Very low HDL levels: clinical assessment and management

ABSTRACT In individuals with very low high-density lipoprotein (HDL-C) cholesterol, such as Tangier disease, LCAT deficiency, and familial hypoalphalipoproteinemia, there is an increased risk of premature atherosclerosis. However, analyzes based on comparisons of populations with small variations in HDL-C mediated by polygenic alterations do not confirm these findings, suggesting that there is an indirect association or heterogeneity in the pathophysiological mechanisms related to the reduction of HDL-C. Trials that evaluated some of the HDL functions demonstrate a more robust degree of association between the HDL system and atherosclerotic risk, but as they were not designed to modify lipoprotein functionality, there is insufficient data to establish a causal relationship. We currently have randomized clinical trials of therapies that increase HDL-C concentration by various mechanisms, and this HDL-C elevation has not independently demonstrated a reduction in the risk of cardiovascular events. Therefore, this evidence shows that (a) measuring HDL-C as a way of estimating HDL-related atheroprotective system function is insufficient and (b) we still do not know how to increase cardiovascular protection with therapies aimed at modifying HDL metabolism. This leads us to a greater effort to understand the mechanisms of molecular action and cellular interaction of HDL, completely abandoning the traditional view focused on the plasma concentration of HDL-C. In this review, we will detail this new understanding and the new horizon for using the HDL system to mitigate residual atherosclerotic risk.

Dislipidemias: Controversias del riesgo residual

Las estatinas son el principal tratamiento para la reducción del colesterol LDL habiendo demostrado un claro beneficio en la reducción de enfermedad cardiovascular (ECV). Sin embargo, a pesar de los pacientes alcanzar la meta de colesterol LDL, queda un remanente de riesgo relativo de ECV entre un 60% a 70%, el cual ha sido denominado Riesgo Residual. Por ello, el enfoque actual se inclina sobre objetivos adicionales al colesterol LDL, siendo el colesterol HDL bajo y/o triglicéridos elevados los objetivos terapéuticos para reducir el riesgo residual. Se han empleado diversas combinaciones de hipolipemiantes asociados a las estatinas para optimizar el perfil lipídico. La mayorías de estas drogas clásicas (fibratos, niacina y ácidos grasos omega-3), así como un nuevo grupo de moléculas inhibidoras de la Proteína Transportadora de Esteres de Colesterol, son capaces de mejorar las concentraciones de colesterol HDL y triglicéridos en asociación con estatinas, sin embargo, dichas combinaciones en la mayoría de los casos, no han demostrado beneficios en reducir la presencia de ECV, incluso, en el caso de la niacina, se observan efectos deletéreos en las combinaciones a pesar de la optimización del perfil lipídico. Estos hechos nos hacen replantear el conocimiento que tenemos sobre la dislipidemia y su tratamiento, por lo que se presenta la siguiente revisión.

Statins are the principal treatment for highest levels of LDL cholesterol, with clear benefits in reduction of cardiovascular disease (CVD). However, although patients reach LDL cholesterol goal, 60% to 70% have a relative risk remnant of CVD, named Residual Risk. By this, the discussion is focused in other objectives beside LDL cholesterol, being the low HDL cholesterol and/or elevated triglycerides a relevant therapeutic target to reduce the residual risk. Many combinations of drugs have been associated to statins to optimize lipid profile. Most of these classics drugs (fibratos, niacin, and fatty acids omega-3) and the new drugs of Cholesteryl Ester Transfer Proteins inhibitors, increase HDL cholesterol and reduce triglycerides combined with statins, however, in mostly of cases these combinations have not reduced CVD; in studies with niacin, the combination increase deleterious effects despite the optimization of lipid profile. These facts make us reconsider the knowledge we have on dyslipidemia and its treatment, so we present the following review.

Prevalence of dyslipidemias in the Mexican National Health and Nutrition Survey 2006 / Prevalencia de las dislipidemias en la Encuesta Nacional de Salud y Nutrición 2006

OBJECTIVE: To describe the prevalence of lipid abnormalities found in the Mexican National Health and Nutrition Survey 2006 (ENSANut 2006). MATERIAL AND METHODS: Information was obtained from 4 040 subjects aged 20 to 69 years, studied after a 9- to 12-hour fast. RESULTS: Median lipid concentrations were: cholesterol 198.5 mg/dl, triglycerides 139.6 mg/dl, HDL-cholesterol 39.0 mg/dl, non-HDL-cholesterol 159.5 mg/dl and LDL-cholesterol 131.5 mg/dl. The most frequent abnormality was HDL-cholesterol below 40 mg/dl with a prevalence of 60.5 percent (95 percentCI 58.2-62.8 percent). Hypercholesterolemia (> 200 mg/dl) had a frequency of abnormality of 43.6 percent (95 percentCI 41.4-46.0 percent). Only 8.6 percent of the hypercholesterolemic subjects knew their diagnosis. Hypertriglyceridemia (> 150 mg/dl) was observed in 31.5 percent (IC 95 percent 29.3-33.9 percent) of the population. CONLUSIONS: The ENSANUT 2006 data confirm that the prevalence of hypoalphalipoproteinemia and other forms of dyslipidemia in Mexican adults is very high.

OBJETIVO: Presentar la prevalencia de las dislipidemias observada en la Encuesta Nacional de Salud y Nutrición 2006 (ENSANUT 2006). MATERIAL Y MÉTODOS: Se incluyeron 4040 individuos con edad entre 20 y 69 años estudiados bajo un ayuno de 9 a 12 horas. RESULTADOS: Las concentraciones medias de los lípidos sanguíneos fueron colesterol 198.5 mg/dl, triglicéridos 139.6 mg/dl, colesterol HDL 39.0 mg/dl, colesterol noHDL 159.5 mg/dl y colesterol LDL 131.5 mg/dl. La anormalidad más común fue la hipoalfalipoproteinemia (colesterol HDL< 40 mg/dl); su prevalencia fue 60.5 por ciento (IC95 por ciento 58.2-62.8 por ciento). La hipercolesterolemia (colesterol > 200 mg/dl) fue la segunda anormalidad en frecuencia, con 43.6 por ciento (IC95 por ciento 41.4-46.0 por ciento). Sólo el 8.6 por ciento de los casos conocía su diagnóstico. La hipertrigliceridemia (> 150 mg/dl) fue observada en 31.5 por ciento (IC95 por ciento 29.3-33.9 por ciento) de la población en estudio. CONCLUSIONES: Los datos de la ENSANUT 2006 confirman que la prevalencia de hipoalfalipoproteinemia y otras formas de dislipidemia es muy alta en los adultos mexicanos.

Prevention of cardiovascular disease based on lipid lowering treatment: a challenge for the Mexican health system / Prevención de la enfermedad cardiovascular basada en tratamiento hipolipemiante: un reto para el sistema de salud de México

OBJECTIVE: To estimate the percentage of Mexican adults that may require lipid-lowering treatment according to National Cholesterol Education Program-III guidelines, using data from the National Health and Nutrition Survey 2006 (ENSANut 2006). MATERIAL AND METHODS: Information was obtained from 4 040 subjects aged 20 to 69 years, studied after a 9 to 12 hours fast. RESULTS: A cardiovascular risk equivalent was found in 13.8 percent and >2 risk factors were present in 31.5 percent of the population. LDL-C concentrations were above the treatment goal in 70 percent of the high-risk group and in 38.6 percent of subjects with >2 risk factors. Nearly 12 million Mexicans should be taught how to change their lifestyles and close to 8 million individuals require drug therapy to decrease their cardiovascular risk. CONCLUSIONS: Thirty percent of Mexican adults require some form of lipid-lowering treatment (lifestyle modifications in 36.25 percent, drug therapy in 24.19 percent).

OBJETIVO: Calcular el porcentaje de adultos que requiere tratamiento hipolipemiante de acuerdo con las recomendaciones del Programa Nacional de Educación en Colesterol-III, usando los datos de la Encuesta Nacional de Salud y Nutrición 2006. MATERIAL Y MÉTODOS: Se incluyeron 4040 individuos con edad entre 20 y 69 años estudiados bajo un ayuno de 9 a 12 horas. RESULTADOS: Un equivalente de enfermedad cardiovascular fue identificado en 13.8 por ciento de los participantes. El 31.5 por ciento de la población tenía >2 factores de riesgo cardiovascular. La concentración de colesterol LDL estuvo arriba de la meta terapéutica en 70 por ciento de los casos con alto riesgo cardiovascular y en el 38.6 por ciento de los sujetos con >2 factores de riesgo. Cerca de 12 millones de mexicanos deben modificar su estilo de vida para reducir su concentración de colesterol LDL. Casi 8 millones califican para recibir tratamiento farmacológico. CONCLUSIONES: Una tercera parte de los adultos requiere alguna forma de tratamiento hipolipemiante (cambios en el estilo de vida: 36.25 por ciento, medicamentos: 24.19 por ciento).

Lipoproteínas de alta densidad (HDL). ¿Un objetivo terapéutico en la prevención de la aterosclerosis? / High densiy lipooproteins (hdl). a therapeutic objective i the atheroscleerosis prevention?

Las lipoproteínas de alta densidad (HDL) son una familia de partículas que difieren en tamaño, densidad y composición química. La heterogeneidad de las HDL resulta de la velocidad de síntesis y de catabolismo de las partículas, y de la acción de enzimas y proteínas de transporte que las remodelan continuamente. Los bajos niveles de colesterol HDL correlacionan con un riesgo elevado de desarrollar enfermedad aterosclerosa coronaria. La disminución de las HDL afecta el transporte reverso de colesterol, que es la vía metabólica responsable de la remoción del colesterol excedente de la células periféricas y su transporte hacia el hígado para reciclarlo o eliminarlo. Las HDL poseen además propiedades antiinflamatorias, antioxidativas, antiagregatorias, anticoagulantes y profibrinolíticas in vitro . Algunas de estas propiedades potencialmente antiaterosclerosas, también se han puesto de manifiesto in vivo con infusiones de HDL. Estas evidencias, además de la protección que se logra en modelos animales genéticamente modificados, permite plantear a las HDL como un objetivo primario en la prevención de la aterosclerosis coronaria. Algunos estudios epidemiológicos han demostrado una reducción importante en el riesgo cardiovascular asociado a elevaciones del colesterol HDL, principalmente en prevención secundaria. En consecuencia, elevar las concentraciones de las HDL a través de medidas higiénicas como el ejercicio aeróbico, la pérdida de peso y eliminar el tabaquismo, es ampliamente recomendado para reducir el riesgo coronario. Cuando las medidas higiénicas fallan, la intervención farmacológica con niacina o fibratos debe ser considerada en ciertos pacientes con niveles bajos de HDL. Por último, las diferentes subclases de HDL no poseen las mismas propiedades antiaterogénicas, lo que sugiere que las intervenciones tanto higiénicas como farmacológicas se deberán enfocar en el futuro hacia incrementos de la funcionalidad de las HDL, más que a incremento en la concentración del colesterol HDL.

High density lipoproteins (HDL) are a family of heterogeneous particles that vary in size, density and chemical composition, as a result of their synthesis and catabolism rates, and a continuous intravascular remodeling by the action of enzymes and transport proteins. Low plasma levels of HDL correlate with a high risk of atherosclerotic heart disease. Such a diminished concentration of HDL affect reverse cholesterol transport, which is the metabolic pathway responsible for the movement of cholesterol excess from peripheral tissues to the liver for recycling or excretion. In addition, HDL possess anti-inflammatory, anti-oxidative, anti-aggregatory, anti-coagulant, and pro-fibrinolytic properties, as has been demonstrated by in vitro studies. Some of those potentially anti-atherosclerotic in vitro-properties has been corroborated by HDL infusion in vivo. Such evidences and the protection of susceptible animals from atherosclerosis by transgenic manipulation of HDL metabolism, raise the possibility to focus the HDL plasma levels as a main target in coronary hearth disease prevention. Intervention trials have shown an important reduction in coronary events by rising HDL-cholesterol, mainly in the secondary prevention. Increasing HDL plasma levels by hygienic intervention such as aerobic exercise, weight loss and stop smoking is strongly recommended to reduce coronary risk in primary prevention. Pharmacological intervention to rise the HDL plasma levels with niacin or fibrates, should be considered in some patients as an alternative when hygienic intervention fails. Finally, it most be taken into account that the different HDL subclasses does not possess the same anti-atherosclerotic properties, suggesting that hygienic and pharmacological interventions should focus to increase HDL functionality rather than HDL-cholesterol plasma levels. (Arch Cardiol Mex 2004; 74:53-67).

Hypoatphalipoproteinemia: Prevalence and the impact of treatment on reaching HDL cholesterol target level in patients with dyslipidemia.

A low serum high density lipoprotein cholesterol (HDL-C) level is a potent predictor of coronary heart disease (CHD). It has been estimated that 11% of the Framingham men have isolated low HDL-C levels and about 30% of dyslipidemia patients have HDL-C level of less than 35 mg/dl (hypoalphalipoproteinemia). In addition, there is uncertainty regarding the management of these patients. There is no epidemiological data on the prevalence low HDL-C level in dyslipidemia patients and the results of treatment on HDL-C on a large number of patients in Indonesia. We conducted a survey in 13 cities in Indonesia to evaluate the prevalence of hypoalphalipoproteinemia among dyslipidemic patients and the impact of treatment with lipid modification drugs on achieving target level of HDL-C 35 mg/dl or more in routine clinical practice. A total number of 1420 dyslipidemia patients (mean age 50 years, male 58%) were included and analyzed in this report. The overall prevalence of hypoalphalipoproteinemia in our study was 35.4% and it was correlated with the risk level of the patients; 21.9% among low risk group (patient with < 2 other risk factor), 39.6% in high risk group (≥ 2 other risk factors) and 44.3% in patients with CHD. After 12 week treatment, the prevalence decreased to 12%, 20% and 18% in low risk, high risk and CHD patients respectively. The magnitude of HDL-C changes correlated inversely with base-line HDL-C and it was highest (59%) in the lowest HDL-C group (< 25 mg/dl) and the least change (23%) was found in group with the highest HDL-C level (≥ 45 mg/dl). Only 46% of patients with low HDL-C value at baseline achieved normal HDL-C level after treatment. In conclusion, the prevalence of low HDL-C in dyslipidemia patients was high especially in high risk group and in CHD patients. The majority of patients with low HDL-C at base-line could not reach the target level for HDL-C of 35 mg/dl or more after 12 weeks treatment with lipid modification drugs.