Effects of Obesity on Lipid-Lowering, Anti-Inflammatory, and Antiatherosclerotic Benefits of Atorvastatin

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1 Effects of Obesity on Lipid-Lowering, Anti-Inflammatory, and Antiatherosclerotic Benefits of Atorvastatin or Pravastatin in Patients With Coronary Artery Disease (from the REVERSAL Study) Stephen J. Nicholls, MBBS, PhD a,b,c, E. Murat Tuzcu, MD a, Ilke Sipahi, MD a, Paul Schoenhagen, MD a, Stanley L. Hazen, MD, PhD a,b,c, Fady Ntanios, PhD d, Chuan-Chuan Wun, PhD d, and Steven E. Nissen, MD a, * The effect of obesity on atherosclerotic burden and its modulation by lipid-lowering therapy is unknown. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study was analyzed to determine the influence of increasing body mass index (BMI) on plasma lipids, C-reactive protein, plaque burden as determined by intravascular ultrasound, and the serial change in these parameters with a moderate or intensive lipid-lowering strategy. Patients with a higher BMI were younger, more likely to be women, and had a greater prevalence of hypertension, diabetes, and the metabolic syndrome. Although a higher BMI was associated with a lower high-density lipoprotein level and higher triglyceride and C-reactive protein levels, there was no apparent influence of BMI on plaque burden. However, with the intensive lipid-lowering strategy, a greater BMI was associated with a lower proportionate decrease in low-density lipoprotein ( % vs %, p 0.008) and a greater proportionate decrease in C-reactive protein (39.7% vs 33.3%, p <0.04). Further, although moderate and intensive lipid-lowering strategies halted plaque progression in subjects with a lower BMI (median progression rates 1.5% and 1.2%, respectively), a significant effect on plaque progression rates was seen only with adoption of an intensive lipidlowering strategy in the most obese subjects (median progression rate 1.88% vs 6.5% with the moderate lipid-lowering strategy, p 0.01). In conclusion, plaque progression in obese patients is attenuated using an intensive, but not moderate, lipid-lowering strategy. These results highlight the need for aggressive risk factor modification and a decrease in vascular inflammation in obese patients Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97: ) The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL study) employed serial measurements of coronary plaque burden using intravascular ultrasound (IVUS) to examine the effects of statins on progression of atherosclerosis. 1 We analyzed the REVERSAL study to determine whether body mass index (BMI) at baseline influenced the extent of coronary atherosclerosis and ability of lipid-lowering strategies to modify its progression. The Departments of a Cardiovascular Medicine and b Cell Biology and the c Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, Cleveland, Ohio; and d Pfizer, Inc., New York, New York. Manuscript received October 9, 2005; revised manuscript received and accepted December 8, This study was supported by Pfizer, Inc., New York, New York. Dr. Nicholls is supported by a Ralph Reader Overseas Research Fellowship from the National Heart Foundation of Australia, Melbourne, Australia. *Corresponding author: Tel: ; fax: address: nissens@ccf.org (S.E. Nissen). Methods Selection of subjects and regimens: The research protocol of the REVERSAL study has been previously outlined in detail. 1 Patients were enrolled if they were 30 to 75 years of age, undergoing coronary angiography for a clinical indication, and demonstrated 1 obstruction of a major coronary vessel with a luminal diameter narrowing 20%. The target vessel for IVUS analysis was required to have not undergone percutaneous intervention and to have no luminal narrowing 50% in a target segment of 30 mm long. Patients were required to have a low-density lipoprotein cholesterol level of 125 to 210 mg/dl after a 4- to 10- week washout period. After a 4-week discontinuation of lipid-lowering medications and a 2-week placebo run-in period, patients were randomized to receive an intensive lipid-lowering strategy with 80 mg/day of atorvastatin and a pravastatin placebo or a moderate lipid-lowering strategy with 40 mg/day of pravastatin and an atorvastatin placebo. Treatments were administered for an 18-month period. Patients were defined as having the metabolic syndrome if they met the diagnostic criteria of the Adult Treatment /06/$ see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 1554 The American Journal of Cardiology ( Table 1 Baseline clinical characteristics of subjects stratified according to baseline body mass index BMI Below BMI at or Above Median Median p Value Age (yrs) (57.0) (56.0) Weight (kg) (79.5) (101.0) BMI (kg/m 2 ) (26.3) (33.7) Men 78.9% 65.3% White 90.4% 86.5% 0.21 Current smoker 29.1% 23.5% 0.19 Previous or 70.9% 76.5% 0.19 nonsmoker Hypertension 60.2% 76.9% Previous statin use 28.3% 29.1% 0.92 Diabetes mellitus 10.0% 27.9% Metabolic syndrome 13.2% 67.7% Continuous variables are expressed as mean SEM (median). Table 2 Baseline plasma markers stratified according to baseline body mass index Plasma Marker BMI Below BMI at or Median Above Median p Value Total cholesterol (229) (230) 0.96 Low-density lipoprotein (147) (145) 0.55 High-density lipoprotein (42) (39) Triglyceride (155) (191) Apolipoprotein-B (150) (153) 0.39 C-reactive protein (mg/l)* 2 (1 5) 4 (2 7) Data are expressed as mean SEM (median). * Median (interquartile range). Panel III. 2 Because waist circumference was not measured in the REVERSAL study, this component was replaced by abmi 30 kg/m 2. Intravascular ultrasound: An IVUS examination was performed in the longest and least angulated target vessel that met the inclusion criteria, after administration of 100 to 300 g of intracoronary nitroglycerin. A 30-MHz, 2.6Fr (0.87 mm) IVUS catheter (Ultracross, Boston Scientific Scimed, Inc., Maple Grove, Minnesota) was advanced into the target vessel and the transducer was positioned distal to a side branch (distal fiduciary site). The catheter was withdrawn at a speed of 0.5 mm/s by a motor drive. Images were recorded on videotape at 30 frames/s. Cross-sectional images, spaced 1 mm apart in the pullback from a distal to proximal fiduciary site, were analyzed in a blinded fashion. Using National Institutes of Health Image 1.62 (National Institutes of Health, Bethesda, Maryland), manual planimetry was used to trace the leading edges of the luminal and external elastic membrane (EEM) borders. Total atheroma Table 3 Baseline intravascular ultrasound parameters of atherosclerotic burden stratified according to baseline body mass index BMI Below BMI at or p Value Median Above Median Normalized total atheroma volume (mm 3 )* (168) (178) 0.27 Percent atheroma volume (%) (40) (38) 0.48 Atheroma volume in 10-mm subsegment with greatest disease severity (mm 3 ) (67) (71) 0.28 Data are expressed as mean SD (median). * Total atheroma volume was normalized over a length that corresponded to the median number of comparable slices in the treatment groups. volume was calculated as the sum of the differences between EEM and lumen areas across all evaluable slices (i.e., total atheroma volume [EEM area lumen area ]) and was then normalized to the length that corresponded to the median number of comparable slices for each treatment group (normalized total atheroma volume [ (EEM area lumen area )/number of slices in pullback] median number of slices in study population). Percent atheroma volume was calculated as the percentage of the sum of EEM areas that was occupied by total atheroma volume (percent atheroma volume [ (EEM area lumen area )/ (EEM area )] 100). Statistical analysis: All randomized patients who completed the trial were included in the analyses. Analyses were performed with SAS 8.12 (SAS Institute, Cary, North Carolina). Categorical variables are presented as frequencies and percentages, and continuous variables are reported as means SDs and medians. Wilcoxon s signed-rank tests were used for within-treatment comparisons. Comparisons between BMI groups were analyzed by Fisher s exact test for categorical variables and analysis of variance and covariance models for continuous variables. Rank-transformed data were used as the dependent variable for continuous variables when the normality assumption was violated. Log-transformed data for C-reactive protein was used as the dependent variable in analysis of covariance models. A p value 0.05 was considered statistically significant. Results BMI and baseline characteristics: Baseline characteristics of subjects, stratified as above or below the median BMI (29.6 kg/m 2 ), are presented in Table 1. Obese subjects were younger and more often women. Obese subjects also demonstrated a greater prevalence of hypertension, diabetes mellitus, and the metabolic syndrome. More than 67% of patients with a baseline BMI above the median met the diagnostic criteria for the metabolic syndrome. The effect of increasing BMI on plasma markers and atherosclerotic burden is presented in Tables 2 and 3. More obese subjects had lower high-density lipoprotein and higher triglyceride

3 Coronary Artery Disease/Obesity and Atherosclerotic Progression 1555 Table 4 Influence of baseline body mass index on ability of lipid-lowering strategies to modify plasma parameters BMI Below Median (n 251) BMI at or Above Median (n 251) Nominal Change Percent Change Nominal Change Percent Change p Value for Percent Change Between BMI Groups Total cholesterol Pravastatin ( 42) ( 19) ( 47) ( 21) 0.73 Atorvastatin ( 90) ( 40) ( 79) ( 36) Low-density lipoprotein cholesterol Pravastatin ( 40) ( 27) ( 40) ( 29) 0.97 Atorvastatin ( 80) ( 55) ( 67) ( 49) High-density lipoprotein cholesterol Pravastatin 2 9 (2) 6 20 (6) 2 6 (1) 5 17 (3) 0.12 Atorvastatin (0) 3 20 (0) 1 8 (0) 3 19 (0) 0.95 Triglycerides Pravastatin ( 23) 5 52 ( 15) ( 31) 9 43 ( 18) 0.35 Atorvastatin ( 49) ( 35) ( 42) ( 23) 0.04 C-reactive protein (mg/l)* Pravastatin 0.2 ( 1 to1) 7 ( 50 to 63) 0 ( 2 to2) 1 ( 40 to 51) 0.35 Atorvastatin 0.5 ( 2 to0) 33 ( 65 to 16) 1 ( 3 to0) 40 ( 65 to 6) 0.04 Data are expressed as mean SD (median). * Median (interquartile range). plasma concentrations. In contrast, baseline plasma lowdensity lipoprotein concentrations were not influenced by BMI. Plasma C-reactive protein levels at baseline was markedly higher with increasing BMI. More obese subjects had C-reactive protein levels that were nearly 2 times than that observed in subjects with a baseline BMI below the median. Remarkably, despite the enrichment in cardiovascular risk factors within more obese subjects (more hypertension, diabetes, and metabolic syndrome; lower high-density lipoprotein levels; and higher triglyceride and C-reactive protein levels), coronary atheroma burden as monitored by IVUS was not increased in this population. Multiple IVUS measurements of coronary plaque burden, including percent atheroma volume, normalized total atheroma volume, and disease burden in the most diseased 10-mm segment, failed to demonstrate significant differences in obese versus nonobese subjects. BMI and effects of statins on plasma markers: The influence of baseline BMI on change in plasma biomarkers after administration of statin therapy is presented in Table 4. BMI influenced the ability of the intensive, but not of the moderate, strategy to decrease total cholesterol. This resulted primarily from the effect of BMI on the degree of low-density lipoprotein cholesterol lowering. Subjects with a baseline BMI below the median demonstrated the greatest proportionate decrease in total cholesterol, low-density lipoprotein cholesterol, and triglycerides. In contrast, baseline BMI had no effect on degree of changes in high-density lipoprotein cholesterol with use of either statin. The intensive strategy resulted in a greater overall proportionate decrease in C-reactive protein, as reported previously. 3 Interestingly, this effect was greatest in subjects with a baseline BMI greater than the median. In contrast, baseline BMI had no effect on the C-reactive protein response to therapy with pravastatin. BMI and effect of statins on disease burden: The rate of progression of total atheroma volume and percent atheroma volume in the moderate treatment group (pravastatin) was numerically greater than the progression rate in the intensive group (atorvastatin). However, the magnitude of these differences was strongly influenced by baseline BMI. For the 2 end points, the benefits of intensive lipid lowering were greatly magnified in the more obese patients (p 0.01 for total atheroma volume and p for percent atheroma volume). In nonobese patients, increases in total atheroma volume of 1.5% and 1.2% with pravastatin and atorvastatin, respectively, did not differ from baseline. Conversely, in obese patients, there was a significant 6.5% increase in total atheroma volume (p 0.006) with pravastatin and a nonsignificant 1.9% decrease (p 0.64) with atorvastatin. Similarly, for percent atheroma volume, there was a significant 1.4% increase (p ) with pravastatin and a nonsignificant 0.4% increase (p 0.19) with atorvastatin in nonobese patients. In contrast, although percent atheroma volume increased by 1.9% (p ) in obese patients who were treated with pravastatin, there was no change ( 0.04%, p 0.55) with atorvastatin. Although BMI affected the response to therapy in the atorvastatin and pravastatin treatment groups, these effects were opposite in direction for the 2 IVUS end points. Thus, more obese patients actually showed less progression when given intensive therapy with atorvastatin but more progression when given moderate therapy with pravastatin. For the 2 IVUS end points, the change from baseline in the intensive treatment group with a baseline BMI greater than the median was negative, indicating a tendency to plaque regression. However, in the moderate treatment group with a

4 1556 The American Journal of Cardiology ( greater BMI, the change from baseline showed unequivocal progression (p for total volume and p for percent atheroma volume). In the intensive arm, change from baseline in the group with a greater BMI showed no progression (p 0.64 for total atheroma volume and p 0.80 for percent atheroma volume). Discussion The present study found no direct relation between BMI and multiple quantitative indexes of coronary atherosclerotic plaque burden at baseline. However, during 18 months of statin treatment, patients with the highest BMI demonstrated a substantially greater impact on atheroma progression from the intensive rather than from the moderate lipid-lowering strategy. The presence of a higher BMI had an opposite effect on the response to therapy for the pravastatin and atorvastatin treatment groups. Obese patients actually showed more benefit in the atorvastatin arm and less benefit in the pravastatin arm. Accordingly, there was a greater likelihood of regression for the more obese participants in the atorvastatin arm. The reasons for the paradoxic influence of obesity on the efficacy of statin therapy remain uncertain, but the differential nonlipidlowering properties (anti-inflammatory effects) of these agents seems a likely explanation. Although increasing BMI had no influence on atherosclerotic burden in the present study, increased BMI at baseline was associated with higher levels of systemic inflammatory markers. This confirms previous findings of a direct relation between visceral adiposity and systemic levels of inflammatory markers 4,5 and suggests that the greater incidence of clinical events in obese subjects with coronary artery disease may result from an increase in plaque vulnerability. Interestingly, a recent report suggested that several markers of adiposity are associated with the rate of progression of coronary artery calcification. 6 However, calcification scores measure the presence of a single plaque component, whereas IVUS assesses the extent of all atherosclerotic components within the lesion. These differences may explain the disparate findings. These findings provide further evidence in support of the concept that statins possess significant nonlipid-lowering properties in vivo. 7 It is likely that statins inhibit the inflammatory cascade by multiple mechanisms. Statins decrease low-density lipoprotein 8 and oxidative stress, 9 which are key promoters of inflammatory events. In addition, it is becoming increasingly recognized that statins may exert direct anti-inflammatory effects at the level of the arterial wall. Inhibition of isoprenylation by statins results in a decrease in the activation and nuclear translocation of the transcription factor, nuclear factor B. 10 Nuclear factor B plays a central role in directing inflammatory events. Similarly, statins inhibit the modification of proteins by myeloperoxidase-catalyzed reactive nitrogen species. 11 These species have been demonstrated to promote multiple inflammatory pathways. In support of this observation, atorvastatin therapy has been shown to decrease systemic levels of nitrotyrosine, a major product of myeloperoxidase-catalyzed pathways. 12 The ability of statins to modulate each of these inflammatory pathways in obese patients in vivo remains to be clarified. This study has several limitations, including the small sample and lack of placebo-treated patients. Additional markers of adiposity, such as abdominal girth, were not recorded. Similarly, it remains to be determined whether moderate and intensive lipid-lowering strategies exert different effects on several novel inflammatory markers that appear to be regulated by adipose tissue, such as adiponectin, plasminogen activator inhibitor-1, and resistin. Nevertheless, these findings demonstrate that, although there is no relation between BMI and extent of atherosclerotic plaque at baseline, obese patients derive the greatest benefit from an intensive lipid-lowering strategy on the progression of atheroma. This may result from nonlipid-lowering properties of high-dose atorvastatin. Although the specific pathway that confers this benefit remains unclear, the presence of a high systemic inflammatory state in patients with the greatest BMI and the finding that these patients showed the greatest C-reactive protein decrease in response to the intensive lipid-lowering strategy suggest that inhibiting 1 inflammatory pathway may be responsible. This adds further support for the need to target risk factors aggressively in the setting of obesity to prevent the development and progression of coronary artery disease. It also provides strong evidence to support the need to encourage weight loss in patients who are treated with a statin for cardiovascular prevention. 1. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291: Grundy SM. Approach to lipoprotein management in 2001 National Cholesterol Guidelines. Am J Cardiol 2002;90(suppl):11i 21i. 3. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, Orazem J, Magorien RD, O Shaughnessy C, Ganz P. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352: Ferroni P, Basili S, Falco A, Davi G. Inflammation, insulin resistance, and obesity. Curr Atheroscler Rep 2004;6: Toni R, Malaguti A, Castorina S, Roti E, Lechan RM. New paradigms in neuroendocrinology: relationships between obesity, systemic inflammation and the neuroendocrine system. J Endocrinol Invest 2004;27: Cassidy AE, Bielak LF, Zhou Y, Sheedy PF II, Turner ST, Breen JF, Araoz PA, Kullo IJ, Lin X, Peyser PA. Progression of subclinical coronary atherosclerosis: does obesity make a difference? Circulation 2005;111: Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol 2001;21: Schectman G, Hiatt J. Dose-response characteristics of cholesterollowering drug therapies: implications for treatment. Ann Intern Med 1996;125:

5 Coronary Artery Disease/Obesity and Atherosclerotic Progression Stoll LL, McCormick ML, Denning GM, Weintraub NL. Antioxidant effects of statins. Drugs Today (Barc) 2004;40: Inoue I, Itoh F, Aoyagi S, Tazawa S, Kusama H, Akahane M, Mastunaga T, Hayashi K, Awata T, Komoda T, Katayama S. Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/ RXRalpha and decrease the transactivation of NFkappaB. Biochem Biophys Res Commun 2002;290: Shishehbor MH, Brennan ML, Aviles RJ, Fu X, Penn MS, Sprecher DL, Hazen SL. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003;108: Shishehbor MH, Aviles RJ, Brennan ML, Fu X, Goormastic M, Pearce GL, Gokce N, Keaney JF Jr, Penn MS, Sprecher DL, et al. Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA 2003;289: