Bevilacqua Maurizio, Guazzini Barbara, Righini Velella, Barrella Massimo, Toscano Rosanna, Chebat Enrica
Endocrinology and Diabetology Service, L. Sacco-Polo University Hospital, Milan, Italy.
Curr Ther Res Clin Exp. 2004 Jul;65(4):330-44. doi: 10.1016/j.curtheres.2004.06.004.
Diabetic dyslipidemia is characterized by greater triglyceridation of all lipoproteins and low levels of plasma high-density lipoprotein cholesterol (HDL-C). In this condition, the serum level of low-density lipoprotein cholesterol (LDL-C) is only slightly elevated. The central role of decreased serum HDL-C level in diabetic cardiovascular disease has prompted the establishment of a target of ≥50 mg/dL in patients with diabetes mellitus (DM).
The aim of the study was to assess the effects of once-daily administration of fluvastatin extended release (XL) 80 mg or atorvastatin 20 mg on serum HDL-C levels in patients with type 2 DM and low levels of serum HDL-C.
This 4-month, prospective, open-label, randomized, blinded-end point (PROBE) trial was conducted at Endocrinology and Diabetology Service, L. Sacco-Polo University Hospital (Milan, Italy). Patients aged 45 to 71 years with type 2 DM receiving standard oral antidiabetic therapy, with serum HDL-C levels <50 mg/dL, and with moderately high serum levels of LDL-C and triglycerides (TG) were enrolled. After 1 month of lifestyle modification and dietary intervention, patients who were still showing a decreased HDL-C level were randomized, using a 1:1 ratio, to receive fluvastatin XL 80-mg tablets or atorvastatin 20-mg tablets, for 3 months. Lipoprotein metabolism was assessed by measuring serum levels of LDL-C, HDL-C, TG, apolipoprotein (apo) A-I (the lipoprotein that carries HDL), and apo B (the lipoprotein that binds very low-density lipoprotein cholesterol, intermediate-density lipoprotein, and LDL on a molar basis). Patients were assessed every 2 weeks for treatment compliance and subjective adverse events. Serum creatine phosphokinase and liver enzymes were assessed before the run-in period, at the start of the trial, and at 1 and 3 months during the study.
One hundred patients were enrolled (50 patients per treatment group; fluvastatin XL group: 33 men, 17 women; mean [SD] age, 58 [12] years; atorvastatin group: 39 men, 11 women; mean [SD] age, 59 [11] years). In the fluvastatin group after 3 months of treatment, mean (SD) LDL-C decreased from 149 (33) to 95 (25) mg/dL (36%; P < 0.01), TG decreased from 437 (287) to 261 (164) mg/dL (40%; P < 0.01), and HDL-C increased from 41 (7) to 46 (10) mg/dL (12%; P < 0.05). In addition, apo A-I increased from 118 (18) to 124 (15) mg/dL (5%; P < 0.05) and apo B decreased from 139 (27) to 97 (19) mg/dL (30%; P < 0.05). In the atorvastatin group, LDL-C decreased from 141 (25) to 84 (23) mg/dL (40%; P < 0.01) and TG decreased from 411 (271) to 221 (87) mg/dL (46%; P < 0.01). Neither HDL-C (41 [7] vs 40 [6] mg/dL; 2%) nor apo A-I (117 [19] vs 114 [19] mg/dL; 3%) changed significantly. However, apo B decreased significantly, from 131 (20) to 92 (17) mg/dL (30%; P < 0.05). Mean changes in HDL-C (+5 [8] vs -1 [2] mg/dL; P < 0.01) and apo A-I (+6 [18] mg/dL vs -3 [21] mg/dL; P < 0.01) were significantly greater in the fluvastatin group than in the atorvastatin group, respectively. However, the decreases in LDL-C (54 [31] vs 57 [32] mg/ dL), TG (177 [219] vs 190 [65] mg/dL), and apo B (42 [26] vs 39 [14] mg/dL) were not significantly different between the fluvastatin and atorvastatin groups, respectively. No severe adverse events were reported.
Fluvastatin XL 80 mg and atorvastatin 20 mg achieved mean serum LDL-C (≤ 100 mg/dL) and apo B target levels (≤ 100 mg/dL) in the majority of this population of patients with type 2 DM, but mean serum HDL-C level was increased significantly only with fluvastatin-16 patients (32%) in the fluvastatin group compared with none in the atorvastatin group achieved HDL-C levels ≥50 mg/dL. The increase in HDL-C in the fluvastatin-treated patients was associated with an increase in apo A-I, suggesting a potential pleiotropic and selective effect in patients with low HDL-C levels.
糖尿病血脂异常的特征是所有脂蛋白的甘油三酯化增加以及血浆高密度脂蛋白胆固醇（HDL-C）水平降低。在这种情况下，低密度脂蛋白胆固醇（LDL-C）的血清水平仅略有升高。血清HDL-C水平降低在糖尿病心血管疾病中的核心作用促使为糖尿病患者设定了≥50mg/dL的目标。
本研究旨在评估每日一次服用80mg氟伐他汀缓释片（XL）或20mg阿托伐他汀对2型糖尿病且血清HDL-C水平低的患者血清HDL-C水平的影响。
这项为期4个月的前瞻性、开放标签、随机、盲终点（PROBE）试验在意大利米兰L. Sacco - Polo大学医院内分泌与糖尿病科进行。纳入年龄在45至71岁、接受标准口服抗糖尿病治疗、血清HDL-C水平<50mg/dL、血清LDL-C和甘油三酯（TG）水平中度升高的2型糖尿病患者。在进行1个月的生活方式改变和饮食干预后，仍表现出HDL-C水平降低的患者按1:1比例随机分组，接受80mg氟伐他汀XL片或20mg阿托伐他汀片治疗3个月。通过测量血清LDL-C、HDL-C、TG、载脂蛋白（apo）A-I（携带HDL的脂蛋白）和apo B（在摩尔基础上与极低密度脂蛋白胆固醇、中间密度脂蛋白和LDL结合的脂蛋白）水平来评估脂蛋白代谢。每2周评估患者的治疗依从性和主观不良事件。在导入期前、试验开始时以及研究期间的1个月和3个月时评估血清肌酸磷酸激酶和肝酶。
共纳入100例患者（每个治疗组50例；氟伐他汀XL组：33例男性，17例女性；平均[标准差]年龄，58[12]岁；阿托伐他汀组：39例男性，11例女性；平均[标准差]年龄，59[11]岁）。在氟伐他汀组治疗3个月后，平均（标准差）LDL-C从149（33）降至95（25）mg/dL（36%；P<0.01），TG从437（287）降至261（164）mg/dL（40%；P<0.01），HDL-C从41（7）升至46（10）mg/dL（12%；P<0.05）。此外，apo A-I从118（18）升至124（15）mg/dL（5%；P<0.05），apo B从139（27）降至97（19）mg/dL（30%；P<0.05）。在阿托伐他汀组，LDL-C从141（25）降至84（23）mg/dL（40%；P<0.01），TG从411（271）降至221（87）mg/dL（46%；P<0.01）。HDL-C（41[7]对40[6]mg/dL；2%）和apo A-I（117[19]对114[19]mg/dL；3%）均无显著变化。然而，apo B显著降低，从131（20）降至92（17）mg/dL（30%；P<0.05）。氟伐他汀组HDL-C（+5[8]对-1[2]mg/dL；P<0.01）和apo A-I（+6[18]mg/dL对-3[21]mg/dL；P<0.01）的平均变化分别显著大于阿托伐他汀组。然而，氟伐他汀组和阿托伐他汀组之间LDL-C（54[31]对57[32]mg/dL）、TG（177[219]对190[65]mg/dL）和apo B（42[26]对39[14]mg/dL）的降低无显著差异。未报告严重不良事件。
80mg氟伐他汀XL和20mg阿托伐他汀在大多数该2型糖尿病患者群体中实现了平均血清LDL-C（≤100mg/dL）和apo B目标水平（≤100mg/dL），但仅氟伐他汀使平均血清HDL-C水平显著升高——氟伐他汀组有16例患者（32%）达到HDL-C水平≥50mg/dL，而阿托伐他汀组无。氟伐他汀治疗患者中HDL-C的升高与apo A-I的增加相关，提示对HDL-C水平低的患者有潜在的多效性和选择性作用。
