Inhibición de PCSK9: una nueva alternativa para reducir el colesterol y prevenir la enfermedad cardiovascular aterosclerosa / Inhibition of PCSK9: a new alternative for cholesterol reduction and prevention of atherosclerotic cardiovascular disease

Resumen La enfermedad cardiovascular aterosclerosa ocupa el primer lugar mundial en morbilidad y mortalidad. El principal factor de riesgo de enfermedad es el colesterol unido a lipoproteínas de baja densidad (C-LDL). El tratamiento farmacológico de elección para reducir el C-LDL son las estatinas; sin embargo, han sido insuficientes para eliminar el riesgo cardiovascular, especialmente en pacientes con formas primarias de hipercolesterolemia relacionadas con mutaciones genéticas, o intolerantes a estatinas. Es de gran importancia el desarrollo de nuevos fármacos para abatir el riesgo que persiste a pesar de la administración de estatinas. La proconvertasa subtilisina-kexina 9 (PCSK9) es un regulador primordial de la cantidad de receptores de LDL, ya que su función es dirigir dichos receptores a su destrucción lisosomal. El advenimiento de anticuerpos monoclonales para bloquear la PCSK9 ha permitido mejorar la cantidad y eficiencia de los receptores de LDL, de esto resulta la disminución notable del colesterol circulante. Hasta el momento, la eficacia e inocuidad de estos anticuerpos resultan aceptables, y los datos preliminares en cuanto a su efecto en la reducción de la morbilidad y mortalidad cardiovasculares son alentadores.

Abstract Atherosclerotic cardiovascular disease represents the leading cause of morbidity and mortality in most countries. The main risk factor for developing this disease is low density lipoprotein cholesterol (LDL-C). The pharmacological treatment of choice for reducing LDL-C is statins; however, in spite of the widespread use of statins, these drugs have been insufficient to eliminate cardiovascular risk. This residual risk is most relevant in patients with primary forms of hypercholes-terolemia associated with genetic mutations, or in those who are intolerant to statins. The development of new drugs to reduce residual cardiovascular risk is of vital importance. Proprotein convertase subtilisin-kexin 9 (PCSK9) is an important regulator of the amount of LDL receptors since its function is to direct these receptors to their lysosomal destruction. The development of monoclonal antibodies to block extracellular PCSK9 has allowed us to improve the quantity and efficiency of LDL receptors, resulting in a significant decrease in plasma cholesterol. Efficacy and safety of these antibodies is currently considered acceptable and preliminary data are encouraging but still insufficient to assess the favorable impact of these antibodies in reducing cardiovascular morbidity and mortality.

[Postprandial lipemia in subjects with primary hypoalphalipoproteinemia and hypoalphalipoproteinemia associated with diabetes]. / Lipemia postprandial en sujetos con hipoalfalipoproteinemia primaria e hipoalfalipoproteinemia asociada a diabetes.

The postprandial (PP) elevations in triglyceride rich lipoproteins (TRL) are potentially atherogenic. We compared PP lipemia in non insulin dependent diabetes mellitus (NIDDM) with hypoalphalipoproteinemia (HA) and patients with primary HA. Eight males in each group, mean age +/- SD 54 +/- 10 years, were studied for 12 hours after the ingestion of a fat load (65 g of fat/square meter of body surface). Plasma glucose, triglycerides (TG) and cholesterol (C) in plasma and in the different lipoprotein fractions were measured. The PP triglyceridemia was significantly greater in NIDDM patients with HA and correlated with the fasting TG concentrations. The curve pattern of the lipemia (% delta) was otherwise similar in the patients with secondary or primary HA; only the triglyceridemia persisted for a longer period of time in the latter but was otherwise similar to that of the NIDDM patients with lower basal triglyceride values. Patients with primary HA may have a disturbed metabolism of triglyceride rich lipoproteins which have a delayed depuration during the postprandium. Basal HDL-C in patients with HA cannot predict the PP triglyceridemia.

[Postprandial lipemia in the non-insulin-dependent diabetes mellitus patient. Effect of gemfibrozil]. / Lipemia postprandial en el paciente con diabetes no insulino-dependiente. Efecto del gemfibrozil.

The postprandial (PP) elevations in triglyceride rich lipoproteins are potentially atherogenic. To describe the characteristics of PP lipemia after a fat load in non insulin dependent diabetes mellitus (NIDDM) and evaluate the response to a fibric acid derivative, seven males with NIDDM were studied for 12 hours after the ingestion of a fat load (65 g of fat/square meter of body surface). Plasma glucose, and triglycerides and cholesterol levels were measured in total plasma and in the different lipoprotein fractions. The fat load study was repeated after four weeks of treatment with gemfibrozil (GEM) 600 mg x 2. PP triglyceridemia correlated significantly with the fasting triglyceride concentrations. Basal triglyceride levels diminished significantly with the use of gemfibrozil and so did the magnitude of the PP triglyceridemia. Otherwise the curve patterns of lipemia were similar before and after the use of the fibrate; only the triglyceridemia persisted for a longer period of time. Patients with NIDDM may have a significant PP lipemia which is not likely related to the diabetes per se as to the increased triglyceride levels frequently observed in these patients.

[Pravastatin vs. probucol in the treatment of hypercholesterolemia. A double-blind study]. / Pravastatina vs. probucol en el tratamiento de la hipercolesterolemia. Estudio doble ciego.

This 16-week, double-blind study compared the efficacy and safety of pravastatin, a new HMG-CoA reductase inhibitor, with probucol in the treatment of hyperlipidemia in 26 patients at the Instituto Nacional de Cardiología "Ignacio Chávez" in Mexico City. Patients had to have a low-density lipoprotein-cholesterol (LDL-C) level in the 75th (or greater) percentile for age and sex greater than 150 mg/ on 2 occasions, and a triglyceride level less than 350 mg/dl. The patients, aged 21 to 75 years, were randomly assigned to receive either pravastatin, 40 mg once daily at bedtime (n = 15), or probucol, 500 mg twice daily (n = 11). Complete lipid profiles were obtained at 4-week intervals. By the end of the study, mean changes in total cholesterol (CT) and LDL-C in the pravastatin group were -28% and -37%, respectively, p less than 0.001 vs baseline. In the pravastatin group, there was a mean increment in HDL-cholesterol (HDL-C) of 9% and consequently a significant reduction in the LDL-C/HDL-C ratio. However, in the probucol group HDL-C levels dropped -21%, p less than 0.01, and no significant change in the LDL-C/HDL-C ratio was observed, accounting for the significant difference in LDL-C/HDL-C ratios between the 2 groups. Both drugs were well tolerated. One pravastatin patient discontinued because of adverse effects (nausea/vomiting and mild muscle pain). These results suggest that once daily administration of pravastatin is an effective therapy for hypercholesterolemia and that it produces a more favorable response in LDL-C/HDL-C ratio than probucol.

[The efficacy of cholestyramine as a hypocholesterolemic agent and its tolerance in a Mexican population]. / Eficacia como agente hipocolesterolemiante y tolerancia de la colestiramina en población mexicana.

The tolerance and efficacy of cholestyramine (12-16 gr/day) was evaluated in 19 patients with primary type-IIa hyperlipoproteinemia. All patients were on an isocaloric low-cholesterol diet that began at least one month before entry, and was continued during the eight weeks of the study. Cholestyramine significantly (p less than 0.001) lowered the plasma levels of cholesterol and of low density lipoprotein cholesterol from means of 288 +/- 46 mg/dl to 244 +/- 44 mg/dl and from 221 +/- 50 mg/dl to 171 +/- 46 mg/dl respectively. These were reductions of 15 and 22%. The magnitude of response to cholestyramine was unrelated to age, sex, cause of the hypercholesterolemia (familial or polygenic) or basal cholesterol levels. The drug was well tolerated. Only one patient was excluded because gastrointestinal discomfort. Because of its safety and efficacy, cholestyramine can be recommended as a first choice drug in the treatment of hypercholesterolemia.

[The effect of psyllium plantago in slightly to moderately hypercholesterolemic patients]. / Efecto del psyllium plantago en pacientes con hipercolesterolemia leve a moderada.

The hypocholesterolemic effect of psyllium plantago (PP) was evaluated in 14 individuals with polygenic hypercholesterolemia. Subjects with secondary dyslipidemias were excluded. Since their admission until the end of the study all the patients had to follow an isocaloric diet, with less than 10% of the calories provided as saturated fats, P/S relation greater than 1 and daily intake of less than 300 mgr of cholesterol. The study was divided in two stages; the first one, from week -6 to 0 evaluated exclusively the response to diet, and the stage II, from week 0 to +12, evaluated the response to PP. The PP in envelopes with 3.4 grs each, was taken dissolved in water three times daily before meals. In the weeks -6, 0, +4, +8 and +12 were done lipid profiles that included; total cholesterol, triglycerides, and high density cholesterol. Cholesterol of the low density lipoproteins was obtained with the formula of Friedewald modified by De Long. The use of PP produced at week 12 a reduction of 8% in total cholesterol and 11% in LDL cholesterol. With non significant changes in triglycerides and HDL-C. We conclude that PP can be used as a complement of diet in the management of polygenic hypercholesterolemia.

[The heart and diabetes mellitus]. / El corazón y la diabetes mellitus.

The atherosclerotic process in the diabetic patient, is more common, it is noticed at early ages, advances more rapidly and almost equally affects males and females. This data, can not be explained on the basis of the association with other coronary heart disease risk factors, there is an intrinsic atherogenic factor attributed to diabetes, and can be related, to the early hyperinsulinemia, coagulation and lipid disorders, hyperglycemia or diabetic microangiopathy. Coronary heart disease has an increased prevalence in diabetic patients, that is not related with diabetes duration or the type of treatment. Early and late morbimortality after acute myocardial infarction and/or revascularization surgery is twice as common in the diabetic patient. Diabetic cardiomyopathy related to small vessels disease is still a matter of controversy and many authors doubt about its relevance in clinical practice. The presence of autonomic neuropathy with the cardiovascular denervation syndrome carries a poor prognosis. Early cardiovascular changes in asymptomatic patients, are detected with non-invasive test, and can help to introduce measures to protect individuals at a greater risk.

[Non-insulin-dependent diabetes mellitus and hyperlipoproteinemia in patients with ischemic cardiopathy]. / Diabetes mellitus no-insulino-dependiente e hiperlipoproteinemia en pacientes con cardiopatía isquémica.

Cardiovascular disease (CVD) constitutes the main cause of death in diabetes mellitus (DM): Previous studies at the "Instituto Nacional de Cardiología de México" have investigated the metabolic alterations of survivors of a myocardial infarction (MI), but none of them had focused on the metabolic profile of the diabetic patient. We compared two groups of patients with ischemic heart disease (IHD), one with (DMG) and one without (NDMG) Diabetes Mellitus, to investigate differences in the prevalence and nature of hyperlipoproteinemias (HLP) and other risk factors of atherosclerosis. DMG consisted of 117 patients (75 male, 42 female) and NDMG consisted of 119 patients (91 male y 28 female). (Female NDMG vs female DMG p less than 0.05). The presence of risks factors of atherosclerosis was investigated in all patients, and total cholesterol (chol) triglycerides (TG) and glucose were measured in post-absorptive phase. There were no differences regarding mean age (DMG: 60 +/- 8 years, NDM: 60 +/- 11 years), Quetelet Index (Kg./mt2: DMG: 26.5 +/- 3, NDMG: 26.7 +/- 3), TG: (DMG: 246.2 +/- 125, NDMG: 223.5 +/- 129) or Chol (DMG: 216 +/- 42 mg/dl, NDMG: 225 +/- 45 mg/dl). Hypertriglyceridemia was significantly higher in patients with DM, as a whole and when both sexes were studied separately (p less than 0.05). Hypercholesterolemia was significantly higher in NDMG (p less than 0.05) and without significance, in diabetic women. (p less than 0.05). Type IV phenotype was higher in DMG (p less than 0.05) whereas phenotypes IIa and IIa + IIb were more prevalent among non-diabetics (p less than 0.001, p less than 0.0001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

[Effects of aerobic physical conditioning on the profile of plasma lipoproteins in a group of healthy volunteers]. / Efectos del acondicionamiento físico aeróbico sobre el perfil de lipoproteinas plasmáticas en un grupo de voluntarios sanos.

To evaluate the effects of aerobic physical conditioning on plasma lipoproteins, we studied 26 previously untrained, apparently healthy, non obese volunteers. All participants underwent a treadmill test performed according to the protocol of Bruce with the direct measurement of maximal oxygen consumption (VO2max). A program of aerobic exercise was prescribed for each volunteer at 70% of their corresponding VO2max. At baseline and at the end of weeks 4, 8 and 12 of the exercise program, cholesterol and triglycerides were measured by enzymatic analysis in total plasma and in the lipoprotein fractions separated by preparative ultracentrifugation and precipitation methods. At the end of week 12, the VO2max measurement was repeated. At the end of the protocol, mean VO2max increased from the value of 39.9 observed at baseline to 94.4 ml/kg/min (p less than 0.01). There were no variations in mean body weight, diet or smoking status of the participants during the exercise program. Cholesterol associated with High-density lipoproteins (C-HDL) increased from 42.5 to 46.1 mg/dl (p less than 0.05). This effect was first noticeable at week 8. We didn't observe significant changes in Total Cholesterol nor the Cholesterol fraction associated with Low-density lipoproteins (C-LDL). Total triglycerides decreased at weeks 4 and 8 but returned to near baseline values at week 12. The C-LDL/C-HDL ratio considered as an index of a high coronary risk decreased from 2.32 at baseline to 2.02 (p less than 0.05) at week 12. Thirteen of the twenty six initial volunteers completed the physical conditioning program as planned, the rest were eliminated at different stages of the protocol due to incomplete adherence to their exercise schedules.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hypoalphalipoproteinemia and atherosclerosis. Genetic and biochemical profile of 10 families]. / Hipoalfalipoproteinemia y ateroesclerosis. Perfil genético y bioquimico de diez familias.

The results of lipoprotein studies performed in 67 members of 10 kindreds with familial hypoalphalipoproteinemia are presented. Probands were ten patients referred to the Lipid Clinic of the National Institute of Cardiology for evaluation of their lipid profile, all of whom had history of a definite myocardial infarction occurring before they had reached age 60. Their only plasma lipid abnormality was a reduction of the cholesterol fraction associated with high-density lipoproteins (C-HDL) below the corresponding age-sex specific fifth percentile. We studied 57 other individuals including probands spouses and available first-degree relatives. All participants were clinically examined and their complete coronary risk factor profile was assessed. After a 12 hour fast, plasma samples were obtained for lipid analysis, total cholesterol and trïglycerides were measured by enzymatic methods, C-HDL was determined in the supernatant after plasma precipitation with magnesium chloride: phosphotungstic acid. Low-density lipoprotein cholesterol (C-LDL) was estimated with the formula proposed by DeLong. For every family a pedigree was constructed and statistically analyzed to assess the within-family clustering of low C-HDL levels and the pattern of transmission of the abnormal phenotypes. Mean C-HDL level for propositii was 24.3 mg/dl, the corresponding value for the C-LDL/C-HDL ratio (atherogenic index) was 4.9 and it was elevated above 3.5 (average coronary risk) in 7/10 (70%) of these patients. Obesity, defined by a Quetelet index above 28 in men and 26 in women was present in 4/10 (40%) of the probands, 3/10 (30%) had stable non insulin-dependent diabetes mellitus, prevalence figures for the other coronary risk factors was very low. In addition to probands, the hypoalphalipoproteinemic phenotype was found in 30/57 (52.6%) subjects including spouses (two cases) and first-degree relatives. For these 30 cases the mean C-HDL value was 32 mg/dl. In all ten reported kindred, we clearly observed either horizontal, vertical or both types of within-family transmission of the aberrant phenotype. This finding was considered to be most compatible with the presence of a primary genetic abnormality affecting C-HDL metabolism in all these kindreds in spite of the fact that some of the probands had some conditions like diabetes or obesity that are sometimes associated with secondary reductions of C-HDL. Due to the lack of a reliable biochemical marker, the distinction between primary and secondary hypoalphalipoproteinemia in individual cases is frequently impossible, for this reason the diagnostic assessment depends on family studies.(ABSTRACT TRUNCATED AT 400 WORDS)

[Metabolic disorders in survivors of myocardial infarct]. / Alteraciones metabólicas en sobrevivientes de infarto miocárdico.

Several lines of evidence have clearly established the role of lipoproteins as risk factors for the development of atherosclerosis. Epidemiologic studies from different countries have found that about one third of myocardial infarction survivors under 60 years of age are hyperlipidemic. The acute stress reaction occurring in the first hours following an acute myocardial infarction causes distinct changes in the patient's metabolic profile, these changes include a significant reduction of total cholesterol and cholesterol associated with low density lipoproteins and a usually mild elevation of blood glucose. With the purpose of establishing the prevalence and severity of lipoprotein disorders found in myocardial infarction survivors living in Mexico city we conducted a prospective study of 106 consecutive admissions to the coronary care unit at the National Institute of Cardiology with the fully proven diagnosis of acute myocardial infarction, we included only patients younger than 60 years of age that could be sampled within the first 72 hours of the appearance of typical symptoms, at this time the coronary risk factor profile was assessed and blood samples were drawn (acute sample). After three months of the diagnosis we sampled 81 of the original 106 patients (chronic sample). The comparison of these 81 patients showed remarkable differences in the lipid values obtained on each sample. The mean value for total cholesterol in the acute sample was 225 mg/dl whereas the corresponding value for the chronic sample was 240.5 mg/dl (p less than 0.005). This difference was also highly significant for the low density fraction. On the basis of the chronic sample analysis we estimated a prevalence of hyperlipoproteinemia of 35.8%. (II: 18.5%, III: 2.5%, IV: 14.8%), an additional subgroup of 10 patients (12.3%) had the hypo-HDL phenotype raising the number of subjects at risk for atherosclerosis to as high as 48.1% considering only the lipoproteins. The prevalence figures for the rest of the risk factors were as follows: 70.3% for tobacco smoking, 35.8% for Systemic Arterial Hypertension, 33.4% for Obesity and 30.8% for Diabetes Mellitus. Among the group of 81 patients, 17 were known diabetics, eight additional cases of Diabetes Mellitus were diagnosed at the chronic phase (two with fasting hyperglycemia and six with diagnostic oral glucose tolerance tests). The "acute plase" glycemia for these eight subjects was significantly higher (mean: 98.4 mg/dl) than the corresponding value for the non diabetic patients (mean: 83.4 mg/dl p less than 0.002), the seventeen known diabetics had a mean glycemia of 150.6 mg/dl in the acute sample.(ABSTRACT TRUNCATED AT 400 WORDS)

Hiperlipidemia familiar combinada.Estudio de una familia. / Combined familial hyperlipidemia. Study of a family

Se estudiaron 15 miembros de una familia con hiperlipidemia familiar combinada, en los que observamos las caracteristicas clinicas principales de este trastorno. El analisis del pedigree y los valores de colesterol y trigilceridos permiten postular un mecanismo de transmision autosomico dominante. El 50 de los individuos de la generacion de los probandos demonstraron valores de lipidos diagnosticos de hiperlipidemia. En base a los valores absolutos de colesterol y trigiceridos, asi como a la electroforesis de lipoproteinas en suero se diagnosticaron los patrones de Fredrickson IIa, IIb, y IV, con una frecuencia similar, de aproximadamente 33% para cada uno de los fenotipos entre los individuos afectados.Los valores medios de colesterol y trigliceridos ajustados para edad y sexo entre los miembros hiperlipidemicos fueron de 308.9 mg/dl (> P95) y 252.1 mg/dl (> P90) respectivamente, mientras que en los casos no afectados correspondieron a 212.1 mg/dl (< P50) para colesterol y 124.9 mg/dl (< P50) para trigliceridos. Se observo claramente en esta familia la existencia de cardiopatia ateroesclerosa prematura, incluyendo 3 casos de muerte a edad temprana por infarto miocardico