Lipoprotein (a) corresponds to an LDL-C particle which is found connected to a specific apolipoprotein: apo (a). Serum levels are genetically determined and the apolipoprotein (a) molecule has an important homology to plasminogen, so there is a competitive effect on the latter. This leads to a prothrombotic effect, thus contributing to atherosclerotic vascular injury [31]. Different studies have shown increased levels of lipoprotein (a) to be an important independent risk factor for coronary artery disease and cerebrovascular disease, especially in Caucasian patients [32, 33].

However, the lack of standardization in the measurement of this lipoprotein limits its use, so its evaluation is not routinely recommended. Nonetheless, its determination could be useful in white patients with CAD and in subjects with a family history of CAD of unknown origin [15].

C-reactive protein (CRP) is a highly sensitive marker of chronic inflammatory conditions such as atherosclerosis, and its elevation has been associated with increased cardiovascular risk. Its levels can be divided into <1 mg/L (low risk), 1–3 mg/L (intermediate risk), and > 3 mg/L (high risk) [34]. However, the JUPITER study recently suggested a simpler stratification: CRP <2.0 vs. ≥2.0 [35].

Although some studies have suggested that CRP could be a better predictor of cardiovascular risk better than LDL-C [36], larger, more recent studies have shown that the dosage adds little to predictions based on the traditional risk factors [34]. In relation to therapeutic drug monitoring, CRP levels seem to play a more important role since, as demonstrated by a recent study, the reduction in risk of coronary events appears to be greater not only when the LDL-C drops below 70 mg/dL but also when CRP has decreased levels in response to treatment (less than 2 mg/L) [37].

The dosage of CRP, however, should not be performed routinely, but may be useful in estimates of intermediate risk or in evaluating residual risk in patients with LDL-C <130 mg/dL [15].

Elevated levels of homocysteine (>15 μmol/L) have also been associated with increased cardiovascular risk [38, 39]. However, reduction in its levels with the use of folic acid, vitamin B6, and vitamin B12 showed no risk reduction [40]. Routine screening is therefore not recommended, but in patients stratified as intermediate risk by the Framingham Risk Score (FRS) (see below), its determination can be useful in modifying the rating for high risk [15].

Serum levels of apolipoprotein B (apo B) reflect the levels of small, dense LDL particles, recognized as atherogenic. Some studies have suggested that the elevation of apoB is equivalent or even superior to LDL-C and non-HDL-cholesterol in predicting cardiovascular risk, even in patients with insulin resistance and DM2 [41–43]. The optimal level of apoB recommended in patients at risk of CAD is below than 90 mg/dL [15].

Perhaps even more useful is the assessment of apoB/apolipoprotein AI (apoA-I), as this ratio has been a stronger risk predictor than the LDL-C/HDL-C ratio [44]. The dosage of apoB and apoA-I is indicated in patients with TG > 150 mg/dL and HDL-C below 40 mg/dL to assess residual risk, even in those with LDL-C within the target range, including patients with CAD and DM2 [15].

The measurement of carotid intima-media thickness (IMT) and the coronary calcium score (CCS) are noninvasive imaging tests and have emerged, in recent years, as markers for CAD.

The CCS is an estimate of the amount of coronary plaques in an individual [45]. A CCS of zero reflects a low likelihood of coronary disease and the patient is classified as low risk, with an annual event rate of only 0.11 % in the asymptomatic individual [46]. This appears to be true even in diabetic patients, as it has already been shown that in these cases a CCS of zero indicates survival similar to nondiabetic patients also with a CCS of zero, so in these cases, lipid-lowering therapy would not need to be as aggressive or even necessary [47]. However, studies comparing the CCS with the carotid IMT have suggested that the latter, when increased, has proved a better predictor of CAD [48].

These tests, in any case, are not yet recommended in all individuals with dyslipidemia and their usefulness would probably be greater in those patients initially classified as intermediate risk, in whom they could provide a better explanation of the need for therapy and lipid goals.

The reduction in LDL-C levels, especially in individuals at risk of CVD, remains the main therapeutic target in dyslipidemia. Table 40.4 shows the goals for each risk category and drug treatment associated with lifestyle modification (LSM) in patients at high or very high risk should be initiated immediately, having statins as first-choice drugs. Even if the initial target is not reached, the reduction of at least 30–40 % in the initial LDL-C levels has shown a decrease in cardiovascular risk [9]. However, a single LDL-C target, in general, is not sufficient to reduce all cardiovascular risk [15].

The goal for TG is < 150 mg/dL. However, the exact level at which TG starts to confer risk is unknown. Endocrine Society Guidelines suggested a new TG classification: mild hypertriglyceridemia (150–199 mg/dL); moderate hypertriglyceridemia (200–999 mg/dL); severe (1,000–1,999 mg/dL); and very severe (≥2,000 mg/dL) hypertriglyceridemia [53]. Lifestyle changes (LSC) should be started in the presence of hypertriglyceridemia, and drug therapy in cases in which LSC failed. Only in those individuals with TG > 1,000 mg/dL, drug therapy should be started immediately, preferably a fibrate, to reduce the risk of pancreatitis [53].

For HDL-C, in the presence of associated hypertriglyceridemia or other risk factors, a target at least >40 mg/dL should be pursued. The major question occurs in individuals with isolated lowering of HDL-C in the absence of CVD and/or risk factors due to the absence of clinical trials supporting the benefit of increasing this lipid in this group of patients [15]. However, once it has been decided to raise their HDL-C levels, regular physical activity should be instituted and smoking cessation should also be encouraged, as these measures are known to be effective in increasing HDL-C. If a drug is required, nicotinic acid remains the most effective option.

All patients with dyslipidemia should initiate LSC, based on diet reorientation (low in saturated fat and high in fiber), regular physical activity, and smoking cessation. This therapeutic approach corresponds to the first option in patients at low risk, in which pharmacological treatment should only be initiated 6 months after an attempt to normalize lipemia with LSC, and in those at intermediate risk, in whom the start of lipid-lowering medication should be considered only 3 months later [9].

The type of fat intake is fundamental to the management of dyslipidemia. The saturated fat intake should be limited (<7 % of total calories), and trans fats should also be avoided, since they are associated with elevated LDL-C, decreased HDL-C, and increased cardiovascular risk. Unsaturated fatty acids should make up 10–20 % of caloric intake. Polyunsaturated fatty acids are represented by omega 3 (found in vegetable oils and cold-water fish), the benefits associated with CVD; omega 6 (found in soybean, corn, and sunflower oil), associated with reduction in LDL-C; and TG, although they can also decrease HDL-C. Monounsaturated fatty acids reduce LDL-C, but with no effect on the HDL-C [9].

Considering the positive effect of omega 3 on the lipid profile and cardiovascular risk, its supplementation (at least 1 g of fish oil a day) has been recommended for patients with CVD [15].

Statins represent the drugs of choice in hypercholesterolemia treatment. They act by inhibiting HMG-CoA reductase, an enzyme involved in the synthesis of endogenous cholesterol. Since the intracellular levels of cholesterol decrease with the use of the drug, there is an increase in LDL-C receptors in cell membranes, enhancing LDL-C clearance [54].

The decrease in LDL-C serum levels can range from 25 to 55 % depending on the drug used. There may also be a fall in triglyceride levels of 15–25 % and an increase in HDL-C of around 2–10 % [55].

Simvastatin (dose of 20–80 mg per day) and pravastatin (dose of 20–40 mg a day) must be taken at night. However, atorvastatin (dose of 10–80 mg per day) and rosuvastatin (dose of 10–40 mg per day), more potent in reducing LDL-C, have a longer half-life and can therefore be administered at any time of the day. Rosuvastatin is the most effective drug for raising HDL-C levels [55].

On the whole, it is not recommended to exceed the dose of 40 mg of simvastatin and of 20 mg of atorvastatin and rosuvastatin, because larger doses will contribute little to the decrease in of LDL-C and there is an increased risk of side effects. Thus, in the absence of response, the most sensible thing to do is to introduce another class of drug.

In general, statins are well tolerated, although the following may occur: hepatotoxicity in 1.4 % of cases (a >3-fold increase in transaminases indicates a dosage reduction or discontinuation of the drug), and myalgia and CPK elevation to 15.4 and 0.9 % of cases, respectively (in cases of a >10-fold rise in CPK or persistence of muscle symptoms, the drug should be discontinued). Rhabdomyolysis is rare, occurring in 0.2 % of individuals, and its risk increases in cases of association of drugs with fibrates (except fenofibrate). Among the contraindications to statin therapy, the following may be mentioned: pregnancy, breastfeeding, and acute liver diseases (in cases of renal failure and chronic liver disease, the drug can be used) [56].

Recent clinical trials suggested that the statins may increase the incidence of diabetes. A meta-analysis of 13 randomized statin trials of over 91,000 patients suggested that these drugs compared with placebo leads to a 9 % increased relative risk for the development of diabetes [57]. However, the benefit of cardiovascular risk reduction by statin therapy seems to exceed the risk of diabetes. A risk–benefit analysis showed that the risk of diabetes was increased, but the statins were favorable in high-risk and secondary prevention populations [58]. A recent analysis from the JUPITER (a primary prevention trial) evaluated 17,603 subjects without previous CVD or diabetes and showed that, in subjects with one or more diabetes risk factors, the statin therapy was associated with a 39 % reduction in the primary endpoint (myocardial infarction, stroke, admission to hospital for unstable angina, arterial revascularization, or cardiovascular death) and a 28 % increase in diabetes (a total of 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed) [59].

The major advantage of statins is their positive effect on cardiovascular disease, constituting a class of drug with strong evidence of reducing overall mortality when used in both primary and secondary prevention.