Effect of ezetimibe/simvastatin vs atorvastatin on lowering levels of LDL-C and non HDL-C, ApoB, and hs-crp in patients with type 2 diabetes

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1 Journal of Clinical Lipidology (8) 2, Effect of ezetimibe/simvastatin vs atorvastatin on lowering levels of LDL-C and non HDL-C, pob, and hs-crp in patients with type 2 diabetes Ruth S. Weinstock, MD, PhD,* Ronald B. Goldberg, MD, John R. Guyton, MD, Theodore Mazzone, MD, dam Polis, M, Joanne E. Tomassini, PhD, Jianxin Lin, MS, rvind Shah, PhD, ndrew M. Tershakovec, MD, MPH Division of Endocrinology, Diabetes and Metabolism, SUNY Upstate Medical University and V Medical Center, 7 E. dams Street, CWB 353, Syracuse, NY 132, US (Dr. Weinstock); University of Miami, Miami, FL, US (Dr. Goldberg); Duke University, Durham, NC, US (Dr. Guyton); University of Illinois, Chicago, IL, US (Dr. Mazzone); Merck & Co., Inc., West Point, P, US (Mr. Polis, Dr. Tomassini, Mr. Lin, Drs. Shah and Tershakovec) KEYWORDS: pob; torvastatin; Ezetimibe/simvastatin; Hs-CRP; LDL-C; Non HDL-C BCKGROUND: In addition to low-density lipoprotein cholesterol (LDL-C), non high-density lipoprotein cholesterol (non HDL-C), apolipoprotein B (pob), and high-sensitivity C-reactive protein (hs-crp) are considered predictive for cardiovascular disease in type 2 diabetes mellitus (T2DM) patients. OBJECTIVE: To assess the proportion of T2DM patients with hypercholesterolemia who attained the optional target level of LDL-C ( mg/dl) and additionally non HDL-C ( mg/dl), pob ( 9 mg/dl), and hs-crp ( 2 mg/l), following treatment with ezetimibe/simvastatin () vs atorvastatin (). METHODS: This post-hoc analysis of a multicenter, randomized, double-blind, 6-week parallel study assessed the proportion of T2DM patients who attained specified LDL-C levels and non HDL-C, pob, and hs-crp with usual, recommended starting doses of (/ mg) vs ( or mg) and next highest doses of (/ mg) vs ( mg) by logistic regression. Baseline triglyceride and hs-crp effects were also evaluated. RESULTS: Significantly higher percentages of patients treated with compared to achieved individual and concurrent target levels of LDL-C ( mg/dl), non HDL-C ( mg/dl), and pob ( 9 mg/dl) at all dose comparisons (P.5 to P.1). Baseline triglyceride levels had no effect on reaching LDL-C levels. ttainment of non HDL-C ( mg/dl), and pob ( 9 mg/dl) was lower at triglycerides mg/dl than mg/dl. chievement of hs-crp level ( 2 mg/l) was comparable for both treatments. Significantly more patients attained both LDL-C ( mg/dl) and hs-crp ( 2 mg/l) at all doses compared to (P.5 to P.1), regardless of baseline CRP levels. CONCLUSION: provides a therapeutic option to T2DM patients for lowering not only LDL-C, but also non HDL-C, pob, and hs-crp. These factors may help guide assessment and treatment of cardiovascular disease risk in these patients. 8 National Lipid ssociation. ll rights reserved. * Corresponding author. address: weinstor@upstate.edu Submitted December 31, 7. ccepted for publication January 6, 8. Patients with type 2 diabetes mellitus (T2DM) are at increased risk for cardiovascular disease (CVD) related morbidity and mortality. 1 This is attributed, in part, to dyslipidemia in these patients, which is characterized by elevated /$ -see front matter 8 National Lipid ssociation. ll rights reserved. doi:.16/j.jacl.8.1.1

2 26 Journal of Clinical Lipidology, Vol 2, No 1, February 8 levels of triglycerides (TG) and TG-rich lipoproteins (very low density lipoproteins [VLDL] and intermediate low density lipoproteins [IDL]), low levels of high-density lipoprotein (HDL), and a predominance of small, dense LDL particles. 2,3 comprehensive approach can reduce CVD risk in T2DM patients through lifestyle modification, glucose control, and lipoprotein-directed pharmacologic intervention. LDL-C lowering is considered a primary treatment target, and statin treatment has been shown to substantially reduce LDL-C and CVD risk in T2DM patients. 1,2,4 7 n LDL-C goal of mg/dl is an accepted treatment target for T2DM patients 1,4,5 ; however, for those patients with established coronary heart disease (CHD) or other atherosclerotic vascular disease, more aggressive lipid-lowering therapy may be warranted. 1,4,5 Current guidelines recommend attainment of LDL-C levels of mg/dl as an option for high-risk patients, 4,5 and this intensive goal is considered reasonable for very high-risk patients, such as those with both CHD and diabetes. 1,4,8 dditional risk factors, such as non HDL-C and apolipoprotein B (pob), may also be considered in guiding assessment and treatment of CHD patients at high risk. 1,4,5,9, Non HDL-C at a level of 1 mg/dl ( mg/dl above the LDL-C goal) is a recommended secondary target for high-risk patients with TG mg/dl by the National Cholesterol Education Program dult Treatment Panel III. 4,5 Non HDL-C at a level of mg/dl is considered a reasonable level for very high risk patients with TG mg/dl. 8 Lipoproteins included in the measurement of non HDL-C contain one molecule of pob per lipoprotein particle pob provides a direct measure of particle number and thus is regarded as a marker of all atherogenic lipoproteins Levels of pob 9 mg/dl can be considered an alternative secondary target for highrisk patients. 5,11,16 Inflammatory markers may also be indicative of CVD risk in hypercholesterolemic and T2DM patients. 17,18 In particular, high-sensitivity C-reactive protein (hs-crp) is regarded as an emerging marker for diagnosis and management of CVD. 4,5,17 Previously, the safety and efficacy of the combination treatment, ezetimibe/simvastatin (), compared to atorvastatin () monotherapy was demonstrated in T2DM patients with hypercholesterolemia (VYTorin versus torvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia [VYTL] study). 19 t the usual starting, and next highest, doses, provided additional improvements in the lipid/lipoprotein profile, hs-crp, and in attainment of LDL-C and mg/dl compared to. 19 This post-hoc analysis of the VYTL study assessed the effect of and on the proportion of these diabetic patients who attained levels of LDL-C mg/dl and, additionally, non HDL-C mg/dl and pob 9 mg/dl. Subgroups of patients who at baseline had TG levels or mg/dl were also analyzed to determine the fraction satisfying achievement of these specified levels with each therapy. The effect of these treatments on attainment of hs-crp 2 mg/l and in those patients who achieved concurrent levels of LDL-C mg/dl was also evaluated. Methods Study design This was a post-hoc analysis of data obtained from a previously described multicenter, double-blind, randomized, parallel-group, 6-week study in T2DM patients (n 1229) with hypercholesterolemia (18 years of age). 19 Eligible patients had confirmed diabetes managed with drugs and/or insulin, or with diet alone. 1 Selected entry criteria at week 1 included LDL-C mg/dl, TG mg/dl, and hemoglobin 1c 8.5%. Patients were stratified at randomization according to LDL-C ranges of to 1, 1 to 1, 1 to 19, and 19 mg/dl and were treated once daily for 6 weeks with the usual starting doses of (/ mg) or ( or mg), and/or the next highest doses of (/ mg) or ( mg). s described previously, 19 the primary efficacy endpoint was the percent reduction from baseline in LDL-C and the secondary endpoint was the proportion of patients attaining LDL-C mg/dl for very high-risk patients. Other efficacy measures included the percent attainment of LDL-C mg/dl and percent changes from baseline in HDL-C, non HDL-C, TG, pob, and hs-crp. Statistical analyses Efficacy was assessed in the modified intent-to-treat (mitt) population, which included all randomized patients with a valid baseline measurement and at least one valid subsequent measurement. Treatment group comparisons of percent reduction from baseline in LDL-C and other efficacy parameters after 6 weeks at the usual start doses ( / vs mg or / vs mg) and the alternative start doses ( / vs mg) were the same as the primary study and were analyzed by an analysis of variance model. logistic regression model with terms for treatment group, Visit 2 LDL-C stratum, and baseline non HDL-C or pob was used to compare the recommended usual starting doses ( / vs mg and / vs mg) and next highest doses ( / vs mg) with regard to the percentage of patients who reached both LDL-C ( mg/dl) and non HDL-C ( mg/dl) and LDL-C ( mg/dl), and pob ( 9 mg/dl) levels for patients with baseline TG and mg/dl. similar model was used for analysis of attainment of both LDL-C ( mg/dl) and hs-crp ( 2 mg/l) concurrently with a term for baseline hs-crp used instead of baseline pob or non HDL-C. s supportive information, treatment group comparisons of the percentage of patients who reached single attainment

3 Weinstock et al Ezetimibe/simvastatin vs atorvastatin on lipids in T2DM 27 Table 1 Baseline characteristics: all randomized patients* mg (n 245) mg (n 247) mg (n 245) mg (n 247) mg (n 245) NCEP TP III risk category n % n % n % n % n % CHD or CHD risk equivalent CHD Diabetes CHD risk factors CHD risk factors Metabolic syndrome LDL-C strata (mg/dl) to to to Triglycerides (mg/dl) HDL-C (mg/dl) mg/dl mg/dl , atorvastatin; CHD, coronary heart disease;, ezetimibe mg/simvastatin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NCEP TP III, National Cholesterol Education Program dult Treatment Panel III. *Derived from all patients randomized, including a patient in the / mg group who was inadvertently randomized without CHD/CHD risk equivalent or diabetes at baseline. Diabetes defined as baseline fasting glucose 126 mg/dl on two or more occasions, a diagnosis of diabetes or use of antidiabetic medications. Metabolic syndrome defined as three or more characteristics: waist circumference (males, 2 cm; females, 88 cm); triglycerides 1 mg/dl; HDL-C ( mg/dl, males or mg/dl, females); blood pressure ( 1/85 mm Hg or on antihypertensives); fasting glucose ( mg/dl or diabetic ). of LDL-C mg/dl, pob 9 mg/dl, and non HDL-C mg/dl in patients with baseline TG and mg/dl and hs-crp 2 mg/l at all hs-crp baseline levels, was also analyzed by logistic regression. sensitivity analysis in the subset of patients with hs-crp 2 mg/l at baseline was also performed. ll treatment comparisons were declared statistically significant if they reached the.5 level. Results Baseline characteristics s reported previously in a clinical trial of T2DM patients with hypercholesterolemia (n 1229), baseline characteristics were generally balanced among the treatment groups, including age, gender, race, body mass index, and waist circumference. 19 Categories of patients with CHD risk 4,5 and those with diabetes (99.9%; 1 patient inadvertently randomized without CHD/CHD risk equivalent or diabetes) and metabolic syndrome (86%) were also welldistributed (Table 1). Distribution of patients by LDL strata was similar among the treatment groups, with the majority of patients in the to 1 mg/dl range. bout % of patients had TG mg/dl and % had HDL-C mg/dl. Baseline mean values for LDL-C ( 145 mg/dl), non HDL-C ( 1 mg/dl), and pob ( 1 mg/dl), and medians for TG ( mg/dl) and hs-crp ( 2.7 mg/l) were also similar among treatment groups (Table 2). Percent change from baseline in LDL-C, non HDL- C, pob, and hs-crp In this study, significantly greater mean reductions from baseline in LDL-C, non HDL-C, and pob were observed with than at all dose comparisons (P.1) in the overall mitt population (Table 3). The lowest dose of (/ mg) reduced hs-crp significantly more than, mg/day (P.2), and comparable reductions were observed at the other doses (Table 3). ttainment of levels of LDL-C < mg/dl, non HDL-C < mg/dl, and pob <9 mg/dl Baseline levels for TG, LDL-C, non HDL-C, and pob in the subgroups of patients with baseline TG and mg/dl were well-balanced across treatment groups (Table 4). For LDL-C, non HLD-C and pob, the mean baseline values were slightly higher in patients with TG

4 28 Journal of Clinical Lipidology, Vol 2, No 1, February 8 Table 2 Baseline values for LDL-C, TG, non HDL-C, pob, and hs-crp: ll randomized patients Parameter (mg/dl) mg mg mg mg mg LDL-C n Mean SD Non HDL-C n Mean SD TG n Median Robust SD pob n Mean SD Hs-CRP (mg/l) n Median Robust SD , atorvastatin; pob, apolipoprotein B;, ezetimibe mg/simvastatin; hs-crp, high-sensitivity C-reactive protein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TG, triglycerides. Table 3 Percent change from baseline in LDL-C, non HDL-C, pob, and hs-crp: Modified intent-to-treat population mg mg mg mg mg Parameter (n 237) (n 238) (n 2) (n 242) (n 241) LDL-C (mg/dl) Baseline mean % Change from baseline Treatment difference 15.3** 9.** 6.6** Non HDL-C Baseline mean % Change from baseline Treatment difference 13.1** 6.7** 5.6** pob Baseline mean % Change from baseline (.9) 44.6 (.9). (.9) Treatment difference.1** 4.5** 4.6** Hs-CRP (mg/l) Baseline median % Change from baseline Treatment difference.2* , atorvastatin; pob, apolipoprotein B;, ezetimibe mg/simvastatin; hs-crp, high-sensitivity C-reactive protein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. *P.2 for specified between-treatment difference. **P.1 for specified between-treatment difference. Least-square means. Treatment differences are / mg minus mg; / mg minus mg, / mg minus mg based on analysis of variance model with terms for treatment and Visit 2 LDL-C stratum ( to 1 mg/dl, 1 to 1 mg/dl, 1 to 19 mg/dl, and 19 mg/dl). Median.

5 Weinstock et al Ezetimibe/simvastatin vs atorvastatin on lipids in T2DM 29 mg/dl. Baseline mean values for TG were twofold higher in the subgroup of patients with TG mg/dl than those with TG mg/dl. Regardless of baseline TG levels, a significantly greater proportion of patients attained levels of LDL-C mg/dl (P.1) and levels of non HDL-C mg/dl (P.5 to P.1) following treatment compared to at all dose comparisons (Fig. 1 to D). greater number of patients also achieved levels of pob 9 mg/dl following treatment than at all dose comparisons. This was significant at the / versus mg comparison (P.1) in patients with normal TG levels ( mg/dl) (Fig. 1E). In patients with high TG levels ( mg/dl), this was significant at the lowest and highest dose comparisons in patients (Fig. 1F). Proportions of patients who attained levels of LDL-C mg/dl were similar across treatment groups for patients with baseline TG levels mg/dl compared to mg/dl (Fig. 1 and B). In patients with elevated baseline TG levels ( mg/dl), the proportions of patients who achieved levels of non HDL-C mg/dl (Fig. 1C and D) and of pob 9 mg/dl (Fig. 1E and F) were reduced compared to those patients with normal baseline TG levels ( mg/dl) in both treatment groups. ttainment of levels of LDL-C < mg/dl and additionally non HDL-C < mg/dl or pob <9 mg/dl t baseline TG levels and mg/dl, significantly greater proportions of patients attained levels of LDL-C mg/dl and additionally non HDL-C mg/dl (P.1 to P.1), following treatment with compared to at all dose comparisons (Fig. 2 and B). Similarly, significantly higher proportions of patients with baseline TG levels and mg/dl attained both LDL-C mg/dl and pob 9 mg/dl with treatment than at all dose comparisons (P.3 to P.1) (Fig. 2B and C). Overall, qualitatively higher proportions of patients with normal baseline TG levels ( mg/dl) attained both LDL-C mg/dl and non HDL-C mg/dl, and LDL-C mg/dl and pob 9 mg/dl compared to those with elevated TG levels ( mg/dl) (Fig. 2 toc). Proportion of patients who attained levels of LDL-C < mg/dl and hs-crp <2 mg/l s reported previously, 19 a significantly greater proportion of patients in the overall mitt population attained individual levels of LDL-C mg/dl for compared to (P.1) at all dose comparisons (Fig. 3). dditionally, attainment of hs-crp 2 mg/l was comparable for both treatments when assessed at all baseline levels of hs-crp (Fig. 3B). Similar results were obtained in an analysis of the subset of patients with hs-crp baseline values Table 4 Baseline value for triglycerides and mg/dl subgroups Baseline TG mg/dl Baseline TG mg/dl mg mg mg mg mg mg mg mg mg mg Parameter (mg/dl), mean SD LDL-C Non HDL-C pob TG , atorvastatin; pob, apolipoprotein B;, ezetimibe mg/simvastatin; HLD-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviations; TG, triglycerides.

6 Journal of Clinical Lipidology, Vol 2, No 1, February 8 Baseline TG < mg/dl Baseline TG mg/dl. LDL-C B. LDL-C % patients (TG < mg/dl) *** 58.6*** *** % patients (TG mg/dl) *** 61.2*** *** vs vs vs N=133 N=1 N=149 N=1 N=143 N=148 C. Non-HDL-C % patients (TG < mg/dl) attaining non-hdl-c < mg/dl 29.3 E. po B 72.9*** 72.9** * vs vs vs N=133 N=1 N=149 N=1 N=143 N=148 D. Non-HDL-C % patients (TG mg/dl) attaining non-hdl-c < mg/dl F. po B vs vs vs N=4 N=98 N=91 N=98 N=98 N= *** 43.9** *** vs vs vs N=4 N=98 N=91 N=98 N=98 N=94 % patients (TG < mg/dl) attaining pob <9 mg/dl *** % patients (TG mg/dl) attaining pob <9 mg/dl *** *** vs vs vs vs vs vs N=129 N=138 N=144 N=138 N=143 N=143 N=2 N=93 N=89 N=93 N=96 N=9 Figure 1 Percent attainment of individual levels of low-density lipoprotein cholesterol (LDL-C) mg/dl among patients with baseline triglycerides (TG) mg/dl () and baseline TG mg/dl (B). Non high-density lipoprotein cholesterol (HDL-C) mg/dl at baseline TG mg/dl (C) and baseline TG mg/dl (D). polipoprotein B (pob) 9 mg/dl at baseline TG mg/dl (D) and baseline TG mg/dl (E). *P.5, **P.1, and ***P.1 for the indicated treatment comparison., atorvastatin;, ezetimibe/simvastatin.

7 Weinstock et al Ezetimibe/simvastatin vs atorvastatin on lipids in T2DM 31 Baseline TG < mg/dl Baseline TG mg/dl. LDL-C and Non -HDL-C B. LDL-C and Non-HDL-C % patients (TG < mg/dl) and non-hdl-c < mg/dl 58.6*** 58.6*** ** % patients (TG mg/dl) and non-hdl-c < mg/dl 43.9*** 43.9*** *** vs vs vs N=133 N=1 N=149 N=1 N=143 N=148 vs vs vs N=4 N=98 N=91 N=98 N=98 N=94 C. LDL-C and pob D. LDL-C and po B % patients (TG < mg/dl) and po B <9 mg/dl *** 56.5*** ** % patients (TG mg/dl) and po B <9 mg/dl *** 46.2* *** vs vs vs N=129 N=138 N=144 N=138 N=143 N=143 vs vs vs N=2 N=93 N=89 N=93 N=96 N=9 Figure 2 Percent attainment of levels of both low-density lipoprotein cholesterol (LDL-C) mg/dl and non high-density lipoprotein cholesterol (HDL-C) mg/dl among patients with baseline triglycerides (TG) mg/dl () and baseline TG mg/dl (B); both LDL-C and apolipoprotein B (pob) 9 mg/dl among patients with baseline TG mg/dl (C) and baseline TG mg/dl (D). *P.3, **P.2, and ***P.1 for the indicated treatment comparison., atorvastatin;, ezetimibe/simvastatin. above the CRP goal ( 2 mg), although overall percentages of patients who attained hs-crp 2 mg/l were lower due to the smaller size of the subset populations (data not shown). Significantly higher proportions of patients treated with versus attained concurrent levels of LDL-C mg/dl and hs-crp 2 mg/l at all dose comparisons (P.5 to P.1) (Fig. 3C). Overall, the percentage of patients who attained both of these levels was relatively less than the percentage who attained LDL-C mg/dl. In patients with baseline hs-crp levels 2 mg/l, significantly higher proportions of patients similarly attained both LDL-C mg/dl and hs-crp levels of 2 mg/l (P.5) for compared to at all dose comparisons; however, the percentage of patient attainment for each was somewhat reduced in this subset of patients (data not shown). Correlation of non HDL-C and pob The correlation coefficients between non HDL-C and pob at week 6 for each treatment group are presented in

8 32 Journal of Clinical Lipidology, Vol 2, No 1, February 8. LDL-C< mg/dl B. hs-crp <2 mg/dl % of patients attaining LDL-C < mg/dl *** 59.7*** *** % patients attaining hs-crp <2 mg/l vs vs vs N=237 N=238 N=2 N=238 N=241 N=242 vs vs vs N=235 N=236 N=238 N=236 N=241 N=239 C. LDL-C < mg/dl and hs-crp <2 mg/dl % patients attaining LDL-C < mg/dl and hs-crp <2mg/L ***.9*** * vs vs vs N=235 N=236 N=238 N=236 N=241 N=239 Figure 3 Percent attainment of levels of low-density lipoprotein cholesterol (LDL-C) mg/dl () and high-sensitivity C-reactive protein (hs-crp) 2 mg/l (B) and both LDL-C and hs-crp 2 mg/l (C) in the modified intent-to-treat population; *P.5 and ***P.1 for the indicated treatment comparison., atorvastatin;, ezetimibe/simvastatin. Table 5 for all patients and for patients with TG and mg/dl. Correlations were very high (.88.95; P.1) and generally similar across treatment groups and between baseline TG levels and mg/dl. Discussion This analysis demonstrated that a greater percentage of patients with diabetes and hypercholesterolemia achieved the optional recommended levels of LDL-C mg/dl and, additionally, non HDL-C mg/dl and pob 9 mg/dl, assessed singly and concurrently, following 6 weeks of treatment with at the usual starting doses (/ mg) compared to ( and mg) and at the next highest doses ( / vs mg). lthough baseline TG levels had no effect on reaching levels of LDL-C mg/dl, attainment of levels of non HDL-C mg/dl and pob 9 mg/dl was less often achieved in patients with elevated baseline TG levels ( mg/dl) compared to those with normal TG ( mg/dl). ttainment of hs-crp 2 mg/dl was comparable between the treatment groups, and the number of patients who attained both LDL- C mg/dl and hs-crp 2 mg/l was significantly greater with treatment compared to at all baseline hs-crp levels, including those with hs-crp 2 mg/l. Results of this analysis are consistent with the greater improvements observed in the overall lipid profile observed in the whole cohort of the VYTL study. 19 This included further reductions from baseline in LDL-C, total cholesterol, non HDL-C, TG, and pob, and increases in HDL- C 19 following treatment with the combination compared to at all dose comparisons. The percentage attainment of the LDL-C goal of mg/dl was near maximal ( 9%) in the VYTL study, and significantly greater numbers of patients receiving also attained the optional target level of mg/dl at all dose comparisons. 19 ll patients (but one inadvertently enrolled without CHD/CHD risk equivalent or diabetes) had T2DM, and 86% had the metabolic syndrome. dditionally, mean LDL-C baseline level was 145 mg/dl, and % of patients had characteristics of dyslipidemia, including elevated TG ( mg/dl) and low levels of HDL-C ( mg/dl). Thus, the VYTL study provided an appropriate population in which to further assess the effect of treatment on the optional target levels of LDL-C of mg/dl, and additionally non HDL-C ( mg/dl), pob ( 9 mg/ dl), and hs-crp ( 2 mg/l).

9 Weinstock et al Ezetimibe/simvastatin vs atorvastatin on lipids in T2DM 33 Table 5 Correlation between apolipoprotein B and non high-density lipoprotein cholesterol at 6 weeks Correlation Treatment coefficients* ll patients EZ/all simvastatin.93 ll atorvastatin.95 Patients with baseline TG mg/dl EZ/all simvastatin.95 ll atorvastatin.94 Patients with baseline TG mg/dl EZ/all simvastatin.88 ll atorvastatin.95 EZ, ezetimibe. *P.1 for all. Both LDL-C mg/dl and non HDL-C mg/dl have been recommended as treatment targets for patients at increased risk for CVD, including those with diabetes. 1,4 Non HDL-C is considered to be predictive of increased risk, even after the LDL-C goal is met 4,5 in hypertriglyceridemic patients (TG mg/dl), and it may be a better indicator of both CHD risk and improvements in the atherogenic components associated with diabetic dyslipidemia than LDL-C lowering. 9, 22 Similarly, pob is suggested to be more predictive of CHD risk than LDL-C and may provide a more accurate assessment of lipoprotein atherogenicity than non HDL-C ,23 This is because pob is a direct measurement of atherogenic particle numbers, the concentration of which is considered to be a better indicator of CHD risk than the cholesterol content measured by non HDL-C. 12 In this analysis, attainment of the optional target level of LDL-C mg/dl was comparable in patients with normal and elevated TGs, whereas the proportion of patients who achieved non HDL-C mg/dl and pob 9 mg/dl was reduced in patients with elevated TG compared to those with normal TGs, assessed either as a single or concurrent level of attainment in individuals who also achieved LDL-C levels of mg/dl. These observations are consistent with an increased presence of dyslipidemia in hypertriglyceridemic patients, typified by a preponderance of small, dense LDL particles, and elevated levels of VLDL cholesterol, 2,12,24,25 which may be better reflected by assessment of non HDL-C and pob levels compared to LDL-C in these patients. dditionally, these results are similar to previous statin studies in which the proportion of high-risk patients with elevated TG who achieved specified levels of non HDL-C and pob was lower than those who reached the corresponding target LDL-C levels (National Cholesterol Education Program dult Treatment Panel III), possibly due to higher levels of small, dense LDL and VLDL. 13,24 In this study, slightly higher baseline levels of pob and non HDL-C in the subgroup of patients with TG mg/dl compared to those with TG mg/dl may have also had a small-to-moderate effect on reaching these goals, whereas baseline levels of LDL-C and achievement of LDL-C goal were similar in these groups. Nonetheless, the twofold higher mean baseline level of TG in patients with elevated versus normal TG indicated a higher prevalence of dyslipidemia in these patients. lthough statins in general and ezetimibe have some limited effect in favorably altering lipoprotein subfractions, 26 the effects of and on LDL size, and small, dense, LDL may have contributed to reduced attainment of non HDL-C and pob target levels. Non HDL-C and pob have been shown to be correlative in predicting CHD risk, although in some studies, concordance of this relationship varies, attributed to the metabolic heterogeneity of the populations studied. 29 Consistent with previous statin treatment studies in which baseline levels of TG did not influence the strength of the correlation of non HDL-C with pob, 14,,23,27, 33 this correlation was relatively strong in all patients in this study, regardless of baseline TG levels. Taken together, results of this study support the view that non HDL-C and/or pob may be better indicators of dyslipidemia in diabetes patients than LDL-C lowering,,22 and that these parameters may provide a more reliable assessment of the atherogenic burden in T2DM patients than LDL-C calculated by the Friedewald formula, which becomes less accurate as TG levels increase. 4,27, It should be noted that although non HDL-C and pob have both been shown to be correlative in predicting CHD risk in clinical practice, pob has not replaced measurement of non HDL-C in clinical practice, and it has not been formally recognized as an alternate target for treatment. 11,12 It is increasingly recognized that there is an inflammatory component to atherosclerosis. 17 Inflammation is often assessed by measurements of inflammatory markers, such as hs-crp, and in diabetes patients, elevated levels of hs- CRP may be indicative of CHD risk. 18 Single studies suggest that changes in hs-crp and LDL-C correlate only weakly, however, a recent meta-analysis of LDL-C lowering intervention trials showed a strong correlation of the two. 34 In the VYTL study, although a trend toward better reduction of hs-crp was observed for compared to, this difference was not significant. Similarly, in the present analysis, the percentages of patients who attained levels of hs-crp 2 mg/l were comparable for both treatments; however, significantly greater attainment of hs-crp 2 mg/l was observed in those individuals who also achieved levels of LDL-C mg/dl, including those with baseline hs-crp levels 2 mg/l. Overall, results of this analysis have shown that significantly more patients with T2DM and hypercholesterolemia attained both individual and paired levels of LDL-C mg/dl, non HDL-C mg/dl, and pob 9 mg/dl, following treatment with compared to. lthough attainment of LDL-C mg/dl was unaffected by elevated baseline levels of TG, attainment of non HDL-C mg/dl and pob 9 mg/dl was reduced with

10 34 Journal of Clinical Lipidology, Vol 2, No 1, February 8 higher baseline levels of TG, likely attributed to the presence of mixed dyslipidemia in these patients. These results support the consideration that, in addition to LDL-C lowering, non HDL-C and pob may be important determinants of lipid abnormalities in T2DM patients with hypercholesterolemia, and especially in those also with elevated TG levels. dditionally, attainment of hs-crp 2 mg/l was comparable between treatment groups, and a significantly greater number of patients concurrently achieved levels of LDL-C mg/dl and hs-crp 2 mg/l with treatment compared to. Conclusion Results of this analysis indicate that more patients are able to achieve the optional, recommended levels of LDL-C mg/dl, and additionally, concurrent levels of either non HDL-C mg/dl, pob 9 mg/dl, or hs-crp 2 mg/l, following treatment with the usual recommended starting doses and the next highest doses of the combination compared to. lthough in this study, it was not documented that levels of pob (at all doses) and of hs- CRP were differentially reduced to achieve significance between treatment groups as observed for LDL-C and non HDL-C, did produce achievement of the LDL-C goal when paired with either non HDL-C, pob, or hs-crp at the specified levels in these type 2 diabetics with common forms of dyslipidemia. ssessment of the full clinical benefits of achieving the recommended levels of these factors on the reduction of CVD risk in these patients requires further study in clinical trials. Financial disclosure This work was supported by Merck/Schering-Plough. Drs. Weinstock, Goldberg, Guyton, and Mazzone are investigators in the study and have received honoraria from the company. Drs. Tershakovec, Tomassini, and Shah, and Mr. Polis and Mr. Lin are employees of Merck & Co., Inc. and may own stock/stock options in the company. References 1. merican Diabetes ssociation. Standards of medical care in diabetes 6. Diabetes Care. 6;29(suppl 1):S4 S Solano MP, Goldberg RB. Dyslipidemia and diabetes. Cardiol Rev. 6;14: Garvey WT, Kwon S, Zheng D, et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes. 3;52: Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program dult Treatment Panel III guidelines. 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