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Pathophysiology/Complications ORIGINAL ARTICLE

Atorvastatin Decreases C-III in –Containing and HDL in Type 2 Diabetes A potential mechanism to lower plasma

1 GEESJE M. DALLINGA-THIE, PHD ON BEHALF OF THE DIABETES ypertriglyceridemia, low levels of 2 INGRID I.L. BERK-PLANKEN, MD, PHD INTERVENTION (DALI) STUDY HDL , and preponder- 2 AART H. BOOTSMA, MD, PHD GROUP* 2,3,4 ance of small, dense LDL particles ANS ANSEN PHD H H J , are risk factors for (CVD) (1,2) and are part of the athero- genic lipoprotein profile often present in patients with type 2 diabetes. The initia- tion of the atherogenic lipoprotein profile OBJECTIVE — Apolipoprotein (apo)C-III is a constituent of HDL (HDL apoC-III) and of remains to be established. Kissebah et al. apoB-containing (LpB:C-III). It slows the clearance of -rich lipoproteins (TRLs) by inhibition of the activity of the (LPL) and by interference (3) demonstrated that in type 2 diabetic with lipoprotein binding to -surface receptors. Elevated plasma LpB:C-III is an independent subjects, apolipoprotein (apo)B and risk factor for cardiovascular disease. We studied the effect of atorvastatin on plasma LpB:C-III VLDL triglyceride secretion was en- and HDL apoC-III. hanced, but did not necessarily lead to hypertriglyceridemia. In Pima Indians, RESEARCH DESIGN AND METHODS — We studied the effect of 30 weeks’ treatment hypertriglyceridemia may develop with- with 10 and 80 mg atorvastatin on plasma apoC-III levels in a randomized, double-blind, out increased triglyceride production due placebo-controlled trial involving 217 patients with type 2 diabetes and fasting plasma triglyc- to a decreased VLDL triglyceride clear- erides between 1.5 and 6.0 mmol/l. ance capacity (4). Wilson et al. (5) RESULTS — Baseline levels of total plasma apoC-III, HDL apoC-III, and LpB:C-III were showed that in a pedigree with type 2 41.5 Ϯ 10.0, 17.7 Ϯ 5.5, and 23.8 Ϯ 7.7 mg/l, respectively. Plasma apoC-III was strongly diabetes, hypertriglyceridemia only de- correlated with plasma triglycerides (r ϭ 0.74, P Ͻ 0.001). Atorvastatin 10- and 80-mg treat- veloped in subjects with decreased li- ment significantly decreased plasma apoC-III (atorvastatin 10 mg, 21%, and 80 mg, 27%), HDL poprotein lipase (LPL) activity due to a apoC-III (atorvastatin 10 mg, 22%, and 80 mg, 28%) and LpB:C-III (atorvastatin 10 mg, 23%, genetic defect. Therefore, delayed effi- and 80 mg, 28%; all P Ͻ 0.001). The decrease in plasma apoC-III, mainly in LpB:C-III, strongly ciency of clearance of triglyceride-rich li- correlated with a decrease in triglycerides (atorvastatin 10 mg, r ϭ 0.70, and 80 mg, r ϭ 0.78; poproteins (TRLs) may be a major cause Ͻ P 0.001). Atorvastatin treatment also leads to a reduction in the HDL apoC-III–to–HDL of the development of hypertriglyceride- cholesterol and HDL apoC-III–to–apoA-I ratios, indicating a change in the number of apoC-III mia in type 2 diabetes. The clearance of per HDL particle (atorvastatin 10 mg, Ϫ21%, and 80 mg, Ϫ31%; P Ͻ 0.001). TRLs in situ is dependent on the presence CONCLUSIONS — Atorvastatin treatment resulted in a significant dose-dependent reduc- of stimulatory and inhibitory factors. In tion in plasma apoC-III, HDL apoC-III, and LpB:C-III levels in patients with type 2 diabetes. vitro studies (6,7) have implicated apoC- These data indicate a potentially important antiatherogenic effect of treatment and may III as a noncompetitive inhibitor of LPL. explain (part of) the triglyceride-lowering effect of atorvastatin. ApoC-III may also attenuate the clearance of TRL remnants by interfering with the Diabetes Care 27:1358–1364, 2004 hepatic lipoprotein receptors (8,9). Stud- ies with genetically modified animals sup- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● port the hypothesis that apoC-III affects the metabolism of TRLs. Transgenic mice 1 From the Department of Internal Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; overexpressing the apoC-III the 2Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; the 3Depart- ment of Biochemistry, Erasmus Medical Center, Rotterdam, the Netherlands; and the 4Department of developed severe hypertriglyceridemia Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands. (10) due to impaired catabolism of TRLs Address correspondence and reprint requests to Dr. G.M. Dallinga-Thie, Laboratory of Vascular Medicine (11,12), whereas mice lacking apoC-III and Metabolism, Room Bd 277, Department of Internal Medicine, Erasmus MC, Dr Molewaterplein 40, 3015 showed a very efficient clearance of VLDL GD Rotterdam, P.O. Box 2040, 3000CA Rotterdam, Netherlands. E-mail: [email protected]. Received for publication 7 October 2003 and accepted in revised form 16 March 2004. particles and had enhanced selective up- *An appendix at the end of this article lists the members of the DALI study group. take of VLDL cholesterol esters (13,14). Abbreviations: apo, apolipoprotein; CVD, cardiovascular disease; DALI, Diabetes Atorvastatin Lipid In healthy control subjects and hy- Intervention; HDL apoC-III, apoC-III in HDL; LpB:C-III, apoC-III in apoB-containing lipoprotein; LPL, perlipidemic patients, plasma triglycer- lipoprotein lipase; TRL, triglyceride-rich lipoprotein. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion ides and apoC-III concentration are factors for many substances. strongly correlated (15,16). Patients with © 2004 by the American Diabetes Association. elevated levels of plasma triglycerides had

1358 DIABETES CARE, VOLUME 27, NUMBER 6, JUNE 2004 Dallinga-Thie and Associates

Table 1 —Baseline characteristics RESEARCH DESIGN AND METHODS — This study is part of the Atorvastatin Diabetes Atorvastatin Lipid Intervention (DALI) study. DALI is a randomized, Placebo 10 mg 80 mg double-blind, placebo-controlled, multi- n 71 72 70 center study conducted in the Nether- Male sex (%) 46.5 61.1 54.3 lands (30). Briefly, 217 patients, aged Ϯ Ϯ Ϯ 45–75 years, with type 2 diabetes for at Age (years) 59 8608608 Յ BMI (kg/m2) 32.2 Ϯ 6.1 30.0 Ϯ 3.8 30.4 Ϯ 4.5 least 1 year and an HbA1c 10%, partic- Fasting glucose (mmol/l) 10.53 Ϯ 3.66 10.52 Ϯ 3007 10.66 Ϯ 2.98 ipating in the DALI study were random- Ϯ Ϯ Ϯ ized to placebo, atorvastatin 10 mg, or HbA1c (%) 8.34 1.14 8.26 1.16 8.42 1.12 LPL (units/l) 126.8 Ϯ 52.4 131.9 Ϯ 52.9 129.5 Ϯ 46.4 atorvastatin 80 mg for 30 weeks to eval- Triglycerides (mmol/l) 2.63 Ϯ 0.91 2.55 Ϯ 0.88 2.84 Ϯ 1.12 uate the effect of treatment on lipid me- Total cholesterol (mmol/l) 6.04 Ϯ 0.81 5.90 Ϯ 0.90 6.02 Ϯ 0.90 tabolism. Type 2 diabetes was defined LDL cholesterol (mmol/l) 3.80 Ϯ 0.79 3.70 Ϯ 0.91 3.74 Ϯ 0.90 according to the American Diabetes Asso- HDL cholesterol (mmol/l) 1.05 Ϯ 0.21 1.05 Ϯ 0.26 1.04 Ϯ 0.24 ciation classification (33). Inclusion crite- ApoA-I (g/l) 1.41 Ϯ 0.19 1.39 Ϯ 0.20 1.40 Ϯ 0.21 ria were fasting plasma triglycerides ApoB (mg/100 ml) 1.28 Ϯ 0.19 1.22 Ϯ 0.20 1.24 Ϯ 0.24 between 1.5 and 6.0 mmol/l, total choles- terol between 4.0 and 8.0 mmol/l, and no Data are means Ϯ SD. history of CVD. Patients were recruited in Leiden, Rotterdam, and Utrecht. The eth- increased plasma levels of apoC-III, with a ments aimed at affecting apoC-III levels ics committees of the participating centers fourfold larger proportion of apoC-III areofgreatinterest.Statinsmaylowerplas- approved the study protocol, and all pro- present in VLDL-sized particles com- ma apoC-III. In 27 patients with primary cedures followed were in accordance with pared with normolipidemic individuals hypertriglyceridemia, 20–40 mg atorva- institutional guidelines. The primary end (17–20). In contrast, patients with a ge- statin for 4 weeks reduced plasma apoC- point was the percentage decrease in netic deficiency in apoC-III had low levels III by 18–30% (28). In 305 patients with plasma triglyceride levels after atorvasta- of plasma VLDL because of an enhanced primary (29), both tin treatment, as described elsewhere fractional catabolic rate and a rapid con- atorvastatin and pravastatin reduced LpB: (30). The secondary end point was version of VLDL into intermediate- C-III by ϳ30%. In contrast, in patients changes in specialized lipid parameters. density lipoprotein and LDL (21). ApoC- with coronary artery bypass graft, lova- Written informed consent was obtained III in apoB-containing lipoproteins (LpB: statin therapy lowered the concentrations from all subjects. C-III) mainly reflects apoC-III present on of apoB-containing lipoproteins (LDL), triglyceride-rich particles and may di- but not plasma apoC-III or LpB:C-III Analytical methods rectly affect LPL activity and (19). samples were drawn after a fasting binding. HDL functions as a sink for sur- Atorvastatin is a powerful HMG-CoA period of 12 h at baseline and after 30 plus apoC-III in plasma, and a high level reductase inhibitor proven to effectively weeks’ treatment at the end of the study. may indirectly affect triglyceride clear- reduce total plasma cholesterol and tri- Plasma was prepared by immediate cen- ance (22). trifugation, and samples were stored at glyceride levels. We showed (30) that A number of clinical studies have re- Ϫ80°C for further analyses. Cholesterol atorvastatin (10 vs. 80 mg daily for 30 vealed that total apoC-III as well as apoC- and triglycerides were determined by the weeks) lowered plasma triglycerides by III present on TRLs (LpB:C-III) are risk enzymatic colorimetric method on a Hi- 25–35% in subjects with type 2 diabetes. indicators for CVD (23,24). In the Moni- tachi 911 automatic analyzer (Boehringer tored Regression Study The mechanism leading to this decrease Mannheim, Mannheim, Germany) and (MARS) (25), apoC-III, particularly in was unclear. LPL activity in postheparin apoB and apoA-I by automated immuno- apoB-containing lipoproteins, was a ma- plasma was not affected by the treatment. turbidimetric assays (Tina-quant; Roche jor risk factor for the severity of CVD in Additionally, it has been shown (31,32) Diagnostics, Mannheim, Germany). patients with mild and moderate athero- that atorvastatin treatment resulted in an Plasma HDL cholesterol was measured sclerosis. In the Cholesterol and Recur- increase in fractional catabolic rate of by a direct enzymatic HDL cholesterol rent Events (CARE) study, LpB:C-III was apoB-containing lipoproteins but no method based on polyethylene glycol– strongly and independently associated change in the apoB production rate. modified on a Hitachi 911 auto- with the risk of CVD (26). However, the In the present study, we established analyzer (Roche Diagnostics, Mannheim, concentration of apoC-III in HDL (HDL the effect of high and low levels of ator- Germany). LDL cholesterol was estimated apoC-III) was the major predictor of glo- vastatin treatment on plasma apoC-III by the Friedewald formula (34). Fasting bal coronary atherosclerosis progression in patients with type 2 diabetes, and, sec- plasma glucose was determined on a Hi- in subjects treated with -colestipol ond, we attempted to determine whether tachi 917 analyzer using an ultraviolet (Cholesterol Lowering Atherosclerosis atorvastatin results in a decrease of both hexokinase method (cat. no. 18,766,899; Study [CLAS]) (27). The important role of LpB:C-III and HDL apoC-III levels as a Boehringer Mannheim). HbA1c was deter- apoC-III in lipoprotein metabolism and as potential mechanism to lower plasma mined by high-performance liquid chro- a risk factor for CVD means that treat- triglycerides. matography, using the Bio-Rad Variant

DIABETES CARE, VOLUME 27, NUMBER 6, JUNE 2004 1359 Atorvastatin and type 2 diabetes

Table 2 —Plasma apoC-III levels at baseline and after 30 weeks of atorvastatin except for the duration of diabetes, which was shorter in the placebo group com- Atorvastatin pared with the atorvastatin 80-mg group. Baseline levels of apoC-III were simi- Placebo 10 mg 80 mg lar in the treatment groups (Table 2). The Ϯ n 71 71 71 mean apoC-III level was 41.5 10.0 mg/l. ApoC-III correlated significantly Total apoC-III (mg/l) ϭ Ͻ Baseline 41.3 Ϯ 9.0 39.8 Ϯ 9.5 43.1 Ϯ 9.9 with plasma triglycerides (r 0.74, P Ϯ Ϯ Ϯ 0.001), apoB (r ϭ 0.24, P Ͻ 0.001), and 30 weeks 41.2 12.0 31.8 10.6* 31.1 11.3* ϭ Ͻ Change (%) 0 Ϫ21.1 Ϫ27.2 total cholesterol (r 0.33, P 0.001). HDL apoC-III (mg/l) Dividing apoC-III levels into quartiles Ϯ Ϯ Ϯ showed that subjects in the highest quar- Baseline 17.6 5.2 16.7 5.3 18.4 6.0 Ͼ 30 weeks 17.6 Ϯ 8.0 14.1 Ϯ 5.2† 13.2 Ϯ 5.8*‡ tile (apoC-III 48.0 mg/l), compared Ϫ Ϫ with those in the lowest quartile (apoC-III Change (%) 0 22.2 28.3 Ͻ LpB:C-III (mg/l) 34 mg/l), exhibited plasma triglyceride Baseline 23.6 Ϯ 6.8 23.1 Ϯ 7.3 24.7 Ϯ 8.6 levels twice as high (3.79 vs. 1.86 mmol/1). 30 weeks 23.6 Ϯ 7.7 17.7 Ϯ 7.8* 17.9 Ϯ 8.7* ApoC-III is a constituent of HDL and tri- Change (%) 0 Ϫ23.4 Ϫ27.5 glyceride-rich apoB-containing lipo- HDL cholestrol (mmol/l) . The average amount of HDL Ϯ Ϯ Ϯ apoC-III and LpB:C-III was 17.7 Ϯ 5.5 Baseline 1.05 0.21 1.05 0.26 1.04 0.24 Ϯ 30 weeks 1.03 Ϯ 0.22 1.11 Ϯ 0.31 1.09 Ϯ 0.28 (12.8–21.8) and 23.8 7.7 mg/l (17.1– Change (%) Ϫ2.0 5.7 4.8 29.5), respectively. LpB:C-III correlated strongly (r ϭ 0.76, P Ͻ 0.001) and HDL ApoA-I (mg/l) ϭ Ͻ Baseline 1.41 Ϯ 0.19 1.39 Ϯ 0.20 1.40 Ϯ 0.21 apoC-III weakly (r 0.28, P 0.001) 30 weeks 1.37 Ϯ 0.18 1.38 Ϯ 0.20 1.34 Ϯ 0.20 with plasma triglycerides (Fig. 1). The Change (%) Ϫ2.8 Ϫ0.7 Ϫ4.3 HDL apoC-III–to–HDL cholesterol ratio, HDL apoC-III to apoAI (mg/mg) representing an estimate of the amount of Baseline 9.11 Ϯ 2.97 8.83 Ϯ 2.71 9.76 Ϯ 3.53 apoC-III per HDL particle, correlated Ϯ Ϯ Ϯ much stronger with plasma triglycerides 30 weeks 9.89 6.05 7.48 2.29 7.44 3.42*‡ ϭ Ͻ Change (%) 8.8 Ϫ18 Ϫ31 (r 0.68, P 0.001) than HDL apoC-III HDL apoC-III to HDL cholesterol (Fig. 2). After log transformation of the (mg/mmol) plasma triglyceride levels, similar correla- Baseline 17.1 Ϯ 5.4 16.5 Ϯ 5.2 18.3 Ϯ 6.1 tions were found (data not shown). Post- 30 weeks 18.2 Ϯ 11.4 13.1 Ϯ 4.1 12.5 Ϯ 5.8*‡ heparin LPL activity only showed a weak Change (%) 6.4 Ϫ20.7 Ϫ31.7 inverse correlation with plasma triglycer- ides (r ϭϪ0.13, P ϭ 0.05) and not with Data are means Ϯ SD. Test for difference among the three groups, adjusted for baseline value: *P Ͻ 0.001; †P ϭ 0.005. Test for difference versus 10 mg atorvastatin, adjusted for baseline: ‡P ϭ 0.05. apoC-III. HbA1c and plasma glucose levels re- mained unchanged after atorvastatin method (cat. no. 270-0003; Bio-Rad). teers, aged 45–75 years, without type 2 treatment. Plasma apoC-III levels were Plasma apoC-III was analyzed with a diabetes and hypertriglyceridemia. significantly decreased after 10-mg (21%) commercially available electroimmuno- and 80-mg (27%; both P Ͻ 0.05) atorva- assay (Hydragel LP C-III; Sebia, Issey-les- Statistical analysis statin treatment compared with placebo Moulineaux, France). HDL apoC-III was Analyses were performed using SPSS for (Table 2). After 30 weeks’ treatment, both determined in the supernatant after pre- Windows (release 9.0). Continuous vari- 10 mg and 80 mg atorvastatin decreased cipitation of the apoB-containing lipopro- ables are presented as mean values Ϯ SD. the HDL apoC-III and LpB:C-III fractions teins with the use of a specific antibody. Pearson’s correlation coefficients were to a similar extent (21–23 and 27–28%, LpB:C-III is calculated by subtracting calculated for associations between differ- respectively). Because the LpB:C-III frac- HDL apoC-III from total apoC-III. ent variables. Mean differences between tion contained the major part of the total the groups were analyzed using ANCOVA apoC-III, atorvastatin decreased the abso- Postheparin plasma LPL activity and adjusted for baseline levels and study lute amount of apoC-III in the LpB:C-III Postheparin LPL activity was measured location. P values Ͻ0.05 were considered fraction more than in the HDL apoC-III using an immunochemical method (35) statistically significant. fraction. in plasma collected 20 min after con- Earlier, we reported (30) that 10 mg tralateral intravenous administration of RESULTS — The baseline characteris- and 80 mg atorvastatin decreased plasma heparin (50 IU/kg body wt; Leo Pharma- tics of 217 randomized patients in the triglycerides in the DALI population by ceutical Products, Weesp, the Nether- DALI study are shown in Table 1. There 25 and 35%, respectively (both P Ͻ lands). Postheparin LPL was also were no significant differences in baseline 0.001). The decrease in total plasma measured in a normolipidemic control characteristics between the placebo and apoC-III strongly correlated with the de- population of 103 male and female volun- atorvastatin 10-mg and 80-mg groups, crease in plasma triglycerides in both the

1360 DIABETES CARE, VOLUME 27, NUMBER 6, JUNE 2004 Dallinga-Thie and Associates

Figure 1—Correlation between LpB:C-III (A) and HDL apoC-III (B) with plasma triglycerides (TG) in type 2 diabetic patients at baseline.

10-mg and 80-mg atorvastatin groups, re- 0.001) than the decrease in HDL apoC-III test this, we calculated the HDL apoC-III– spectively (r ϭ 0.70 and r ϭ 0.78; both (r ϭ 0.43, P Ͻ 0.001). Because atorvasta- to–HDL cholesterol and HDL apoC-III– P Ͻ 0.001). In the 80-mg atorvastatin tin increased HDL cholesterol without an to–apoA-I ratio. Atorvastatin 10 mg and group, the decrease in LpB:C-III corre- effect on apoA-I (Table 2), these data sug- 80 mg dose-dependently lowered both lated more strongly with the decrease in gest that the amount of apoC-III per HDL ratios by 18–21 and 31%, respectively plasma triglycerides (r ϭ 0.80, P Ͻ particle was lowered by atorvastatin. To (P Ͻ 0.005) (Table 2).

Figure 2—Correlation between HDL apoC-III–to–HDL cholesterol ratio and plasma triglycerides (TG) at baseline (r ϭ 0.68, P Ͻ 0.001).

DIABETES CARE, VOLUME 27, NUMBER 6, JUNE 2004 1361 Atorvastatin and type 2 diabetes

CONCLUSIONS — We show that ance (45). Batal et al. (20) demonstrated the assessment of CVD risk and of the treatment of type 2 diabetic patients for increased apoC-III synthesis using stable efficacy of treatment strategies. 30 weeks with 10 mg and 80 mg atorva- isotope techniques in hypertriglyceride- statin resulted in a significant lowering of mic subjects. They suggested that the in- APPENDIX apoC-III in the non-HDL (LpB:C-III) and creased apoC-III synthesis caused HDL (HDL apoC-III) fractions. High LpB: impairment in apoB clearance. Our data DALI Study Group (in alphabetical C-III has been found (25,26,36,37) to be are consistent with a mechanism in type 2 order) associated with increased CVD risk. HDL diabetic patients in which apoC-III syn- Erasmus Medical Center, Rotterdam, De- apoC-III was a strong indicator of CVD thesis and triglyceride synthesis are in- partment of Internal Medicine: I.I.L. progression after hypolipidemic treat- creased, resulting in elevated plasma Berk-Planken, N. Hoogerbrugge, and H. ment (27). Therefore, the decrease in apoC-III levels, impairment of TRL (and Jansen. Erasmus Medical Center, Depart- these variables may represent an impor- apoC-III) clearance, and, finally, hypertri- ment of Biochemistry and Clinical Chem- tant antiatherogenic effect of statin treat- glyceridemia. Atorvastatin treatment re- istry: H. Jansen. Gaubius Laboratory ment. The association of apoC-III with duced plasma triglycerides and total TNO-PG Leiden: H.M.G. Princen. Leiden CVD risk probably arises from its inhibi- plasma apoC-III levels by 21–28% in both University Medical Center: M.V. Huis- tory effect on the clearance of VLDL and HDLs and TRLs. The decrease in plasma man and M.A. van de Ree. University intermediate-density lipoprotein. triglycerides was strongly correlated with Medical Center Utrecht, Julius Center for Hypertriglyceridemia is an indepen- the decrease in apoC-III. Because apoC- General Practice and Patient Oriented Re- dent risk factor for CVD in type 2 diabetes III is a constituent of TRLs, an enhanced search: R.P. Stolk and F.V. van Venrooij. (38), whereas intermediate-density li- clearance rate of TRLs will lower plasma University Center Utrecht, Division of In- poprotein (39,40) has been shown to be apoC-III and, especially, LpB:C-III. How- ternal Medicine: J.D. Banga, G.M. highly atherogenic. LPL activity only mar- ever, even though this accounts for a drop Dallinga-Thie, and F.V. van Venrooij. ginally correlated with plasma triglycer- in total plasma apoC-III, it does not ex- ides and was not a major determinant of plain the decrease in HDL apoC-III by Acknowledgments— The DALI study was the plasma triglyceride level in the present atorvastatin treatment. Schoonjans et al. study. This is quite conceivable. LPL ac- supported by a grant from Pfizer, the Nether- (46) showed that simvastatin decreased lands. tivity, determined in vitro after heparin apoC-III mRNA and plasma apoC-III lev- injection, reflects the maximum available els in rats. Therefore, part of the lowering amount of enzymatically active lipase. of apoC-III may be due to inhibition of the References The in situ clearance capacity, however, is 1. Hokanson JE, Austin MA: Plasma tri- apoC-III synthesis by atorvastatin and also dependent on stimulatory and inhib- glyceride is a risk factor for cardiovascular may explain (part of) the triglyceride- itory factors. ApoC-III is an effective in- disease independent of high density lipo- lowering effect of atorvastatin. hibitor of LPL activity (6,7) and is present cholesterol: a meta-analysis of in TRLs and HDL. Part of apoC-III is ex- After atorvastatin treatment, the HDL population based prospective studies. changeable between these lipoproteins apoC-III–to–HDL cholesterol and HDL J Cardiovasc Res 3:213–219, 1996 2. Jeppesen J, Hein HO, Suadicani P, Gyn- (20,41). ApoC-III will be transferred from apoC-III–to–apoA-I ratios were de- creased, suggesting that apoC-III in HDL telberg F: Triglyceride concentration and HDL to TRLs in the presence of elevated ischemic heart disease: an eight-year fol- concentrations of TRLs, such that HDL was no longer present in excess. Under these conditions, during (partial) degra- low-up in the Copenhagen Male Study. apoC-III concentrations decrease (41, Circulation 97:1029–1036, 1998 42). After (partial) degradation of triglyc- dation of triglycerides in TRLs, apoC-III 3. Kissebah AH, Alfarsi S, Adams PW: In- erides in TRL by LPL, apoC-III transfers may be transferred to HDLs. The relative tegrated regulation of very low density back to HDL (41,43,44), such that clear- depletion of apoC-III in the TRLs abol- lipoprotein triglyceride and apolipopro- ance of the triglyceride-rich particles may ishes the inhibited degradation of the tein-B kinetics in man: normolipidemic proceed uninhibited. We found that the TRLs, such that clearance proceeds and subjects, familial hypertriglyceridemia HDL apoC-III–to–HDL cholesterol ratio plasma triglycerides are lowered. In this and familial combined . Metabolism 30:856–868, 1981 (a measure of the amount apoC-III per mechanism, inhibition of apoC-III syn- thesis by could play a pivotal role 4. Howard BV, Reitman JS, Vasquez B, Zech HDL particle) correlated more strongly L: Very-low-density lipoprotein triglycer- with plasma triglycerides than HDL in the triglyceride-lowering capacity of ide metabolism in non--dependent apoC-III. It is conceivable that in condi- statin treatment. diabetes mellitus: relationship to plasma tions where HDL becomes “saturated” Although the proposed mechanisms insulin and free fatty acids. Diabetes 32: with apoC-III, it is evenly distributed over have to be verified by kinetic studies, our 271–276, 1983 HDL and TRLs and impairs further deg- results demonstrate that atorvastatin may 5. Wilson DE, Kwong LK, Elbein SC, La- radation of the TRLs. This could explain lower the elevated risk for atherosclerotic louel JM: Genetic predisposition to hyper- the strong correlation between the HDL disease in patients with type 2 diabetes in lipidaemia in diabetes: the end of the apoC-III–to–HDL cholesterol ratio and several ways. It effectively reduces total beginning. J Intern Med Suppl 736:53–61, 1994 the plasma triglyceride level. cholesterol and triglycerides and elevates 6. Wang C, McConathy WJ, Kloer HJ, High apoC-III levels may result from HDL cholesterol, but, additionally, it low- Alaupovic P: Modulation of lipoprotein increased apoC-III synthesis, which is ers atherogenic LpB:C-III and HDL apoC- lipase activity by : effect of triggered by increased triglyceride syn- III. Therefore, measurement of apoC-III apolipoproein C-III. J Clin Invest 75:384– thesis and secretion (43) or delayed clear- in different lipoproteins may be helpful in 390, 1985

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