What’s the prevalence of atherogenic dyslipidemia in Latin America?

To determine the prevalence of AD in LA a search of all studies done in LA was made using representative samples of the general or regional population that included a serum lipid profile (see Table I on the appendix).

Table I: Therapeutic changes in lifestyle that have influence on AD.¹¹⁰ 

The 1992-1993 Health Survey from Mexico included 2,256 adults from 20 to 69 years of age with blood samples taken after 9-12 hours of fasting. In this urban sample, selected from 417 cities with populations higher to 2,500 inhabitants, it was reported a prevalence of HDL-C < 35 mg/dL in 46.2% of men and in 28.7% of women; there were no differences in prevalence between different age ranges. A level of triglycerides (TRG) > 150 mg/dL was found in 49.7% of men and in 30.8% of women, with an increase across years of age. A combination of low HDL-C and moderately high TRG (values > 200 mg/dL) was observed in 12.9% of the total sample, but being more prevalent in men than women (20.9% vs. 7.2%, respectively).¹²

This same survey was repeated in 2006 in a sample of 4,040 individuals with a similar age range finding a higher frequency of this combination of low HDL and high TRG (18.3% in total, meaning a 41.8% of increment as compared with the previous study).¹³

The Chilean National Health Survey from years 2010-2011 used a national randomized sample of 4,965 subjects from 18 to 74 years of age. The prevalence of TRG ≥ 150 mg/dL measured after 9 hours or more of fasting was 31.2%, being more frequent in men than in women (35.6% vs. 27.1%, also after a fasting of 9 or more hours, was 45.4% (more frequent in women than in men: 52.8% vs. 37.6%, respectively).¹⁴

A national study on CRFS, with a nationwide population sampling made in Dominican Republic: EFRICARD,¹⁵ which included 4,976 adults between 18 and 75 years old reported: a prevalence of HDL-C < 40 mg/dL of 30.7 being significantly higher in men than in women (40% vs. 26.4%. p < 0.0001), and a prevalence of TRG > 150 mg/dL of 21%, also being more prevalent in men (26.3 vs. 18.3% p < 0.004).

In the Latin American Consortium of Studies in Obesity (LASO)¹⁶ an analysis of the results obtained from 11 cross sectional independent population studies was made. This study was performed in eight LA countries (Argentina, Chile, Colombia, Costa Rica, Dominican Republic, Peru, Puerto Rico and Venezuela) on 31,009 participants and showed a 53.2% in the prevalence of low HDL-C (defined as < 40 mg/dL in men and < 50 mg/dL in women), and a prevalence of 25% in high TRG level (≥ 150 mg/dL). There was no central laboratory for sample processing.

The study CESCAS I,¹⁷ a prospective cohort study made from 2013 to 2014 in 4 cities from the southern cone of America (2 cities from Argentina, 1 from Chile and 1 from Uruguay), included 7,524 subjects from 35 to 74 years of age and reported a prevalence of 34.1% in low HDL-C (< 40 mg/dL) and of 26.5% of TRG ≥ 200 mg/dL. There are some reports from different studies made using randomized general population samples coming from different LA countries: In Peru, the studies PREVENCION¹⁸ made in Arequipa; CRONICAS,¹⁹ made in Lima, Puno and Tumbes; MIGRANT,²⁰ made in Ayacucho and Lima; studies made on Sao Paulo, Brasil;^21,22 on the city of Talca, in Chile,²³ and in Mexico City (see results on Table I).²⁴

In Venezuela, a study made in 3,108 subjects with 20 or more years of age from the city of Maracaibo²⁵ showed an age-adjusted prevalence of AD was 24.1% with a low HDL-C frequency of 65%. Data from 4 other more recent studies, also made in Venezuela, has suggested that the prevalence of AD in this country is 24.7%.²⁶

It could be concluded, despite of all this scattered data, that there is an urgent need to design a global LA epidemiological study in order to find out the real prevalence of AD in our region.

Are the lipid alterations found in LA similar than the ones present in the rest of the world?

When comparing HDL-C and TRG data from LA with the one from other countries, a higher prevalence of these alterations is found in LA.

In USA, the National Survey on Nutrition and Health (NHANES 2009-2010) showed a low HDL-C prevalence (30.1%, 95% CI: 29.9-33.2%) which is lower than the prevalence found in LA.²⁷ In Spain, a study made in the province of Murcia showed a prevalence of low HDL-C of 27.3% (95% CI: 25.1-29.4%).²⁸ Both studies, the American and the Spanish ones used as a cut point a level of HDL-C < 40 mg/dL in men and < 50 mg/dL in women. These results sugest that in LA the reported prevalence of low HDL-C is higher than the one reported in some other parts of the world, being the highest prevalence in women as compared with men.

If we consider as high a TRG level ≥ 150 mg/dL, the prevalence of hypertriglyceridemia showed in the LA studies -with the only exception of LASO study¹⁶- is, in general, higher than the one found in the NHANES study were it was 24.3% (95% CI: 21.6-26.9%).²⁷ Same happens in the above mentioned Spanish study were it was of 22.8% (95% CI: 25.1-29.4%).²⁸ In LA the hypertriglyceridemia prevalence is higher in men than in women.

Finally, it must be mentioned one study made in Venezuela that showed a lower prevalence of low HDL-C in the Amerindian population as compared with whites and African-descendants.²⁶

In LA there are no studies that have quantitated the levels of small and dense LDL-C (sdLDL-C).

Which could be the causes for the prevalence of these lipid abnormalities in LA: socioeconomic and cultural, feeding patterns, genetic/epigenetic?

What mechanisms can cause atherogenic dyslipidemia?

Insulin resistance seems to be the main mechanism for AD production. TRG and cholesterol esters are the two most important lipids on circulation; since they are hydrophobic, most combine each one with apoproteins to form lipoproteins and be transported in plasma. Cholesterol is transported by all lipoproteins but mostly by HDL-C and LDL-C.

In general TRG are transported by VLDL, quilomicrons and its remnants; because of its high TRG content all these lipoproteins are collectively called TGRLP. Also, the lipoproteins, besides its content of TRG or C, its size and its density, can be characterized by the kind of apoproteins they have. So, apoprotein B100 (apoB100) is found into VLDL, IDL and LDL-C, and this group is collectively called Non High Density Lipoprotein-Cholesterol (Non-HDL-C). On the contrary, HDL-C has apoprotein A1 (apoA1). Patients with AD have excess of TRG in plasma and hypertriglyceridemia is frequently and independently associated with some metabolic conditions as diabetes mellitus type II, obesity and the metabolic syndrome.^38,39

Under normal conditions TRG lipolysis on adipocytes is suppressed by insulin (Figure 1) but in the states of insulin resistance associated with abdominal obesity and overweight this phenomenon does not occur (step 1 on Figure 1) resulting in an augmented production of free FA (FFA) on the portal circulation. These FFA arrive to the liver to be used for an augmented synthesis of TRG by the hepatocyte, being its immediate consequence (step 2 on Figure 1) an overproduction of particles of VLDL-C big and rich in TRG, with apoprotein CIII (apoCIII) that have a longer time of permanence in plasma. Lipolysis of this excess of TRG from VLDL produces remnants of VLDL, IDL and, finally, small and dense particles of LDL-C (step 3 in Figure 1).^40,41

Figure 1: Origin of atherogenic dislipidemia. 

Simultaneously, high TRG content on VLDL favors an exaggerated interchange of it for cholesterol between VLDL and HDL-C due to the action of the enzyme cholesterol-esters transfer protein (CETP) (step 4 on Figure 1) producing HDL-C particles abnormally charged with TRG; these particles are later depleted of its TRG content by the enzymes hormone sensible lipoprotein lipase and hepatic lipase (step 5 on Figure 1) producing small and dense HDL-C particles that are less efficient for the reverse cholesterol transport mechanism and are eliminated more rapidly from circulation and consequently reducing its blood concentration.⁴² In patients with visceral obesity low concentrations of plasmatic HDL-C and apoA1 are related to lower levels of adiponectin.⁴³

May excess of triglycerides be considered as the father of atherogenic dyslipidemia?

Due to their higher size and high content of TRG, on states of insulin-resistance the half-life of TGRLP is prolonged and consequently on the post-prandial period of these patients the plasma TRG are elevated for a longer time than in normal people. This phenomenon is known as post-prandial hyperlipidemia.⁴⁴

When there is an excess of plasma TRG, cholesterol is transported on a higher proportion by TGRLP and so, hypertriglyceridemia must be considered as a marker of the increase on atherogenic particles like the sdLDL-C (Table I).⁴⁴

Patients with moderately elevated TGRLP are identified by TRG levels > 200 mg/dL, from these concentrations onward plasma VLDL are partially metabolized particles called VLDL remnants that have a higher cholesterol esters content; in fact, with TRG concentrations > 200 mg/dL or when TRG/HDL-C ratio is > 3.8, more than 40% of plasma cholesterol is bound to the TGRLP. Also, on these patients half-life of quilomicrons and TRG remnants is > 12-24 hours.³⁹

VLDL and its remnants are equal or more atherogenic than LDL-C and although its size is relatively higher than the one of the LDL-C, they have the capacity to penetrate the sub-endothelial space and be phagocyted by macrophages without previous oxidation.

In these patients LDL-C measurement sub-estimates the total charge of atherogenic particles and for this reason on patients with a high level of TRG, the measurement of Non-HDL cholesterol gives us a better estimation of cardiovascular risk since Non-HDL-C includes the cholesterol present on the LDL-C + the one present on the TGRLP.

Which is the role of insulin-resistance? What is first?

The above mentioned alterations on metabolism and lipid kinetics coexist because they have a common base and are frequently found in patients with insulin-resistance and type II diabetes mellitus. Insulin-resistance seems to be a fundamental step on the sequence of abnormalities driving to AD as it is suggested by the strong correlation between insulin secretion response to a glucose oral charge and TRG plasma levels in which a higher resistance to insulin implies higher hypertriglyceridemia.

How is atherogenic dyslipidemia related to associate metabolic conditions?

Insulin-resistance, obesity and type II diabetes mellitus produce increase accumulation of TRG as fat on the liver and this is known as non-alcoholic steatohepatitis. Non esterified or free FA represent the main source of the lipid excess that is accumulated in the liver particularly on states of insulin-resistance (Figure 2). The mechanisms involved in the production of these lipid abnormalities are basically two: 1) excess of hepatic lipids favors an increased incorporation of TRG to the VLDL-C particles that are later secreted contributing to the increase of apoB100 and apoCIII in plasma. 2) There is an over-stimulation of the endothelial hepatic cell lipase that degrades HDL-C particles.^45,46

Figure 2: Relationship between hypertriglyceridemia and atherogenic dyslipidemia 

It is not know the mechanism by which the hepatic lipid excess stimulates the synthesis of the lipoprotein regulators but the most accepted hypothesis states that FA oxidation increase their production as well as some coagulation factors. Under physiologic conditions, insulin stimulates phosphorilation of a transcription factor known as «fork-head box protein 01» (FOX01); this protein belongs to a family that plays an important role on the regulation of genes implied in cell growing and neo-glycogenesis.⁴⁷ On the states of insulin-resistance this pathway is not activated and neo-glycogenesis and de novo lipogenesis are stimulated.⁴⁸

Chronic hyperinsulinemia also induce de novo lipogenesis by inducing the stimulation of the regulatory element of sterols link to protein 1-c that slows intrahepatic degradation of apoB100,⁴⁹ and diminishes expression of LDL-C receptors and consequently the clearance of LDL-C.

Which is the role of apolipoprotein CIII?

The apoCIII is a small apolipoprotein that is mainly synthesized in the liver and circulates in plasma associated to TGRLP. It is related to a higher cardiovascular risk probably by inhibiting the union of the apoB100 to its hepatic receptor, reducing in this way the clearance of VLDL by the liver. Also, it has been suggested that apoCIII could inhibit endothelial lipoprotein lipase.⁵⁰

There are some epidemiological evidences that suggest a relationship between apoCIII and AD:

1. In case and controls studies with clinical and angiographic end points and in observational prospective studies, the apoCIII plasmatic concentrations are strong independent risk factors for cardiovascular disease (CVD).

2. Humans with genetic deficiency of apoCIII have low levels of TGRLP and low incidence of AD.⁵⁰

Is atherogenic dyslipidemia a cause of cardiovascular disease? Epidemiologic evidences

Plasmatic elevation of LDL-C is one of the most important risk factors for coronary heart disease (CHD) and cerebrovascular disease. Intervention studies with lipid lowering drugs, mainly with statins have shown that reductions in LDL-C produce substantial drops in cardiovascular morbidity and mortality; however, despite of these benefits still persist an important level of residual risk.⁵¹ Multiple causes explain the persistence of this residual risk: coexistence of other risk factors, level of individual basal risk, familial and genetic factors, and presence of AD.

It has been proposed that high TRG levels, as an important element of AD, have a predictive capacity for cardiovascular events but a good deal of epidemiological data (see Table II) shows that the Non-fasting TRG levels are most robust predictors of cardiovascular events than the fasting TRG, even after reaching LDL-C goals.

Table II: Effects of alimentary fats on the lipid profile and platelet aggregation. 

In the Women’s Health Study⁵² made in 26,509 female subjects, the association between fasting TRG levels and risk of cardiovascular events was not significant (p = 0.90) but when data from non-fasting subjects was considered there was a significant association (p = 0.006) even after an analysis of covariance for total cholesterol, HDL-C and indicators of insulin resistance.

Similarly, the Copenhagen Heart Study⁵³ showed that total mortality and accumulated incidence of cardiovascular events (ischemic ictus, MI and ischemic heart disease) were proportionally related to the increase in non-fasting TRG levels (p = 0.001). These associations were not adjusted for other lipid parameters.

In patients with IHD treated with statins this association was also demonstrated: In the study PROVE IT, TIMI 22, made in patients with an acute coronary syndrome treated with statins to optimal levels of LDL-C, a value of fasting TRG > 200 mg/dL was associated to a higher number of events even after adjustment for HDL-C and LDL-C levels (HR: 0.8; p = 0.025).⁵⁴ Other studies have not found this positive association between TRG levels and cardiovascular events.⁵⁵

Based on the disparities found between fasting and non-fasting TRG, it has been suggested that TGRLP levels could be a better marker of risk instead of values of TRG.

A recent Mendelian randomization study,⁵⁶ an approach that minimizes inverse causality problems and avoid confusion factors, has been made in 73,513 individuals from the cohort of the Copenhagen Heart Study (11,984 developed an ischemic event during the study). In this study a genotype analysis for gen variants that could affect levels of cholesterol, LDL-C, non-fasting cholesterol remnants and HDL-C was made to all participants looking for a causal association between lipoproteins and ischemic heart disease (IHD). The results shown that an increase in 39 mg/dL in non-fasting cholesterol remnants was proportionally associated with a 2.8 times increased risk of IHD independently of low levels of HDL-C. This finding implies that the cholesterol content transported in TGRLP is related to IHD.

Other studies⁵⁷ with similar methodology have shown a positive association between TGRLP and IHD, low grade inflammation, and total mortality; so, it is fair to conclude in the association of AD with CVAD.

Can atherogenic dyslipidemia produce cardiovascular disease? Pathophysiologic evidences

Atherogenesis is the result of a certain accumulation of plasmatic lipid particles and of an endothelial dysfunction process that allows them to enter the arterial intima. There, processes of inflammation, oxidation and cell migration originate an atherosclerotic plaque and its different clinical manifestations.

Former epidemiologic studies have shown that there is a lineal and continuous relationship between plasma cholesterol levels and atherosclerosis⁵⁸ and is this relationship the one that has allowed to affirm that, in principle, high plasma cholesterol is the single, independent and totally necessary factor for the genesis of atherosclerosis. However, total value of plasma cholesterol does not allow for a clear difference between healthy and sick individuals in a certain population because the distribution curves of both groups for this continuous variable overlap.⁵⁹ For this reason, and others derived from basic research, it has been established that the pathogenetic relationship between cholesterol and atherosclerosis does exist but with all cholesterol sub-fractions considered as atherogenic (VLDL and its remnants, IDL, LDL-C and Lp(a); all these molecules share an apoB100 in their composition to facilitate their union to cellular receptors allowing them to give cholesterol esters to the tissues.⁶⁰

Under normal conditions, approximately 90% of particles with apoB100 are LDL-C molecules⁶¹ and represent a strong support for the relationship between this sub-fraction and coronary morbidity and mortality; however, in patients with AD this proportion changes and the percentage of cholesterol transported by LDL-C diminishes to two thirds due to the increase in cholesterol transported by VLDL and its remnants, and IDL.

Why LDL small and dense particles are more atherogenic?

Patients with insulin-resistance and AD have an increase in TGRLP with a longer residence time in plasma, facilitating the interchange of TRG and cholesterol esters between TGRLP and LDL-C due to the action of CETP. This produces a structural modification in the LDL-C particles that generates sdLDL-C.

There are some reasons why these sdLDL-C could be more atherogenic than their higher and less dense counterparts:

Between 40 and 50% of all patients with coronary heart disease (CHD) have significant levels of sdLDL-C.⁶⁷ Some cross sectional and prospective studies of cases and controls have shown the relationship between LDL-C particle size and CHD incidence: on the Quebec Cardiovascular Study, men with LDL-C particle size less than 25.6 nm had a 2.2 times increase on the coronary events incidence in comparison to their counterparts with particles higher than 25.6 nm. The coronary ischemic event predictive value of these small size particles was independent from other plasmatic lipid fractions of these patients.⁶⁸

Also, on the Cardiovascular Health Study,⁶⁹ patients with a MI or angina had higher LDL-C concentration and a higher number and smaller size of these particles in comparison to healthy participants.

The Diabetes and Atherosclerosis Intervention Study (ADIS)⁷⁰ made in type II diabetes mellitus patients treated with lipid lowering drugs, showed that LDL-C final size was inversely correlated with the porcentual increase of the coronary stenosis of these patients.

The ARIC study⁷¹ made in 11,419 subjects followed across approximately 11 years showed that the higher quartile of sdLDL-C as compared with the lower one was associated to an increased risk of coronary events (HR: 1.51; 95% CI: 1.21-1.85); even more, sdLDL-C had a higher predictive power (HR: 1.61; 95% CI: 1.04-2.0) on individuals considered of low risk for coronary events according to their LDL-C levels.

Recently, the prospective study of cohorts Ludwigshafen⁷² showed in 1,643 patients without lipid lowering drugs, who were sent for a coronary angiography and followed for 9.9 years, that LDL-C particles of smaller size (< 16.5 nm) were associated to a higher risk of total mortality (HR: 1.24; 95% CI: 0.95-1.63) and cardiovascular mortality (HR: 1.54; 95% CI: 1.06-2.12) than particles of intermediate size (16.5-16.8 nm). These results were considered as robust even after adjustment for sex, age and other CVRF.

Can triglyceride rich lipoproteins generate atherosclerosis?

As we have already said, TGRLP are a group of particles with varying sizes, densities, and lipoprotein content that have in common a significant proportion of TRG on their composition. This group comprises quilomicrons, VLDL type 1 (higher and less dense), VLD type 2 (of a lower size), quilomicrons remnants, VLDL remnants and IDL.

The TGRLP value is obtained by withdrawing HDL-C and LDL-C values from the total cholesterol (this is also called Non-HDL/Non-LDL cholesterol). From a pathophysiologic point of view these particles could also have an atherogenic potential due to different reasons (Figure 3):⁷³

Figure 3: Atherogenic dyslipidemia and atherogenesis 

TGRLP have been found on human atherosclerotic plaques and on animal preparations suggesting their contribution to plaque formation and to the progress of CVAD.^77-79

Another fact implied on the pro-atherogenic role of TGRLP is mediated by lipoprotein lipase (LpL) expressed on the endothelial luminal surface. This enzyme hydrolyses TGRLP and liberates FFA that penetrate by simple diffusion into the endothelial cells where are partially transformed in the hydrophilic Acil-CoAs required for multiple cellular functions. However, when there is a significant proportion of saturated FFA, they can develop pro-apoptotic effects and a direct inhibition of the endothelial nitric oxide synthase, inducing toxicity and endothelial dysfunction in a direct way.

Saturated FFA are also implied on the activation of the kappa-beta nuclear factor and, consequently, on the production of pro-atherogenic cytokines and chemokines as well as adhesion molecules that increase recruitment of monocytes to the arterial wall.⁸⁰ These effects are not produced by mono or poli-unsaturated FFA, being this the reason for the suggested prevention and/or reduction of these deleterious effects with the ingestion of unsaturated omega-3 FFA.

Apart from the apoB100, TGRLP have as a regular constituent the apoCIII that develops multiple pro-atherogenic actions.⁸¹ ApoCIII modulates the activities of different enzymes implied on lipoprotein metabolism and so it can elevate plasmatic concentration of TGRLP by inhibiting its degradation by endothelial LpL, and for reducing its capture by the lipoprotein remnants hepatic receptor. Also, apoCIII can reduce some protective actions of HDL-C, increase endothelial cells apoptosis and produce some direct anti-inflammatory effects as it has being suggested by some experimental studies.^82-84

Finally, TGRLP could favor pro-thrombosis by stimulation of tissue factor production from endothelial cells and monocytes,⁸⁵ by promoting thrombin generation⁸⁶ and reducing fibrinolytic activity.⁸⁷

Is atherosclerosis development stimulated by low levels of HDL-C? Is there an effect of TGRLP on HDL-C?

There are multiple anti-atherosclerotic actions related to the HDL-C particles that can be summarized as: 1. reverse cholesterol transport,⁸⁸ 2. endothelial protection,⁸⁹ 3. anti-inflammatory,^90-92 4. anti-apoptotic,⁹³ 5. anti-oxidative,⁹⁴ 6. anti-thrombotic actions.^39,94 All these properties have contributed to the elaboration of a functional athero-thrombotic protection hypothesis that could explain a beneficial effect of HDL-C increase. Some data from human research using infusions of synthetic recombinant HDL or recombinant apoA1/phospholipidic complex have shown the restauration of endothelial function in hypercholesterolemia patients and the reduction of atherosclerotic plaques in patients with acute coronary syndromes;^95,96 similar results have also been obtained in other patients with coronary or peripheral atherosclerotic lesions but further confirmation is being required.³⁹

On the contrary, low levels of HDL-C have been associated to the increased production of cardiovascular events.⁹⁷ In the meta-analysis of the Collaboration Group of Emergent Risk Factors⁹⁸ made in 302,430 participants from 68 prospective studies, it was shown that for an increment of 15 mg/dL of HDL-C the Hazard Ratio for coronary events, adjusted for lipid factors and clinical data, was 0.71 (95% CI: 0.68-0.71).

Low levels of HDL-C are inversely associated to lipoproteins with apoB100 and for this reason have been considered as biomarkers of atherogenic lipoproteins. This circumstance has been underlined for the lack of association between levels of HDL-C and risk of coronary events in the AFCAPS/TexCAPS study,⁹⁹ in trials with high intensity statins therapy,¹⁰⁰ in the lack of reduction of cardiovascular events in niacin trials,^101,102 and in trials made with CETP inhibitors.^100,103

It must be mentioned that the use of high intensity statins could increase the expression of micro RNA-33 and hence reduce the expression of ABCA-1 with the consequence of a reduction in the reverse cholesterol transport which could theoretically diminish the beneficial effect of treatments that increase HDL-C.¹⁰⁴ Finally, studies of Mendelian randomization have also failed in demonstrate the relationship of HDL-C with production of cardiovascular events.¹⁰⁵

HDL-C is a group of particles differing in physical and functional properties, so there are some bigger and lighter (buoyant) known as HDL-C2, and other smaller and dense also known as HDL-C3; these differences are related to their function¹⁰⁶ and, although there has been some controversy over its prognostic value, some recent studies have shown a protection effect with the HDL-C3 but not with HDL-C2 or HDL-C total.¹⁰⁷

Finally, it must be considered that HDL-C particles especially HDL-C3 can be made dysfunctional and with less anti-atherogenic capacity under increases in oxidative stress and inflammation.^108,109 Also, high plasmatic levels of TGRLP generate higher interchange of TRG, from these TGRLP, for cholesterol coming from HDL-C due to the action of CETP; this interchange produces smaller and dysfunctional HDL-C 3 rich in TRG that are more rapidly metabolized, liberating apoA1 that is eliminated by the kidney. Consequently, this causes a significant reduction on the pools of apoA1 and HDL-C with normal function.⁴²

How can the development of AD on a population and individual scale be prevented?

The measures targeted to improve eating habits and lifestyle help prevent and minimize complications associated with dyslipidemia. In LA, as described in the epidemiology section, some of the most important causes of AD are malnutrition (in which high intake of sugar and refined carbohydrates with a high caloric density are common), an inadequate relationship between saturated and poli-unsaturated fat intake, and a sedentary lifestyle and obesity.^3,31 The physician is responsible for knowing how to modify these variables and for the reduction of cardiovascular risk in our continent.

Multiple interventions have demonstrated their effectiveness at improving the different parameters of AD. Their isolated, short-term impact in associated cardiovascular morbidity and mortality is controversial; still, what is really important is that a global, complete, and long-lasting change is necessary to obtain a significant improvement of cardiovascular risk (Table III).

Table III: Therapeutic objectives based on basal level of triglycerides. 

*GCVR = global cardiovascular risk.

TRG are the lipid parameter that best and faster respond to improvements in lifestyle (eating habits, working out, weight loss, abdominal fat reduction). The amount of the TRG response to these changes is directly proportional to their basal level.

The key to prevent AD is nourishment with a proper caloric content, adapted to daily energetic consumption, offering a balance of the macro and micronutrients needed to an appropriate corporal function. The consumption of UPF (carbohydrate-enriched foods that can be easily and rapidly absorbed), as well as a higher consumption of saturated fat and processed products, low on fiber and nutrients, are the principal issues to fix because of their connection to AD.

Classical clinical studies, like the Lyon Heart study and the recent PREDIMED¹¹¹ based on a Mediterranean diet have demonstrated a lower cardiovascular risk, with benefits to some cardiometabolic parameters. This diet is characterized for its high consumption of olive oil, unprocessed fruits, nuts, vegetables and integral cereals; includes a moderate consumption of fish and poultry and a low consumption of dairy products, and red and processed meat and sweets. European guidelines 2016 recommend the consumption of a Mediterranean diet and they specify the following:¹¹²

What specific diets must be recommended to patients in order to prevent or treat AD?

Adjustment of caloric intake to the patient’s ideal weight with a lower consumption of simple carbohydrates and saturated FA, completely avoiding trans fats, and having a higher consumption of PUFA, as well as fruits rich in fibers and vegetables, are the desired modifications for the diet in the patient with AD or cardiovascular risk.

A meta-analysis of 15 controlled clinical trials showed that the consumption of omega 3 obtained exclusively from fish reduces weight, body fat composition and waist circumference dramatically.¹¹⁶

PREDIMED (PREvention with MEDiterranean Diet¹¹¹ evaluated the effects of two nutritional interventions on the primary prevention of cardiovascular diseases in individuals with a high cardiovascular risk. The patients were randomized in three groups: Mediterranean diet with an olive oil supplement, Mediterranean diet supplemented with nuts and a control diet in which a low-fat diet was advised. PREDIMED’s Mediterranean diet reduced total mortality by 28% and the risk of cardiovascular mortality by 5%.

The effects of the PREDIMED study on cardiovascular morbidity and mortality demanded adjustments in the classic DASH diet which became HF-DASH diet (modified) allowing a higher consumption of calories derived from fatty foods with cholesterol (e. g.: eggs), increasing from 8 to 14% the amount of calories coming from saturated fats, and reducing the amount of energy from carbohydrates, essentially sugar and juices, by 12% (see appendix).¹²⁰ These changes improved adherence, and significantly reduced the plasmatic levels of TRG.¹²¹

What kind of physical exercise should be recommended to patients in order to prevent and treat AD?

Regular physical activity can reduce cardiovascular risk and mortality. Its clinical benefits are related to the improvement of the values of blood pressure, positive effects on weight control, sensitivity to insulin and glycemic control, lipid profile, and coagulation cascade. There is also an inverse relationship between the level of physical activity and the risk of CHD, having reported reductions of cardiovascular events up to 23%. It is suggested performing aerobic dynamic exercises 5 to 7 times a week for at least 30 minutes (between 2.5 and 5 hours a week), ideally complemented by adding resistance exercises on 2 to 3 days per week, with a total weekly charge of 1 to 1.5 hours. There is evidence that suggests that performing repetitive physical exercises daily for ten minutes could be more beneficial to senior citizens or in patients with a disability than long exhausting sessions.¹²²

Physical activity is usually measured in METS/week. A MET is a unit of measurement of basal metabolism and it is defined as the energy consumed while being seated resting, which is usually 1 Kcal/minute. The expected energetic consumption in an adult is 1,200 to 1,500 kcal/day, depending on the sex, age, physical activity and others.

The most suitable activities for training are those that include exercising many muscles in a continuous and rhythmic form and with a moderate intensity and duration (walking, jogging, swimming, and cycling). The physical activity to develop must be moderate, that is, with a 40 to 59% from the maximal volume of oxygen consumption or from the heart rate reserve (which corresponds to an absolute energy consumption between 4.8 and 7.1 METS in young individuals; 4.0 to 5.9 METS in middle-aged subjects; 3.2 to 4.7 in senior citizens and 2.0 to 2.9 in very old patients.¹¹⁰

Should the lipid profile be done while fasting or not?

This is one of the questions that continue to be controversial. Some recent publications^56,123 state that, comparatively, performing the lipid profile without fasting is more useful and more informative to the prediction of cardiovascular risk than the one made on fasting. Moreover, Friedewald¹²⁴ has assured that the endothelium tends to be more exposed to postprandial lipids.

The European Atherosclerosis Society and the European Federation of Clinical Chemistry and Laboratory Medicine¹²³ recently issued a joint consensus statement in which they affirm that fasting in not routinely required in order to determine the lipid profile. This statement recommends to do the lipid profile without fasting. Abnormal values and measurements must be reported, these being complementary but not exclusive. For this reason, in this document we do not recommend measuring while fasting.

Which of these must be the therapeutic goal in AD: TRG, HDL, apoB100, Non-HDL Cholesterol, or remnants?

Without any doubt the LDL-C must continue to be the primary goal in the treatment of the dislipidemic patient since this is the lipoprotein with the highest amount of evidence that proves its direct association with the risk of CVAD, both in observational epidemiologic studies and in randomized studies with pharmacological therapy which have demonstrated an effective reduction of cardiovascular events when lowering the LDL-C levels^51,125,126 That is why, traditionally, guidelines and agreements from multiple scientific societies consider that using LDL-C therapeutic goals can be useful in treatment and follow-up of patients with dyslipidemia.¹²⁷

However, after the last ACC/AHA 2013 Joint Guidelines did not consider therapeutic goals but only indication of statins depending on their intensity and the individual risk, a controversy in the academic world shows up: does it make sense to consider therapeutic goals or not?¹²⁸ Regarding this issue, our working group unanimously believes that therapeutic goals are necessary to both the physician and the patient since these allow calculating the intensity of the pharmacological treatment and stimulating the patient to know their risk and keep their therapy. Multiple national guidelines in LA share this view and agree on the need to employ LDL-C goals.^129,130

It is true that randomized studies have not had statin dose-adjustments in their design or other drugs to reach a therapeutic goal. However, when analyzing results there is no doubt that the achieved LDL-C levels are associated to a specific CV risk.¹³¹ An argument to support our view can be found in the study IMPROVE-IT, in which obtaining LDL-C low values (70 vs. 50 mg/dL) while using statins + ezetimibe, was accompanied by a higher reduction of cardiovascular events despite receiving both arms similar doses of statin.¹³²

In patients with AD, once the LDL-C goal is reached, we must consider as a second therapeutic target the Non-HDL-C levels; this value comprises all TGRLP plus LDL-C and gives us more information on the atherogenic potential of plasma from patients with AD.^133,134 We consider that in patients with AD, the sole evaluation and treatment of LDL-C underestimates the residual risk given by the LPRTG.

Determining the level of Non-DHL-C is easy and inexpensive and offers and excellent correlation with plasmatic levels of apoB100.¹³⁵ It must be remembered that apoB100 is the most precise sign of lipoproteic atherogenic risk since it can be found in all potentially atherogenic particles, including the underestimated Lp (a).^136,137 However, its analysis is very expensive and it cannot be easily found everywhere. Although the relationship between apoB100 and apoA1 was analyzed and a great risk among its high tertiles was seen in the study INTERHEART,⁹ classical studies with statins have reported neither information about the levels of apoB100 nor their therapeutic objectives. As a result, and considering that there is a close relationship between plasmatic concentration of apoB100 and Non-HDL-C, the most reasonable thing to do is to evaluate the latter.

Fibrates

Fibrates lower TRG levels in a 36%, levels of Non-HDL-C between 6% and 16% and increase HDL-C in a 10%, and the levels of LDL-C drop to 8%. In patients with severe HTG, a slight increase of LDL-C induced by fibrates can be seen.

So far, RCT intended to study the effect of fibrates on cardiovascular morbidity and mortality have shown some disparities:^140-143 some studies suggest a moderate benefit, especially when there are other risk factors besides HTG, which is the case of low HDL-C or metabolic syndrome patients. On the other hand, there are negative results in other RCT.

Meta-analysis of RCT have also suggested benefits with the use of fibrates in HTG. Jun’s meta-analysis made with 18 RCT that used fibrates to demonstrate their effect on cardiovascular risk, which included 45,058 individuals, showed a significant reduction of CVAD (RR 10%; p = 0.048), but with no effect in the total mortality.¹⁴⁴ Another meta-analysis, with 5,068 patients with TRG levels of > 200 mg/dL and HDL-C < 40 mg/dL showed a 29% lowering in the number of cardiovascular events. Possibly, this patient profile is to present date the one that has obtained the greatest benefit in the reduction of cardiovascular morbidity and mortality in the RCT made with fibrates.¹⁴⁵

Fibrates are drugs that have to be used with precaution when being combined with statins since there is risk of suffering from severe myopathy, rhabdomyolysis and damage to the liver; for this reason, although there is no clear contraindication of their combined use, except with gemfibrozil which cannot be combined with statins, patients undergoing this combination of drugs must be monitored in order to detect muscular symptoms and muscular and hepatic enzyme changes.

Omega-3 FA

The preparations of omega 3 FA that have been defined as pharmacological products by the Food and Drugs Administration of the United States of America, and which have been clinically tested, are purified formulations of EPA and/or DHA presented as mixtures of highly purified ethylic esters (> 90%) of EPA and DHA, or as sole presentations of carboxylic acids of them.

Free formulation presentations that are sold as supplements contain variable concentrations of fish oil, they are not purified and may contain other FA. Also, they could have a variable concentration of toxins and must not be use as treatment drugs for HTG. Omega 3 FA on doses of 2-4 g/day have shown a reduction on TRG levels between 25 and 34%, a drop of 20-42% on VLDL-C levels and increases of 1-3% on HDL-C levels and a slight increase of 5-11% on LDL-C levels.¹⁴⁶ Overall, the higher the basal TRG levels, the greater the benefit.

Just like fibrates, RCT with omega 3 FA have shown controversial results.^147,148 One meta-analysis made with these studies¹⁴⁹ included 63,030 patients and showed a significant reduction in cardiovascular mortality (RR: 0.86; 95% CI: 0.75-0.99; p = 0.03), but it was not beneficial to the total mortality or to a combined cardiovascular end point of MI, stroke and cardiovascular death (p = 0.24 and p = 0.28, respectively). It is important to say that in an analysis of subgroups from this last meta-analysis made on patients with TRG basal levels > 150 mg/dL in contrast to those with < 150 mg/dL, a benefit on the compound end point was shown (RR: 0.82; IC 95%: 0.74-0.91; p = 0.006).

Results of the GISSI-Prevenzione (Gruppo Italiano per lo Studio della Sopravvivenza)¹⁵⁰ proved that the use of the combination of highly purified ethilic esters of EPA and DHA administered to post-MI patients achieved TRG reductions of 16-20%, and reduced greatly the risk of re-infarction and death after a 3-year follow-up period.

1.8 g of EPA were used as treatment in JELIS (Japanese Study of Lipid Intervention) showing a reduction of 18% in major coronary events. The effects were more notorious in patients with TRG > 200 mg/dL and HDL-C < 40 mg/dL (with AD) who showed a 53% risk reduction as compared with the effect obtained with statin monotherapy.¹⁵¹

The ORIGIN clinical trial¹⁵² with a 2 x 2 factorial design was made with the intention to study the cardiovascular protective effects of Insulin Glargine or Omega 3 FA vs. placebo on patients with type II diabetes mellitus or disglycemia. Omega 3 FA reduced TRG levels on an average of 23% but did not show effect on cardiovascular events reduction; this fact, that seems paradoxical, could be due that placebo group received olive oil that has mono unsaturated FA with some cardiovascular protection properties.

Heterogeneity on the results of RCT may be related to the inclusion of subjects with normal basal levels of TRG (< 150 mg/dL), which is why new studies with omega 3 FA are required to include patients with high cardiovascular risk and TRG levels between 200 and 500 mg/dL.^153,154 The most common gastrointestinal adverse effects associated to omega 3 FA are nausea and diarrhea, although these effects are very limited with highly purified preparations. The observed rate of treatment stopping on RCT is similar between omega 3 FA and placebo, and there is no alteration on hepatic function.^155,156 Finally, it must be said that there is no interaction whatsoever with statins or other lipid lowering drugs, and for this reason omega 3 FA can be safely used in combination with statins, fibrates or in triple therapy.

8.3. Niacin. Niacin reduces TRG levels in a 20%, LDL-C in a 12%, Non-HDL-C between 7% and 39% and increases the levels of HDL-C in a 16%. But, so far big RCT with niacin added to statins have not shown reductions on cardiovascular risk.^101,157-160 A post-hoc analysis have suggested that in patients with TRG > 200 mg/dL and HDL-C < 32 mg/dL (with AD), niacin seems to reduce CVAD events in a 37% (p 0.05).¹⁶¹

Frequent adverse effects limit the use of niacin: the most common is cutaneous vasodilatation or «flushing» which, according to some reports, can be observed in up to 70% of the patients.^161-163 Other adverse effects to consider are hyperglycemia, gastrointestinal effects and myopathy.

To evaluate the possible reduction on adverse effects and increases on clinical benefits with the use of niacin, the study HPS-THRIVE was performed on patients with atherosclerosis that were receiving statins.¹⁵⁷ This study used, against placebo, a combination of extended release niacin with laropiprant, a selective inhibitor of prostaglandin D which is responsible for the cutaneous adverse effects of niacin. HPS-THRIVE did not show reductions on cardiovascular events on these patients and, contrary to expectations, with the combination of niacin and laropiprant there was an excess of cutaneous, muscular, gastrointestinal and metabolic adverse effects. These results together with the ones obtained on the AIM-HIGH Study¹⁶¹ raise a significant doubt on the use of niacin as a combination therapy on hyperlipidemic patients.

Why should AD be treated?

So far, we have exposed, discussed and detailed, epidemiological and pathophysiological evidences that prove that:

Having said that, this group concludes unanimously that in LA does exist the necessity to perform a big multicentric international study to evaluate the usefulness of treatment on patients with AD with Omega 3 FA and/or fibrates. Also, a consensus was reached to change current treatment paradigms on patients with AD in LA where, after an optimal statins treatment, Non-HDL-C must be used as a surrogate of TGRLP and treated with the aim to reduce cardiovascular residual risk, both at an individual and a general level.¹⁶⁴

How can AD be treated?

The treatment of AD should, at least conceptually, modify underlying metabolic alterations: reduce TRG and sdLDL-C, increase HDL-C and accelerate the clearance of all TGRLP.

To this date, none of the big clinical trials have specifically tested the treatment of AD, therefore the therapeutic approach for patients with this lipid condition is derived from post-hoc analysis of subgroups and from meta-analysis. It is important to say that there are no single drugs that can produce by themselves all the required lipid changes; therefore, combinations of drugs (omega 3 FA and/or fibrates) are suggested, especially on secondary prevention and in patients with cardiovascular high risk and AD that persist with HTG despite optimal treatment with statins.

Maki and collaborators in a recent meta-analysis¹⁶⁵ done on a group of RCT made with fibrates, niacin, or omega 3 FA, alone or combined with statins, demonstrate that even though there is no global reduction of cardiovascular risk in all individuals, on the subgroup with elevated TRG and low HDL-C (constitutive elements of AD), there was an important statistical reduction of cardiovascular risk.

Which levels and from which lipid particle must be chosen to treat patients with atherogenic dyslipidemia?

As was previously mentioned, the metabolic alteration that best defines AD is HTG; therefore, the basal level of TRG must be considered as the starting point for establishing therapeutic objectives and for choosing the most appropriate drug therapy^166,167 after correction of LDL-C. Also, Non-HDL-C, for its higher capacity to predict cardiovascular risk must be considered as a secondary objective.¹⁶⁸

As shown in Table V, TRG levels are used to define the primary therapeutic objective. So, TRG levels > 500 mg/dL demand as a primary goal the risk reduction of pancreatitis, being secondary to this the reduction of cardiovascular risk.¹⁶⁹ On the contrary, TRG levels between 200 and 499 mg/dL demand as a primary objective the LDL-C reduction; and secondarily the Non-HDL-C reduction as a combined approach to reduce cardiovascular risk.

Table V: Therapeutic goals according to risk.¹³² 

Low HDL-C is associated to an increase in cardiovascular risk; however, pharmacologic interventions aimed to increase low HDL-C have not consistently shown a risk reduction of clinical events or mortality. Therapeutic changes in lifestyle and particularly exercise, more than drugs, are the most efficient way to increase HDL-C.¹²⁷

What is the treatment algorithm for the patient with AD? (Figure 4)

Figure 4: Proposed treatment algorithm for high or moderate risk patients with atherogenic dyslipidemia. 

The following algorithm is suggested for the treatment of patients with AD:

What kind of statin should be chosen?

We adopted the recommendations of the Guidelines to control the high cholesterol levels in adults to reduce cardiovascular risk so as to choose the correct statin and dosage to achieve the LDL-C goal (Table VI).¹³¹

Table VI: Statin treatment intensity.¹²⁸ 

Therapy to reach Non-HDL-C goal

Besides its known effect on LDL-C, statins reduce plasmatic levels of TRG in 15-50% and increase HDL-C up to a 15%. These last effects are proportional to the basal level of TRG. As a result, statins are the first therapeutic option to treat patients with dyslipidemia. If Non-HDL-C levels remain high after having reach LDL-C level goals, a combined therapy must be chosen in order to reduce them (Table VII).

Table VII: Therapeutic recommendations based on basal level of TRG. 

Patients with AD that can make the most of the combined therapy are those with TRG > 200 and HDL-C < 40 mg/dL. The major intervention studies with statins (post hoc analysis of > 4,000 patients) support the concept of an added cardiovascular benefit when combining statins with omega 3 FA or fibrates in these patients.^{145,149,175,176} The new generation of fibrates such as fenofibrate and ciprofibrate have been proved to be safer in combination therapy with statins.