Diabetes mellitus type 2 and angina pectoris : novel insights in diagnosis, prognosis and treatment Wiersma, J.J.

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1 UvA-DARE (Digital Academic Repository) Diabetes mellitus type 2 and angina pectoris : novel insights in diagnosis, prognosis and treatment Wiersma, J.J. Link to publication Citation for published version (APA): Wiersma, J. J. (2008). Diabetes mellitus type 2 and angina pectoris : novel insights in diagnosis, prognosis and treatment General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 01 Feb 2018

2 C h a p t e r10 High-dose atorvastatin versus usual-dose simvastatin for secondary prevention in patients with cardiovascular disease and diabetes mellitus type 2: sub analysis of the IDEAL trial Jacobijne J Wiersma Lysette N Broekhuizen S Matthijs Boekholdt Erik SG Stroes Mieke D Trip Dick CG Basart John JP Kastelein To be submitted Proefschrift Wiersma.indb :59:09

3 Abstract 150 Background Intensive lowering of low-density lipoprotein cholesterol (LDL-c) with high-dose statin therapy compared with standard-dose therapy results in additional reduction of cardiovascular events in patients with previous myocardial infarction (MI). Whether similar benefits can be achieved in patients with diabetes mellitus with a previous MI has not been investigated thoroughly. Methods The prospective randomized open-label IDEAL trial randomized people with a previous MI to receive high-dose atorvastatin (80 mg daily) vs. usual-dose simvastatin (20 mg daily). In this sub analysis, we analyzed a total of 1069 patients with diabetes mellitus and previous MI. Patients were followed for a mean period of 4.8 years. Occurrence of major coronary events (coronary death, nonfatal acute MI or cardiac arrest with resuscitation) was defined as the primary outcome. Results Baseline levels of LDL-c were 116 mg/dl for both treatment groups. Treatment with high-dose atorvastatin 80 mg daily resulted in a significant LDL-c reduction by 36% compared with 11% with simvastatin 20 mg daily (p<0.001). The primary outcome occurred in 73 (13.7%) patients receiving atorvastatin and 74 (13.8%) patients receiving simvastatin (hazard ratio 1.03, 95%CI 0.74 to 1.42, p=ns). Analyses for secondary outcomes including any cardiovascular event and any coronary heart disease also showed non-significant differences between the treatment groups. Conclusion In this sub analysis of the IDEAL trial among diabetic patients with prior MI, there was a slight indication that high-dose statin therapy has less effect on the population with diabetes mellitus compared with the non-diabetic patients. However, no differences in treatment effects between diabetics and non-diabetic patients were observed. Proefschrift Wiersma.indb :59:10

4 Introduction Diabetes mellitus type 2 is a worldwide epidemic, and its prevalence is rapidly increasing in both developing and developed countries 1. Coronary heart disease (CHD) is the major cause of morbidity and mortality among patients with diabetes 2, 3. Furthermore, diabetic patients with a prior history of myocardial infarction have a poorer prognosis and a higher mortality rate than non-diabetics with a prior myocardial infarction 4, 5. Diabetes mellitus is associated with a specific dyslipidemia that is characterized by hypertriglyceridemia, reduced levels of high-density lipoprotein cholesterol (HDL-c), and a preponderance of small dense low density lipoprotein (LDL) particles 6, 7. Modifying this dyslipidemia with statin therapy has been shown to dramatically reduce cardiovascular risk among patients with diabetes, even in the absence of prevalent CHD In recent years, several trials have tested the efficacy and safety of high-dose versus usual-dose statin therapy for secondary prevention of CHD These trials have shown incremental benefit of intensive lipid-lowering by high-dose statin therapy 17. Whether this clinical benefit extends to patients with diabetes mellitus and prevalent CHD has been investigated in two sub analyses of these trials, with inconsistent results 18, 19. The IDEAL (Incremental Decrease in End points through Aggressive Lipid Chapter Statin therapy in diabetics, sub analysis of IDEAL Lowering) trial was designed to investigate the efficacy and safety of aggressive lipid lowering therapy with atorvastatin 80 mg compared to usual-dose simvastatin 20 mg in patients with previous myocardial infarction. Although the incremental reduction of the primary outcome of major coronary events with high-dose versus usual-dose statin therapy was non-significant, there were significant reductions in the risk for other outcomes, including non-fatal myocardial infarction and coronary revascularization. The objective of this analysis was to investigate whether high-dose versus usual-dose statin treatment resulted in an incremental reduction in cardiovascular risk among patients with prevalent CHD and diabetes mellitus type 2. Methods Study design This was a pre-specified sub analysis of the IDEAL trial to evaluate the effect of highdose atorvastatin (80 mg daily) compared with usual-dose simvastatin (20 mg daily) in 1069 patients with diabetes mellitus. Patients were included in the current analysis if they had a prior history of diabetes mellitus, except for uncontrolled diabetes, which Proefschrift Wiersma.indb :59:10

5 Figure 1. Flow of diabetic participants diabetics at baseline 532 Atorvastatin 537 Simvastatin 8888 randomized subjects 4439 Atorvastatin 4449 Simvastatin 7819 non-diabetics at baseline 3907 Atorvastatin 3912 Simvastatin 232 discontinued 134 Atorvastatin 98 Simvastatin 1438 discontinued 845 Atorvastatin 593 Simvastatin was an exclusion criterion. Detailed descriptions of the study design and of the principal results have been published previously 15, 20. Briefly, 8888 men and women aged 80 years or younger with a history of a definite myocardial infarction were enrolled. Recruitment and randomization took place from March 1999 to March 2001 and patients were followed up until March After dietary counseling, patients fulfilling the eligibility criteria were randomized to receive simvastatin 20 mg daily or atorvastatin 80 mg daily (Figure 1). Patients were followed at the participating centers after 12 and 24 weeks and every 6 months thereafter. The dose of simvastatin could be increased to 40 mg if, at 24 weeks, plasma total cholesterol level was higher than 190 mg/dl (5.0 mmol/l). The dose of atorvastatin could be decreased to 40 mg in case of adverse events. If LDL-c decreased to less than 39 mg/dl (1.0 mmol/l), an investigator would be notified and could consider reducing the statin dose. All lipid and lipoprotein levels were measured from fasting blood samples. Measurements were made at baseline, at 12 and 24 weeks, at 1 year, and yearly thereafter. All measurements were made at a central laboratory. The results of lipid and lipoprotein measurements were not revealed to study personnel during the study except in cases of titration of simvastatin at 24 weeks. Study outcomes The primary outcome was time to first occurrence of a major coronary event, defined as coronary death, hospitalization for nonfatal acute myocardial infarction, or cardiac arrest with resuscitation. Potential myocardial infarction cases were adjudicated according to current guidelines of the Joint European Society of Cardiology/American College of Cardiology 21. There were 3 pre-specified composite secondary outcomes: (1) major cardiovascular events (any primary event plus stroke; the diagnosis of stroke required evidence of a neurological deficit, usually localized, lasting 24 hours or until death, Proefschrift Wiersma.indb :59:10

6 usually confirmed by diagnostic imaging); (2) any CHD event (any primary event, any coronary revascularization procedure, or hospitalization for unstable angina); (3) any cardiovascular event (any of the former plus hospitalization with a primary diagnosis of congestive heart failure and peripheral arterial disease, defined as new clinical diagnosis or hospitalization for such disease). In addition, individual components of the composite end points were also pre-specified as secondary outcomes, as was all-cause mortality. Statistical Analysis Based on previous experience, it was projected that therapy with simvastatin 20 mg daily would result in a mean 35% LDL-c reduction from untreated levels, while the reduction with atorvastatin 80 mg daily was estimated at 55%, creating a difference in LDL-c plasma levels of about 40 mg/dl (1 mmol/l). Data are presented as number of patients (%), mean (standard deviation (SD)) or as median (interquartile range, (IQR)). Continuous baseline variables were compared by Student s unpaired t test or Mann-Whitney test; categorical variables were compared by χ 2 or Fisher s exact test where appropriate. Lipid changes at 1 year were calculated using analysis of covariance (ANCOVA) with baseline levels as covariate. Percent changes and confidence intervals were based on least squares means. Kaplan-Meier hazard rates were calculated to quantify the incidence of outcome occurrence during follow-up, and a log-rank test was used to calculate the difference between survival curves by treatment allocation. Hazard ratios (HR s) and their 95% confidence intervals (95%CI) were calculated using a Cox proportional hazards model. Tests for heterogeneity were used to determine whether the treatment effects observed in patients with diabetes differed from patients without diabetes. Statistical analysis was performed using SAS, version 8.2 (SAS Institute Inc, Cary, NC). All analyses in this report are based on the intention-to-treat principle including all randomized patients who had diabetes at baseline. Two-sided P values of <.05 were regarded as statistically significant. Chapter Statin therapy in diabetics, sub analysis of IDEAL Results This report is based on 1069 patients with known diabetes at baseline, representing 12% of the total of 8888 patients randomized in the IDEAL trial. Compared to the total IDEAL study population, patients with diabetes mellitus were slightly older, more overweight, and had slightly higher systolic blood pressure. Diabetics were more Proefschrift Wiersma.indb :59:10

7 154 likely to have experienced more than one previous MI. Baseline LDL-c (121 mg/dl vs. 116 mg/dl) and total cholesterol (195 mg/dl vs. 191 mg/dl) levels were higher in the non-diabetic patients, as were levels of triglycerides (173 mg/dl vs. 148 mg/dl). Baseline HDL-c levels were lower in the diabetic patients (43 mg/dl vs. 46 mg/dl). The distribution of diabetic subjects was nearly identically between the atorvastatin and simvastatin groups. Figure 1 shows the breakdown of subjects in the atorvastatin and simvastatin groups by diabetic status. A total of 532 patients were allocated to high-dose atorvastatin and 537 patients were randomized to usual-dose simvastatin. By the end of the study 232 diabetic patients had discontinued study medication, 134 patients in the atorvastatin group and 98 patients in the simvastatin group. Most patients switched to a different statin. Baseline characteristics and baseline cholesterol levels of the diabetic patients were similar between the two treatment groups (table 1). The majority of patients were of male gender, approximately three quarter of patients had a current or previous history of smoking and the mean body mass index was 29 kg/m 2. Patients had moderately regulated glucose levels of approximately 160 mg/dl (8.9 mmol/l), with glycosated hemoglobin of 6.6%. People randomized to high-dose and usual-dose statin therapy had baseline LDL-c levels of ± 35.1 and ± 34.8 mg/dl, HDL-c levels of 42.9 ± 10.4 and 43.0 ± 11.8 mg/dl and triglyceride levels of ± 90.0 and ± mg/dl, respectively. Lipid changes At one year follow-up, treatment with atorvastatin 80 mg led to an average decrease in LDL-c levels of 35.69% (95%CI to ), compared with a decrease of 13.98% (95%CI to ) in patients on simvastatin therapy, p<0.001 (table 2). Triglyceride concentrations were lowered by 14.2% (95%CI to ) in the atorvastatin group compared with 5.2 % (95%CI 1.98 to 8.36) in the simvastatin group (p<0.001). Use of atorvastatin resulted in a decrease of HDL-c levels of 3.35% (95%CI to -1.86) compared with a small increase of 0.75% (95%CI to 2.23) in patients receiving simvastatin (p=0.001). These findings are comparable with the findings in non-diabetic patients, although the beneficial effect of treatment on HDL-c and apoa-i concentrations was more apparent in non-diabetic patients. For apoa-i levels, diabetes status had a borderline significant effect on the treatment-induced changes of lipoprotein levels at 1-year follow-up (p for interaction = 0.045). For the other lipid and lipoprotein levels, no significant differences of treatment effects at 1-year follow-up were observed between the diabetic and non-diabetic patients (p-values for heterogeneity >0.05 for each). Proefschrift Wiersma.indb :59:10

8 Table 1. Baseline characteristics. Characteristics Simvastatin 20 mg N=537 Atorvastatin 80 mg N=532 Age (years) 63.2 ± ± 8.9 Male sex 432 (80.4%) 403 (75.8%) Smoking - current 93 (17.3%) 77 (14.5%) - previous 321 (59.8%) 317 (59.6%) - never 123 (22.9%) 138 (25.9%) Systolic blood pressure (mmhg) ± ± 20.0 Diastolic blood pressure (mmhg) 80.2 ± ± 10.1 BMI (kg/m2) 28.9 ± ± 4.5 Total cholesterol (mg/dl) ± ± 41.7 LDL cholesterol (mg/dl) ± ± 34.8 HDL cholesterol (mg/dl) 42.9 ± ± 11.8 Triglycerides (mg/dl) ± ± Apolipoprotein A-I (g/l) 1.3 ± ± 0.2 Apolipoprotein B (g/l) 1.2 ± ± 0.3 Fasting glucose (mg/dl) ± ± 53.0 HbA1C (%) 6.6 ± ± 1.2 Prevalent disease >1 Previous MI 126 (23.5%) 111 (20.9%) 2 months since last MI 58 (10.8%) 55 (10.3%) Coronary angioplasty only 71 (13.2%) 87 (16.4%) CABG surgery only 115 (21.4%) 112 (21.1%) Both angioplasty and CABG 25 (4.7%) 21 (4.0%) Table 1. Baseline characteristics of diabetes patients enrolled in the IDEAL trial by randomization status. Data are presented as mean ± standard deviation or number (percentage). Abbreviations: BMI= body mass index; LDL= low-density lipoprotein; HDL=high-density-lipoprotein; MI=myocardial infarction;cabg=coronary artery bypass grafting. To convert LDL-c, HDL-c and total cholesterol to mmol/l, multiply by To convert triglycerides to mmol/l, multiply by Chapter Statin therapy in diabetics, sub analysis of IDEAL Primary and secondary outcomes In the IDEAL trial, the primary outcome of coronary death, nonfatal MI, or cardiac arrest with resuscitation occurred in 9.3% of patients receiving atorvastatin and in 10.4% of patients receiving simvastatin, (HR 0.88, 95%CI 0.77 to 1.01, p=0.07), as described previously (figure 2). 15 Among people with diabetes at baseline 73 (13.7%) in the atorvastatin group experienced a primary outcome during follow-up compared with 74 (13.8%) in the simvastatin group (HR 1.03, 95%CI 0.74 to 1.42, p=ns) (table 3.). Furthermore in the IDEAL study, the secondary outcomes: any CHD event, major and any cardiovascular event and peripheral arterial disease and the occurrence of myocardial infarction, were reduced in favor of high-dose atorvastatin treatment. In the diabetic population, intensive lipid lowering with high-dose atorvastatin did not result Proefschrift Wiersma.indb :59:10

9 156 Table 2. Lipid and lipoprotein changes by treatment allocation at 1 year follow-up Percentage change (1-year vs. baseline) Simvastatin 20 mg P-values Atorvastatin 80 mg Difference H geneity Total cholesterol Diabetes (-10.64, -8.04) (-27.29, ) <.0001 No diabetes (-8.46, -7.52) (-23.47, ) < LDL-cholesterol Diabetes (-15.84, ) (-37.54, ) <.0001 No diabetes (-12.05, ) (-32.21, ) < HDL-cholesterol Diabetes 0.75 (-0.73, 2.23) (-4.84, -1.86) No diabetes 3.68 (3.14, 4.22) 1.09 (0.54, 1.64) < Triglycerides Diabetes 5.17 (1.98, 8.36) (-17.36, ) <.0001 No diabetes (-2.42, -0.10) (-19.12, ) < Apolipoprotein A-I Diabetes 2.76 (1.76, 3.77) (-4.15, -2.13) <.0001 No diabetes 4.60 (4.23, 4.96) 0.25 (-0.13, 0.62) < Apolipoprotein B Diabetes (-7.38, -3.68) (-29.27, ) <.0001 No diabetes (-7.48, -6.14) (-27.71, ) < Table 2. Data presented are percent changes 1 year follow-up compared to baseline along with 95% confidence intervals. P-values for difference concern the difference between simvastatin and atorvastatin groups within each diabetic category. P-values for heterogeneity concerns testing for interaction between treatment effect and diabetic status. All results are calculated by analysis of covariance (ANCOVA) with terms for treatment, diabetic status, and diabetic status by treatment interaction, and using baseline level as covariate. The percent changes and confidence intervals are based on least squares means. in significant reductions of any of the pre-defined secondary outcomes (figure 2, table 3). However, for all individual outcomes, 95% confidence intervals overlap for diabetic and non-diabetic populations indicating that the treatment effects are comparable between diabetics and non-diabetics. In support, tests for heterogeneity of treatment effect by diabetes status were non-significant for all outcomes. Cox regression models of primary and secondary outcomes were fitted to subsets of the diabetic population defined by lipid parameters (LDL-c or mg/dl, HDL-c or 38.7 mg/dl, triglycerides or 150 mg/dl and apob or 1.1 g/l). Tests for heterogeneity of treatment effects by baseline lipid or lipoprotein levels were all non-significant. Discussion Recent trials suggest that high-dose statin therapy is more effective than standard-dose therapy in reducing cardiovascular risk among patients with prevalent cardiovascular disease 13, 22. On the other hand, both the IDEAL trial and the A-to-Z trial did not reach statistical significance for their pre-specified primary outcome. A meta-analysis of the Proefschrift Wiersma.indb :59:10

10 Figure 2. Proportions and hazard ratios of primary and secondary outcomes Chapter Statin therapy in diabetics, sub analysis of IDEAL Hazard ratios for primary and secondary outcomes in patients with and without diabetes. occurrence of a major coronary event, defined as coronary death, hospitalization for nonfatal acute myocardial infarction, or cardiac arrest with resuscitation. 4 randomized studies comparing high-dose versus usual-dose statin therapy enrolling a total of 27,548 patients, concluded that high-dose statin therapy had significant benefit in preventing predominantly non-fatal cardiovascular events 17. Part of the differences in outcome between the above-mentioned randomized trials can be related to the differences between study populations and outcome definitions 15. Proefschrift Wiersma.indb :59:11

11 158 Table 3. Proportions and hazard ratios of primary and secondary outcomes Proportions Simvastatin Atorvastatin 20 mg 80 mg P Values HR 95% CI Difference H geneity Major coronary events No Diabetes 389 (9.9%) 338 (8.7%) 0.86 (0.74, 1.00) Diabetes 74 (13.8%) 73 (13.7%) 1.03 (0.74, 1.42) Any cardiovascular event No Diabetes 1173 (30.0%)1001 (25.6%) 0.83 (0.76, 0.90) <.0001 Diabetes 197 (36.7%) 175 (32.9%) 0.91 (0.74, 1.12) Major cardiovascular event No Diabetes 504 (12.9%) 439 (11.2%) 0.86 (0.75, 0.97) Diabetes 104 (19.4%) 94 (17.7%) 0.94 (0.71, 1.24) Any CHD No Diabetes 922 (23.6%) 774 (19.8%) 0.83 (0.75, 0.91) <.0001 Diabetes 137 (25.5%) 124 (23.3%) 0.93 (0.73, 1.18) (non)-fatal stroke No Diabetes 136 (3.5%) 122 (3.1%) 0.88 (0.69, 1.12) 0.3 Diabetes 38 (7.1%) 29 (5.5%) 0.81 (0.50, 1.31) Peripheral arterial disease No Diabetes 141 (3.6%) 103 (2.6%) 0.72 (0.56, 0.93) Diabetes 26 (4.8%) 24 (4.5%) 0.97 (0.56, 1.69) All-cause mortality No Diabetes 306 (7.8%) 303 (7.8%) 0.98 (0.83, 1.14) 0.8 Diabetes 68(12.7%) 63 (11.8%) 0.97 (0.69, 1.37) Table 3. Results of Cox regression models of diabetic and non-diabetic patients. Data are presented as proportions (number (percentage), and hazard ratios (HR) (95%CI). P-values for differences is a test of treatment effect in each group. The single p-value for heterogeneity test for diabetes by treatment interaction. In the current sub analysis of the IDEAL trial we observed that although high-dose atorvastatin resulted in a significantly larger LDL-c reduction of 36% versus 14% in the standard-dose group, the reduction of the primary outcome was comparable, approximately 14%. Among people without diabetes, high-dose atorvastatin resulted in an absolute LDL-c reduction of 22.9% (95%CI to -21.8) at 1 year: from mg/dl to 79.1 mg/dl in the atorvastatin group compared with mg/dl to mg/dl in the simvastatin group. The reduction in the primary outcome was 9.3% in atorvastatin treated patients vs. 10.4%, p=0.07. Although the point estimates for risk of major coronary events were substantially different, the confidence intervals overlap and the results are therefore consistent with each other. Our results are consistent with two recent post-hoc analyses of other trials comparing different statin dosing regimens. Similar non-significant trends were found in the diabetic sub analysis of the PROVE IT-TIMI 22 study regarding their primary outcome, although significance was found in the occurrence of the secondary outcome of acute cardiac events, which consisted of cardiac death, non-fatal MI and hospitalization for unstable angina (21.1% vs. 26.6% reduction, p=0.03) 19. However the follow-up of these ± 900 patients was only two years and the study may have been underpowered to reach significant differences. The recently published sub-analysis of the TNT study did find a significant positive effect of high- Proefschrift Wiersma.indb :59:11

12 dose atorvastatin in 1501 diabetic patients, with significantly less primary outcomes (cardiac death, non-fatal MI, resuscitated cardiac arrest or fatal and non-fatal stroke) (13.8% vs. 17.9%, p=0.02) and less cerebrovascular events (7.0% vs. 10%, p=0.04) 18. However, no significant differences were found in the rates of their secondary outcome major coronary events (comparable with the primary outcome of the IDEAL study), between the high-dose versus standard-dose therapy, as described as a confidence interval crossing unity. Moreover the non-significant outcomes of peripheral disease and all-cause mortality are also comparable between these two trials. The diabetics in the TNT trial were younger, less often of male gender, more obese and with lower baseline level of LDL-c and total cholesterol and higher levels of HDL-c. Furthermore, inclusion criteria of the TNT also included patients who underwent revascularization and patients with (a history of) angina pectoris. These differences in characteristics might explain the overall slightly lower event rates in these diabetics compared with our diabetics. Subsequently, the lower baseline cholesterol levels result in lower endof-treatment levels which provide an explanation for the different outcomes of primary outcomes between the two trials. Secondly, a lack of statistical power in the IDEAL sub study may have resulted in a non-significant finding. The IDEAL trial was designed to have 90% power to detect an anticipated 21% relative risk reduction (from 10% to 7.9%) in the primary outcome variable with atorvastatin over 5 years using a 2-tailed level of.05. Given these estimates, the current sub analysis is underpowered to detect the pre-specified relative risk reduction of 21% and approximately 3000 patients per group would have be needed for sufficient power. Chapter Statin therapy in diabetics, sub analysis of IDEAL An important observation in this diabetic cohort is that HDL-c levels were decreased with 3.35% in diabetic patients receiving high-dose atorvastatin. No such reduction was found in both the diabetic patients receiving low-dose statin therapy and the nondiabetic group. We therefore hypothesize that although high-dose statin therapy has beneficial effects in reducing LDL-c levels in diabetics, this high dose statin therapy also leads to a reduction of the anti-atherogenic HDL-c levels. This second effect might explain the non-significant differences of the primary and secondary outcomes. One might speculate based on these findings that diabetics with a prior MI may benefit from a high dose statin therapy in combination with a HDL-increasing drug. Unfortunately, both the sub analyses of the TNT-study and the PROVE-IT study provided no information on levels of HDL-c after treatment with high-dose treatment to support our hypothesis. Proefschrift Wiersma.indb :59:11

13 160 The potential cardiovascular benefits of statin therapy observed in this IDEAL sub analysis are also consistent with findings in previous diabetic analyses 8, 10, 12, 23. Moreover, due to the high-dose statin therapy, LDL-c levels were reduced significantly to or beyond recommended targets. These targets are based on the guidelines of the NCEP ATP III and the ADA for treatment of diabetic patients with established coronary artery disease at high risk for cardiovascular events, and they stated that on must primarily focus on lifestyle and LDL-c reduction with at least 30%, to a target of <70 mg/dl. The percentage reduction found in our study is comparable with the subanalyses of the TNT and PROVE-IT-TIMI-22 trials, between 30-44%. Conclusion It is well established that statin therapy results in a significant reduction of cardiovascular risk among patients with diabetes and a prior MI, and also that high-dose statin therapy results in incremental risk reduction compared with usual-dose statin therapy. The IDEAL study found an, albeit non-significant, reduction of the primary outcome of major coronary events with high-dose versus usual-dose statin therapy. However, high-dose statin therapy did result in significant reduction of secondary endpoints, including non-fatal myocardial infarction and coronary revascularization. In this sub analysis of the IDEAL trial among diabetic patients with prior MI, there was a slight indication that high-dose statin therapy had less effect on the population with diabetes mellitus compared with the non-diabetic patients, but we did not see any differences in treatment effects between diabetics and non-diabetic patients. Based on our data, we can hypothesize that diabetic patients may benefit from a combination of high-dose statin therapy with HDL-increasing therapy. Proefschrift Wiersma.indb :59:11

14 Reference List (1) Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for Diabetes Care 2004 May;27(5): (2) Bonow RO, Gheorghiade M. The diabetes epidemic: a national and global crisis. The American Journal of Medicine 2004 March 8;116(5, Supplement 1):2-10. (3) Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care 1979 March 1;2(2): (4) Miettinen H, Lehto S, Salomaa V et al. Impact of diabetes on mortality after the first myocardial infarction. The FINMONICA Myocardial Infarction Register Study Group. Diabetes Care 1998 January 1;21(1): (5) Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993 February 1;16(2): (6) Nesto RW. Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome. Am J Cardiovasc Drugs 2005;5(6): (7) Syvanne M, Taskinen MR. Lipids and lipoproteins as coronary risk factors in non-insulindependent diabetes mellitus. The Lancet 1997 July;350(Supplement 1):S20-S23. (8) Colhoun HM, Betteridge DJ, Durrington PN et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004 August 21;364(9435): (9) Haffner SM, Alexander CM, Cook TJ et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999 December 13;159(22): (10) Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. The Lancet 2003 June 14;361(9374): (11) Keech A, Simes RJ, Barter P et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005 November 26;366(9500): (12) Keech A, Colquhoun D, Best J et al. Secondary Prevention of Cardiovascular Events With Long- Term Pravastatin in Patients With Diabetes or Impaired Fasting Glucose: Results from the LIPID trial. Diabetes Care 2003 October 1;26(10): (13) LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005 April 7;352(14): (14) de Lemos JA, Blazing MA, Wiviott SD et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004 September 15;292(11): (15) Pedersen TR, Faergeman O, Kastelein JJ et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005 November 16;294(19): (16) Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004 April 8;350(15): (17) Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006 August 1;48(3): (18) Shepherd J, Barter P, Carmena R et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care 2006 June;29(6): Chapter Statin therapy in diabetics, sub analysis of IDEAL Proefschrift Wiersma.indb :59:12

15 162 (19) Ahmed S, Cannon CP, Murphy SA, Braunwald E. Acute coronary syndromes and diabetes: Is intensive lipid lowering beneficial? Results of the PROVE IT-TIMI 22 trial. Eur Heart J 2006 October;27(19): (20) Pedersen TR, Faergeman O, Kastelein JJ et al. Design and baseline characteristics of the Incremental Decrease in End Points through Aggressive Lipid Lowering study. Am J Cardiol 2004 September 15;94(6): (21) Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined--a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000 September;36(3): (22) Ray KK, Cannon CP, McCabe CH et al. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005 October 18;46(8): (23) Goldberg RB, Mellies MJ, Sacks FM et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation 1998 December 8;98(23): Proefschrift Wiersma.indb :59:12

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