prevention. Non-HDL-C predicts ASCVD risk similarly or better than LDL-C ( Fig. 8.5 ). In contrast to calculated LDL-C, non-HDL-C is not sensitive to elevated triglycerides and can be measured in the nonfasting state; therefore it is a better measure of atherogenic lipids in those with elevated triglyceride levels (∼ above 200 mg/dL; 2.3 mmol/L). Elevations in non-HDL-C reflect increasing levels of atherogenic remnant lipoproteins and often occur with worsening hyperglycemia and insulin resistance, obesity, physical inactivity, and increased carbohydrate and alcohol intake. Lastly, non-HDL-C is significantly associated with ASCVD risk among those on statins as well as among those at high risk ; therefore non-HDL-C is an easy measure of residual risk that can be lowered by intensifying lifestyle change and/or lipid-lowering therapy.
