Low-density Lipoprotein Cholesterol

Hyperglycemia

myocardial enlargement台州市中心医院中西医结合科张茂华

congestive heart failure

prevalence ["prevələnt] 1.流行，盛行，普遍

Low-density Lipoprotein Cholesterol

Recent evidence suggests that there is a limit to the benefit gained by attempting to reduce hyperglycemia [,haipəglai"si:mi:ə] 高血糖. No reduction in clinical events from arterial disease was observed in two large trials when mean hemoglobin A1C (HbA1c) was maintained well below 6.5% compared to a target around 7.5%.^[6,7] The news is different with blood pressure reduction which has reproducibly shown benefit in stroke rates, and in progression of both retinal and renal disease.^[8,9] The myocardial enlargement and dysfunction seen in diabetics with higher blood pressure is greatly reduced by aggressive lowering of blood pressure.^[10,11] Statins have provided a powerful tool for reducing LDL-C and several large trials have demonstrated 25% to 35% reduction in coronary artery disease, stroke, and amputations in diabetic populations.^[12,13] There is also evidence of reduced hospitalization for congestive [kən"dʒest] heart failure and improvement in renal function.^[14,15] However, these significant advances have not eliminated vascular disease risk in most diabetics and even with good control of LDL-C, the incidence of related clinical events remains higher in diabetics than in non-diabetics with comparable risk factors.^[16] With the rising prevalence of type 2 diabetes, this is a major threat to more than 8% of the adults in the United States.^[17]

Current Guidelines for Managing Lipoproteins in Diabetes

Low-density Lipoprotein Cholesterol

 

LDL-C has been the major focus (the focus of a disease 病的主要患部。)of risk assessment in most of the guidelines including those of the National Cholesterol Education Program (NCEP),^[18] the American Diabetes Association (ADA),^[5] and the joint panel of the AHA and the ACC.^[19] The LDL-C focus has followed logically from several facts: most of the cholesterol in plasma is carried by LDL, LDL-C is easily assessed, genetic [dʒə"netik] defects in the LDL receptor lead to higher plasma levels and are associated with very early vascular disease, and the major, and most convincing [kən"vinsiŋ] (a convincing argument 有说服力的论点)clinical trials have used interventions [,intə"ven∫ən] that reduce LDL-C.^[13] Most importantly, we have very effective and safe drugs that reduce LDL-C including statins, bile acid sequestrants,9、（ se?ques?trant ["skwəstrənt; "sekwəstrənt] (plural se?ques?trants【化学】多价螯合作用)）and ezetimibe. It is now quite feasible to reduce LDL-C by more than 50% in the majority of patients with type 2 diabetes.^[20] Since the NCEP guidelines were first issued in 1988, the goals for LDL-C reduction have been reduced.^[18,19] Initially, treatment to lower LDL-C below 130 mg/dL was considered appropriate for diabetics. In the third iteration [,itə"rei∫n] of the guidelines issued in 2002,^[18] it was recommended that the diagnosis of diabetes mellitus should confer an estimated risk equivalent to a non-diabetic individual with known coronary disease and that the goal should be an LDL-C below 100 mg/dL. More recently, clinical trials have reduced LDL-C well below 100 mg/dL and these have shown additional benefit compared with patients with mean values closer to 100 mg/dL.^[21,22] This led a joint panel of the AHA and the ACC to recommend that an LDL-C goal of < 70 mg/dL be considered in diabetic patients with known vascular disease.^[19] This recommendation is further supported by a recent study in diabetic American Indians that demonstrated significant slowing of progression of carotid [kə"rɒtid] 颈动脉artery disease when 70 mg/dL was the target of treatment compared with those with LDL-C near 100 mg/dL.^[11]

Plasma Triglycerides and non-High-density Lipoprotein Cholesterol

It is now well documented that the triglyceride (TG)-rich lipoproteins also confer risk^[23-25] and because these are more commonly elevated in diabetes, the consideration of this risk factor is also important in preventing macrovascular disease. It is now believed that the remnants of very-low-density lipoproteins (VLDL-R) and chylomicrons (C-R) are major causative elements in atherosclerosis in addition to LDL-C. Therefore, it is recommended that the cholesterol content of VLDL-R and C-R be used in risk assessment and goal setting. A simple and direct way of affecting this is to include all of the cholesterol in these 3 lipoprotein groups when setting targets. When the TG level exceeds 200 mg/dL, the target should be all cholesterol except the high-density lipoprotein-cholesterol (HDL-C). So by subtracting the measured value of HDL-C from the total plasma cholesterol, one derives the concentration of "non-HDL-C." The current NCEP guidelines suggest that the target for this parameter should be no higher than 30 mg/dL above the goal for LDL-C set after considering all risk factors.^[18] So by this standard, all diabetics should have a non-HDL-C < 130 mg/dL and in those with vascular disease or multiple other risk factors, the goal should be < 100 mg/dL.

High-density Lipoprotein Cholesterol

The risk related to HDL has been a much more difficult issue to manage. There is no question that the HDL-C is an extremely important risk factor. Observational studies in communities or in placebo-treated patients in clinical trials provide an estimate of at least a 1% increase in event rates for coronary artery disease for every 1% reduction in HDL-C.^[26] HDL-C below 40 mg/dL places diabetics in a much higher risk group than those with values well above 50 mg/dL. Women show a greater relative increase in risk when the HDL-C is in this low range. The ADA has recommended that clinicians attempt to raise HDL-C above 40 mg/dL when levels are found to be low.^[5] The official statement of the NCEP, although recognizing the associated risk of low HDL-C, has not fostered target setting. The rationale was that there were no dependable interventions that could increase HDL-C to a prespecified value in individual patients and that could be used to dependably titrate this parameter to a target value. Furthermore, there are no clinical trials that have shown convincingly that the HDL-C elevation itself has contributed to risk reduction.^[27] Several trials have been able to relate a sum of the absolute change in both LDL-C and HDL-C to change in rates of myocardial infarction and coronary death or to change in quantitative angiography of the coronary vessels.^[28] The 1 trial that was able to elevate HDL-C as the dominant feature of treatment (using the cholesterol ester transfer protein inhibitor torcetrapib) resulted in a significant increase in cardiovascular death.^[29] Ongoing research is attempting to determine if the drug had intrinsic and perhaps unique toxicity or alternatively, that the raising of HDL-C by this mechanism was detrimental to effective transport of cholesterol and other lipids from peripheral tissues to the liver for excretion.

Metabolic Syndrome

Assessing risk in diabetes using LDL-C and HDL-C and then targeting LDL-C has been a very successful approach to risk reduction. However, it became evident approximately 10 years ago that this was not sufficient to fully reduce the high rate of vascular disease in developed countries.

In the 2002 version of the NCEP guidelines,^[18] an additional focus was placed on the common occurrence of obesity, high blood pressure, insulin resistance low HDL-C and triglycerides. These were used with specific criteria for making the diagnosis of the "metabolic syndrome." This concept was put forward initially by the World Health Organization (WHO) in 1998.^[30] The NCEP guidelines represented modified version of the WHO criteria with emphasis on recognizing combinations of any 3 or more of the following as a higher risk state: (1) low HDL, (2) increased waist size, (3) modest elevations in triglyceride, (4) blood pressure, and (5) blood glucose.

The concept was that the diagnosis of the metabolic syndrome would lead to more aggressive treatment and the reduction of LDL-C and non-HDL-C to lower values. Many considered this a way of identifying a group that was in the early phases of type 2 diabetes and hoped that it would inspire earlier and more consistent treatment of relevant risk factors. It was recognized at the time that this did not exclude diabetics and that a patient can have both the metabolic syndrome and diabetes, the latter being defined solely by the blood glucose criteria in clinical use. Some have suggested that the diagnosis of type 2 diabetes mellitus without meeting criteria for diagnosis of the metabolic syndrome does not confer significant added risk to the classical risk factors defined in the Framingham Heart Study. The important point is that the classification of cohorts in observational studies using these metabolic syndrome criteria has been documented repeatedly to define higher risk populations after adjusting for age, gender, cigarette smoking, and LDL-C.^[31,32] Those retrospectively defined as having the metabolic syndrome in some studies also appear to have greater relative benefit from reduction of LDL-C or non-HDL-C.