Dyslipidemia in patients with diabetes is characterized by high triglyceride levels, an increased number of small, dense LDL particles, and low levels of HDL cholesterol. Overall LDL cholesterol may also be elevated. High triglyceride levels manifest as high triglyceride-rich remnant lipoproteins (VLDL) and alter the metabolism of LDL and HDL particles. Because a mixed dyslipidemic profile increases the risk of developing cardiovascular disease, it is also referred to as the atherogenic lipid triad or atherogenic dyslipidemia. Atherogenic dyslipidemia contributes to an increased risk for cardiovascular disease.
Atherogenic dyslipidemia arises from disordered metabolism of VLDL which leads to concordant enrichment of LDL and HDL particles with triglycerides through the action of cholesteryl ester transfer protein. Subsequent triglyceride hydrolysis in these particles by hepatic lipase leads to smaller, denser LDL and HDL, and depletion of apolipoprotein AI from HDL. A portion of this apolipoprotein AI undergoes renal clearance, resulting in lower plasma apolipoprotein AI concentrations.
In all of these major statin trials, significant residual cardiovascular risk remains even after reducing LDL cholesterol. According to Libby, in the best of circumstances, the decrease in cardiovascular events due to statin treatment still allows two-thirds of cardiovascular events to occur. Libby concludes, “To address the majority of cardiovascular events that still occur despite our most powerful existing therapies, we must combine lifestyle change and evaluate new pharmacological strategies that will move us toward the goal of eradicating cardiovascular disease in the future.” 4S: Scandinavian Simvastatin Survival Study LIPID: Long-Term Intervention with Pravastatin in Ischaemic Disease CARE: Cholesterol and Recurrent Events HPS: Heart Protection Study WOS: West of Scotland Coronary Prevention Study AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study
This meta-analysis of 17 population-based prospective studies of triglycerides and cardiovascular disease (CVD) demonstrated that triglyceride level is a significant, independent risk factor for CVD. In univariate analysis (nonadjusted), an increase in triglycerides of 89 mg/dl (1.00 mmol/l) was associated with a significant 1.32-fold increased CVD risk in men (n=46,413) and a significant 1.76-fold increased CVD risk in women (n=10,864). In a multivariate analysis (after adjusting for HDL cholesterol levels), an increase in triglycerides of 89 mg/dl was associated with a significant 1.14-fold increased CVD risk in men (n=22,293) and a significant 1.37-fold increased CVD risk in women (n=6,345). The important finding from this study is that even after adjusting for HDL cholesterol, a statistically significant increase in the risk of CVD was associated with high triglyceride levels for both men and women, corroborating that triglyceride level is an independent risk factor for CVD for both sexes.
Although statins reduce LDL cholesterol and cardiovascular disease (CVD) risk, statins do not eliminate CVD risk associated with high triglycerides. The CVD event rates (coronary heart disease death, nonfatal myocardial infarction, percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting) from the pooled analysis of Cholesterol and Recurrent Events (CARE) and Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) (n=13,173) are plotted according to quintiles of baseline triglyceride levels. Lines are best fit linear regressions with the entire range of baseline triglyceride concentrations. The high CVD risk associated with a high triglyceride level is not eliminated by statin therapy.
In the Framingham Heart Study, increased levels of LDL cholesterol and reduced levels of HDL cholesterol contribute independently to risk of coronary heart disease.
Analysis of event rates from the Heart Protection Study (HPS) and the pooled analysis of Cholesterol and Recurrent Events (CARE)/Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) event rates revealed that statin therapy does not eliminate the cardiovascular disease (CVD) risk associated with low HDL cholesterol levels. In HPS, high HDL cholesterol was defined as ≥43 mg/dl (1.11 mmol/l), and low HDL cholesterol was defined as <35 mg/dl (0.90 mmol/l). In the pooled CARE/LIPID analysis, high HDL cholesterol was defined as >44 mg/dl (1.14 mmol/l), and low HDL cholesterol was defined as <30 mg/dl (0.78 mmol/l). Patients with low HDL cholesterol treated with statins have higher CVD event rates (i.e., residual CVD risk) than patients with high HDL cholesterol treated with statins. Thus, the high CVD risk associated with a low HDL cholesterol level is not eliminated by statin therapy.
In the Boston Area Heart Study, a case-control analysis showed increased relative risk for myocardial infarction with increasing quartiles of triglyceride. As in other studies, this risk was attenuated by adjusting triglyceride levels for HDL cholesterol. However, a very strong risk relationship was observed with consideration of both high triglycerides and low HDL, as assessed by the triglyceride/HDL cholesterol ratio. Subsequent studies have shown that this ratio is related to a number of other atherogenic indices, including small LDL diameter, reduced insulin sensitivity as well as fractional HDL esterification rate, the latter being a component of reverse cholesterol transport.
In addition to the fact that small LDL is a marker for a spectrum of metabolic risk factors for cardiovascular disease, there are a number of properties of smaller LDL particles that may contribute directly to disease risk. These include reduced LDL receptor affinity and slower plasma clearance, greater uptake and binding to arterial proteoglycans, and more rapid oxidation. In addition, since smaller particles carry less cholesterol than larger cholesterol, at any given level of LDL cholesterol, individuals with smaller LDL (LDL phenotype B) have a greater number of LDL particles. Since there is one apolipoprotein B molecule per LDL particle, plasma apolipoprotein B level is an index of total LDL particles, and in general is correlated with plasma levels of small LDL.
The Triglyceride Reduction in Metabolic Syndrome (TRIMS) study was designed to assess the effects of fenofibrate therapy on atherogenic dyslipidemia in patients with the metabolic syndrome and hypertriglyceridemia [triglycerides ≥300 mg/dl (3.39 mmol/l) and <1,000 mg/dl (11.3 mmol/l)]. The results emphasized in this slide demonstrate that a favourable shift in LDL particle size (from small, dense LDL particles to larger, more buoyant LDL particles) is strongly associated with end-of-treatment triglyceride values. The left panel shows that those patients with end-of-treatment triglyceride levels <200 mg/dl (2.26 mmol/l) (n=22) showed the largest median increase in LDL particle diameter (0.56 nm), while those with higher end-of-treatment triglyceride levels (200-299 mg/dl; 2.26-3.38 mmol/l) (n=33) showed a median increase in LDL particle diameter of 0.31 nm, and those with end-of-treatment triglyceride levels of ≥300 (3.39 mmol/l) (n=29) showed essentially no change in LDL particle diameter (median increase of 0.02 nm). Thus, there was a significant inverse relationship between end-of-treatment triglyceride value and change in LDL particle diameter (p value for trend=0.019). The right panel shows that when 26 patients were individually matched for % change from baseline triglyceride concentrations (~52% reduction), those patients with end-of-treatment triglyceride levels <200 mg/dl (2.26 mmol/l) (n=13) experienced a significant reduction in the amount of cholesterol carried by small, dense LDL particles (39%), a significant increase in the amount of cholesterol carried by large, buoyant LDL particles (135%), and a significant reduction in LDL particle number (21%), compared with those patients with end-of-treatment triglyceride levels ≥200 mg/dl (2.26 mmol/l) (n=13). This data collectively supports the conclusion that a threshold exists below which the triglyceride level must be reduced (<200 mg/dl) in order to produce favourable shifts in LDL particle size. Note: large LDL=23.0-20.6 nm; small LDL=20.5-18.0 nm
The Coronary Drug Project, conducted during 1966 to 1974, was a randomized, double-blind, placebo-controlled trial of 5 lipid-modifying agents in 8,341 men with previous myocardial infarction. Among the 5 drug treatment regimens, only niacin significantly reduced the risk of (1) cardiovascular events during a mean follow-up of 6.2 years and (2) total mortality during 6.2 years with study treatment plus an additional 9 years of post-trial follow-up.
In the Coronary Drug project, a retrospective analysis indicated reduced risk for nonfatal myocardial infarction across the full spectrum of plasma glucose levels, with the greatest benefit in those who would now be classified as having type 2 diabetes.
ADVENT (Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan® Trial) evaluated the efficacy and safety of Niaspan in patients with dyslipidemia associated with type 2 diabetes. During a 16-week, double-blind, placebo-controlled trial, 148 patients with stable type 2 diabetes were randomized to placebo (n=49) or 1,000 (n=45) or 1,500 mg/day (n=52) of Niaspan. Sixty-nine patients (47%) also received concomitant therapy with statins. The primary safety endpoint variable was the change from baseline to week 16 in HbA1c level. The primary efficacy endpoint variables were the changes from baseline to week 16 in HDL cholesterol and triglyceride levels. Niaspan had a significant effect on HDL cholesterol, which increased from baseline in a dose-dependent manner and was significantly greater compared with placebo at all study visits. A dose-related reduction in triglyceride levels also occurred in the Niaspan treatment groups. During treatment, changes in HbA1c were small in all groups. At week 16, mean changes in HbA1c were –0.02% with placebo, +0.07% with Niaspan 1,000 mg (not significant vs. placebo), and +0.29% with Niaspan 1,500 mg (marginally significant, p=0.048). Any potential increase in the risk of microvascular disease associated with this small increase in HbA1c would be expected to be offset by a decreased risk of macrovascular disease resulting from improvements in lipoprotein profiles.
In the Helsinki Heart Study, analysis of the joint effect of triglycerides and HDL cholesterol demonstrated that the risks of a cardiac event were similar in gemfibrozil- and placebo-treated subjects with high HDL cholesterol levels (≥42 mg/dl; 1.09 mmol/l) and either low (≤200 mg/dl; 2.26 mmol/l) or high (>200 mg/dl) triglyceride levels, or with low HDL cholesterol levels (<42 mg/dl) and low triglyceride levels. Placebo-treated subjects with low HDL cholesterol levels and high triglyceride levels, however, had a particularly high risk of a cardiac event, whereas this risk was substantially reduced with gemfibrozil.
In this study, treatment of men with reduced levels of HDL cholesterol with the fibrate gemfibrozil at a dose of 600 mg twice a day resulted in a significant reduction in the primary endpoint. Although this occurred in conjunction with substantially reduced plasma triglycerides and a modest increase in HDL cholesterol, it was not possible to ascribe the cardiovascular benefit to a specific lipid change. VA-HIT: Veterans Affairs HDL Intervention Trial
In this recently published prospective substudy of the Department of Veterans Affairs HDL Intervention Trial (VA-HIT), Otvos et al. assessed the effect of gemfibrozil treatment on LDL and HDL subclass particle numbers and mean particle sizes as measured by nuclear magnetic resonance spectroscopy (n=1,061 subjects). Gemfibrozil treatment reduced the total number of LDL particles by 5% (from baseline). This reduction was caused by a significant 20% decrease in the number of small LDL particles, which was partially offset by a 36% increase in the number of large LDL particles (left panel). As a result of this shift in LDL subclass composition, average LDL particle size significantly increased from 20.4 to 20.9 nm with gemfibrozil treatment (data not shown). Despite the decrease in LDL particle number, the LDL cholesterol level remained unchanged due to the shift toward larger LDL particles. The number of HDL particles in the gemfibrozil treatment group was increased by 10% from baseline (right panel). This increase was the result of a 21% increase in small HDL particles, which was partially offset by reductions in medium and large HDL particles. There was no significant change in HDL particle size with gemfibrozil treatment (data not shown). Thus, although gemfibrozil raised HDL cholesterol levels only modestly (6%), there was a 21% increase in the number of small, relatively cholesterol-poor HDL particles. Note that the * refers to p≤0.0005 vs. placebo at 7 months. Thus, total LDL particle number was significantly decreased in the gemfibrozil group after 7 months of treatment, compared with placebo after 7 months (significantly increased number of large LDL particles and significantly decreased number of small LDL particles). Furthermore, the number of HDL particles was significantly increased in the gemfibrozil group after 7 months of treatment, compared with placebo after 7 months (significantly increased number of small HDL particles and decreased number of medium HDL particles). Author’s note: Although the data was not shown in the manuscript, it was mentioned that separate analyses were conducted for the subset of subjects with diabetes or insulin resistance. LDL particle number decreased less in the diabetes/insulin resistance subgroup than in the overall population (2% vs. 5%), and the increase in LDL particle size was smaller (0.3 vs. 0.5 nm). Changes in HDL particle number and size were very similar in the diabetes/insulin resistance subgroup as in the overall population.
Otvos et al. also examined whether levels of the LDL and HDL subclasses measured at baseline and at 7 months after treatment were related to coronary heart disease (CHD) events. This table shows the odds ratios (OR) for a new CHD event associated with a 1-SD increment of each lipoprotein particle measured at baseline and after 7 months of treatment with placebo or gemfibrozil [as assessed in separate logistic regression models adjusted for major nonlipid CHD risk factors (age, hypertension, smoking, body mass index, and diabetes) and treatment group]. Both baseline and treatment numbers of LDL and HDL particles were strong, independent predictors of new CHD events. A 1-SD increment of LDL particle (350 nmol/l) during the trial was associated with an OR of 1.28 (p=0.0003), while the OR of a 1-SD increment of HDL particle (4.8 mol/l) was associated with an OR of 0.71 (p=0.0001). Note that mean LDL and HDL particle sizes were not significantly associated with CHD events. Because both LDL particle and HDL particle numbers had significant, independent associations with new CHD events, but LDL particle and HDL particle sizes did not, the authors concluded that CHD risk is better reflected by the number of lipoprotein particles than by the size of these particles. Author’s note: Although the data was not shown, it was mentioned that separate analyses were conducted for the subset of subjects with diabetes or insulin resistance. The associations between lipoprotein particle parameters and new CHD events in the diabetes/insulin resistance subgroup were virtually identical to those in the overall population. The numbers of LDL particles (OR=1.30) and HDL particles (OR=0.68) were significant, independent predictors of new CHD events in the diabetes/insulin resistance subgroup, as well. VA-HIT: Veterans Affairs HDL Intervention Trial
A post-hoc analysis in this trial indicated that among nondiabetic patients with low HDL levels, the greatest benefit of gemfibrozil treatment was in those in the upper quartile of plasma insulin levels. This suggests a preferential benefit in cardiovascular patients with insulin resistance. VA-HIT: Veterans Affairs HDL Intervention Trial
The Bezafibrate Infarction Prevention trial, a double-blind study in subjects with prior myocardial infarction (MI) and/or stable angina, found no significant reduction in risk for a primary endpoint event (fatal MI, nonfatal MI, or sudden death) with bezafibrate vs. placebo. In a post-hoc subgroup analysis, however, bezafibrate significantly reduced the risk for a primary endpoint event in subjects with baseline triglycerides ≥200 mg/dl (2.26 mmol/l). In this post-hoc subgroup analysis, Tenenbaum et al. evaluated the effect of bezafibrate on the primary endpoint in subjects with the metabolic syndrome. Metabolic syndrome was defined as having 3 of the following 5 risk factors: fasting glucose level ≥110 mg/dl (6.11 mmol/l), triglyceride level ≥150 mg/dl (1.69 mmol/l), HDL <40 mg/dl (1.03 mmol/l) in men or <50 mg/dl (1.29 mmol/l) in women, systolic blood pressure 130 mmHg or diastolic blood pressure ≥85 mmHg, or body mass index ≥28.0 kg/m 2 . Subjects, aged 45 to 74 years, received either bezafibrate 400 mg/d (n=740) or placebo (n=730). Most subjects were men (89%); 78% of subjects had sustained a previous MI. The mean follow-up period was 6.2 years for MI and 8.1 years for cardiac mortality. A new MI occurred in significantly fewer patients in the bezafibrate group (11.1%; 82/740) than in the placebo group (15.2%; 111/730) (p=0.02), as shown in this slide. Compared with placebo, bezafibrate was associated with a reduced risk for any MI and nonfatal MI, with hazard ratios (HRs) of 0.71 (95% CI: 0.54-0.95; p=0.02) and 0.67 (95% CI: 0.49-0.91; p=0.009), respectively. There was no reduction in risk for a fatal MI (HR=1.26, 95% CI: 0.57-2.77; p=0.60), but an overall benefit was observed for the primary endpoint (HR=0.75, 95% CI: 0.58-0.97; p=0.03). As shown in this slide, there was a trend toward reduction in cardiac mortality in the bezafibrate group (HR=0.74, 95% CI: 0.54-1.03; p=0.056). Among 575 patients with augmented features of metabolic syndrome (4 to 5 risk factors), cardiac mortality was significantly lower with bezafibrate vs. placebo (HR=0.44, 95% CI: 0.25-0.80; p=0.005). The results of this post-hoc analysis suggest that bezafibrate may reduce the risk of nonfatal MI in patients with the metabolic syndrome.
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial is a controlled, multicentre trial that includes 9,795 patients with type 2 diabetes and without coronary heart disease (CHD). Patients were randomized to receive placebo or fenofibrate (200 mg/day) for 5 years. The primary outcome of the study is CHD death, though nonfatal myocardial infarction was proposed as an additional endpoint in an amendment to the initial study design.
The placebo patients experienced notable reductions in both total cholesterol and LDL cholesterol, with fenofibrate treatment showing additional effects beyond those observed in the placebo patients at the end of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. The reduction in LDL cholesterol seen in the placebo patients, and a portion of the reduction observed in the fenofibrate patients, are likely due to the substantial proportion of patients who started statin therapy during the trial. Note that the baseline lipid profiles of the overall patients are more “normal” than those typically observed in patients with type 2 diabetes. Furthermore, note that in those patients who started other lipid-lowering therapy, LDL cholesterol levels were higher than those who did not. HDL cholesterol levels were also lower in the subset of patients who started other lipid-lowering therapy.
Fenofibrate was associated with a nonsignificant, 11% reduction in the incidence of the primary endpoint, nonfatal myocardial infarction or coronary heart disease death (5.2% event rate for the fenofibrate group compared with 5.9% for the placebo group, p=0.16). FIELD: Fenofibrate Intervention and Event Lowering in Diabetes
When the primary endpoint is separated into the individual components of nonfatal myocardial infarction and coronary heart disease (CHD) mortality, the data reveals that fenofibrate significantly reduced the incidence of nonfatal myocardial infarction (event rate for placebo is 8.4 and event rate for fenofibrate is 6.4) by 24% (p=0.01) and nonsignificantly increased the endpoint of CHD death (event rate for placebo is 3.7 and event rate for fenofibrate is 4.4) by 19% (p=0.22). FIELD: Fenofibrate Intervention and Event Lowering in Diabetes
Fenofibrate treatment had a particularly beneficial effect in patients who had no prior cardiovascular disease (CVD). In this primary prevention population (78% of the total population), fenofibrate reduced the incidence of the primary endpoint (coronary heart disease events) by 25% (p=0.014) and the incidence of total CVD events by 19% (p=0.004). FIELD: Fenofibrate Intervention and Event Lowering in Diabetes
In addition to the beneficial effects on macrovascular disease, fenofibrate also significantly improved 2 indicators of microvascular disease. Patients treated with fenofibrate experienced lower rates of laser treatment for retinopathy and a reduced progression of albuminuria than those patients treated with placebo. Fenofibrate is the only lipid-lowering agent that has been shown to improve both macrovascular and microvascular disease in patients with type 2 diabetes. FIELD: Fenofibrate Intervention and Event Lowering in Diabetes
Fenofibrate treatment was well tolerated. One of the important aspects of this study was the finding that even in a study conducted in almost 10,000 patients, lasting 5 years, and in the presence of a significant proportion of patients taking fenofibrate plus statins, relatively few clinically significant muscle-related adverse events were observed. In particular, only 3 out of the 9,795 patients experienced myositis. Notably, only 4 patients experienced rhabdomyolysis (1 placebo and 3 fenofibrate), which fully resolved after discontinuation of the study medication, and none of these patients were on combination therapy with a statin. Moreover, the incidences of alanine aminotransferase elevation and creatine phosphokinase elevation were not significantly different between placebo and fenofibrate treatment. Therefore, this study provides important corroborating evidence that fenofibrate therapy is safe, even when combined with statins. Not shown on this slide, but also important to note, is that plasma creatinine levels were 14% higher in the fenofibrate group at the end of the study, compared with levels in the placebo group (p<0.001) 1 . Importantly, fenofibrate-associated changes in creatinine were reversible in patients studied 8 weeks after ceasing fenofibrate therapy 1 . Furthermore, fenofibrate-associated changes in creatinine plasma levels have been reported not to be due to accelerated muscular cell lysis, a fall in glomerular filtration rate, or an impairment in renal function; instead, they may be due to increased metabolic production of creatinine 2 . Also important to note is that at the end of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, plasma levels of homocysteine were 35% higher in the fenofibrate group than in the placebo group 1 . This elevation in the plasma concentration of homocysteine was reversible in the patients studied 8 weeks after ceasing therapy with fenofibrate 1 . Although high homocysteine levels are associated with cardiovascular disease, there is conflicting evidence about whether lowering serum homocysteine levels reduces cardiovascular disease 3,4 . It is not clear if the fibrate-induced increase in homocysteine has any clinical significance. References 1. Keech A, et al. Lancet. 2005; 366:1849-61. 2. Hottelart C, El Esper N, Rose F, Achard JM, Fournier A. Nephron. 2002; 92:536-541. 3. Clarke R, et al. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA . 2002; 288:2015-22. 4. Clarke R, Lewington S. Homocysteine and coronary heart disease. Semin Vasc Med . 2002; 2:391-99.
Results from the recent SAFARI trial demonstrate that combination therapy with simvastatin plus fenofibrate was significantly more effective than simvastatin monotherapy at correcting the levels of all the major lipids: triglycerides, VLDL cholesterol, LDL cholesterol, and HDL cholesterol. In this trial, 618 patients with combined hyperlipidemia were enrolled in a randomized, double-blind, active-controlled, 18-week efficacy and tolerability study comparing simvastatin (20 mg/day) with simvastatin (20 mg/day) plus fenofibrate (160 mg/day). The combination therapy was more effective than statin monotherapy and was well tolerated. Note that the ~5% reduction seen in LDL cholesterol with combination therapy is approximately equivalent to that typically seen with increasing simvastatin to 40 mg/day.
An analysis of LDL particles in the SAFARI trial demonstrated that simvastatin monotherapy did not significantly change the distribution of LDL particles, whereas the combination therapy significantly increased the number of LDL A and AB subclasses, the particles that are larger and less dense than the B subclass. Thus, only the combination therapy significantly improved the distribution of LDL particles.
In a study by Athyros et al., the effect of a statin (atorvastatin)-fenofibrate combination on lipid profiles was evaluated in 120 patients with type 2 diabetes who were free of coronary artery disease. Patients were also evaluated for each drug given as monotherapy. After 24 weeks, combination therapy with atorvastatin and fenofibrate was statistically significantly more effective at reducing total cholesterol, LDL cholesterol and triglycerides compared with either monotherapy. The investigators concluded that the atorvastatin-fenofibrate combination had a highly beneficial effect on all lipid parameters in patients with type 2 diabetes and combined hyperlipidemia.
The risk of adverse effects of statin-fibrate combination therapy is dependent on pharmacokinetic interactions that alter statin metabolism and clearance 1-3 . High levels of statins can cause liver function abnormalities, myopathy, and in rare cases, rhabdomyolysis. A number of studies have investigated the pharmacokinetic interactions between different fibrates and statins to explain the variations in adverse events reported by patients who are receiving particular statin-fibrate combination therapies. These studies have concluded that there is a difference between fibrates in their ability to affect the pharmacokinetics of statins, and among statins in their susceptibility to metabolic interactions with the fibrates. References 1. Pan WJ, et al. J Clin Pharmacol. 2000; 40: 316-23. 2. Backman JT, et al. Clin Pharmacol Ther. 2000; 68: 122-9. 3. Kyrklund C, et al. Clin Pharmacol Ther. 2001; 69: 340-5.
This slide summarizes the changes in serum LDL and HDL cholesterol and triglycerides following daily treatment with 1,000 niaspan/20 mg lovastatin (Advicor™) vs. 40 mg lovastatin for 28 weeks. Reductions in LDL cholesterol were slightly greater for lovastatin, whereas the increases in HDL cholesterol and reductions in triglycerides were greater for the niaspan+lovastatin combination.
The HDL-Atherosclerosis Treatment Study (HATS) was a 3-year double-blind, placebo-controlled, National Heart, Lung and Blood Institute sponsored study that, in part, evaluated niacin therapy of HDL cholesterol management in patients also on an LDL cholesterol–lowering statin regimen. The study included 160 patients with coronary artery disease (CAD) who had low HDL cholesterol and normal LDL cholesterol levels. Patients were randomly assigned to 1 of 4 regimens – statin (S; simvastatin) and niacin (N), S and N plus antioxidant vitamins (AV), antioxidants, or placebo. For the purpose of this graph, we will be discussing the effects of N on HDL cholesterol parameters. Niacin was started at 250 mg twice daily and increased linearly to 1,000 mg twice daily at 4 weeks; the mean dose was 2.4 g/day. Antioxidants (total daily doses: 800 IU vitamin E, 1,000 mg vitamin C, 25 mg -carotene, and 10 µg selenium) were given twice daily. The primary outcomes were angiographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, myocardial infarction, stroke, or revascularization). Patients receiving N had a significant increase in HDL cholesterol of 26%. The addition of AV blunted the magnitude of this increase in HDL cholesterol. For the angiographic primary endpoint – the change in severity of the most severe stenosis in 9 proximal coronary segments – a slight regression was observed with the addition of N (-0.4%) and progression was slowed with N and AV (+0.7%) treatment when compared to placebo (+3.9% mean change in stenosis). The composite clinical endpoint of death from coronary causes, confirmed myocardial infarction or stroke, or revascularization was reduced by 89% in patients treated with N compared with placebo (p=0.04). There were no statistically significant differences in clinical endpoints in the group receiving both N and AV compared with placebo. The authors concluded that the addition of N in CAD patients with low HDL cholesterol and “normal” LDL cholesterol resulted in a slight regression of coronary atherosclerosis and a significant reduction (89%) in clinical coronary events over 3 years compared with placebo.
Baseline lipid concentrations were similar in the 2 study groups. LDL cholesterol levels in both groups remained well controlled, with mean values <100 mg/dl (2.59 mmol/l). At 12 months, HDL cholesterol had significantly increased in the niacin group (from 39 to 47 mg/dl; 1.01 to 1.22 mmol/l), but was unchanged in the placebo group. Triglycerides also decreased significantly in the extended-release niacin group. There was no difference in the highly sensitive C-reactive protein measurements between the 2 study groups. ARBITER 2: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol
The change in carotid intima-media thickness (CIMT) from baseline to 12 months was 0.044 mm in the placebo group (p<0.001) and 0.014 mm in the extended-release niacin group (p=0.23). Thus, the increase in CIMT was 3-fold greater in the placebo than in the extended-release niacin group. ARBITER 2: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol
In a trial of a large group of Japanese patients on statin therapy, there was a benefit of 1.8 g added omega-3 fatty acid (eicosapentaenoic acid) on both primary and secondary prevention of cardiovascular events.
Update on management of atherogenic dyslipidemia of insulin resistance, obesity, and type 2 diabetes: beyond LDL cholesterol
UPDATE ON MANAGEMENT OF ATHEROGENIC DYSLIPIDEMIA OF INSULIN RESISTANCE, OBESITY, AND TYPE 2 DIABETES: BEYOND LDL CHOLESTEROL <ul><li>Ronald M. Krauss, MD </li></ul><ul><li>Children’s Hospital Oakland Research Institute </li></ul><ul><li>UC Berkeley and UCSF </li></ul>
Atherogenic Dyslipidemia in Obesity, Insulin Resistance, and Metabolic Syndrome <ul><li>High triglyceride (TG) levels </li></ul><ul><ul><li>TG-rich remnant lipoproteins (VLDL) </li></ul></ul><ul><ul><li>Altered metabolism of LDL and HDL particles </li></ul></ul><ul><li>Absolute levels of LDL cholesterol are commonly not significantly increased, number of LDL particles </li></ul><ul><ul><li>Predominantly small, dense LDL particles </li></ul></ul><ul><li>Low levels of HDL cholesterol (may reduce reverse cholesterol transport) </li></ul>Adapted from Haffner SM Diabetes Care 2003; 26: S83-6 and Garvey WT et al. Diabetes 2003; 52: 453-62
Metabolic Basis for Atherogenic Dyslipidemia: Concordant Increase in VLDL and Small LDL and Reduction of HDL Smaller LDL HL Apo AI Renal clearance LPL Remnants LPL/HL VLDL TG CETP Cholesterol HDL TG LDL TG Smaller HDL Apo AI: apolipoprotein AI CETP: cholesteryl ester transfer protein HL: hepatic lipase LPL: lipoprotein lipase TG: triglycerides
Triglyceride Level is an Independent Cardiovascular Disease (CVD) Risk Factor – Meta-Analysis of 17 Studies <ul><li>Adapted from Austin MA et al. Am J Cardiol 1998; 81: 7B-12B </li></ul>Relative CVD risk † Men (n=22,293) Women (n=6,345) Men (n=46,413) Women (n=10,864) * * * * † Associated with an 89 mg/dl (1.00 mmol/l) increase in triglycerides *p<0.05
Triglyceride Level Remains a Cardiovascular Disease (CVD) Risk Factor in Patients Treated With Statins - CARE and LIPID <ul><li>Adapted from Sacks FM et al. Circulation 2000; 102: 1893-900 </li></ul>CVD event rate* Placebo Pravastatin Triglyceride levels (mg/dl) Slope=0.018 p=0.02 Slope=0.029 p<0.001 n=13,173 *Coronary heart disease death, nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty <98 99-126 127-158 159-207 >207
Coronary Heart Disease (CHD) Risk: HDL Cholesterol vs. LDL Cholesterol as Predictor* <ul><li>Adapted from Castelli WP Can J Cardiol 1988; 4 (Suppl A): 5A-10A </li></ul>* Data represent men aged 50 – 70 from the Framingham Heart Study Relative risk of CHD after 4 years LDL cholesterol (mg/dl) 85 65 45 25 HDL cholesterol (mg/dl)
Statin Therapy Does Not Eliminate Cardiovascular Disease (CVD) Risk Associated With Low HDL Cholesterol <ul><li>Adapted from HPS Collaborative Group Lancet 2002; 360: 7-22 and Sacks FM et al. Circulation 2000; 102: 1893-900 </li></ul>CARE: Cholesterol and Recurrent Events HPS: Heart Protection Study LIPID: Long-Term Intervention with Pravastatin in Ischaemic Disease CVD event rate (%) High HDL cholesterol + statin Low HDL cholesterol + statin
Relative Risk of Myocardial Infarction (MI) According to Triglycerides (TG) and HDL Cholesterol: Case-Control Study in CAD Patients <ul><li>Adapted from Gaziano et al. Circulation 1997; 96: 2520-5 </li></ul>Quartiles of TG Quartiles of TG, adjusted for HDL cholesterol Quartiles of log TG/HDL cholesterol
LDL Cholesterol Underestimates the Number of LDL Particles When Levels of Small LDL Are Increased Apo B Similar LDL cholesterol <ul><li>Slower plasma clearance </li></ul><ul><li>Greater artery uptake & retention </li></ul><ul><li>Faster oxidation </li></ul><ul><li>More particles </li></ul>Cholesteryl ester Larger LDL (phenotype A) More cholesterol/particle Smaller LDL (phenotype B) Less cholesterol/particle
Favourable Shift in LDL Particle Size is Strongly Associated With End-of-Treatment Triglyceride (TG) Values <ul><li>Adapted from Davidson MH et al. Clin Cardiol 2006; 29: 268-73 </li></ul>Median increase in LDL particle diameter (nm) TG level † (mg/dl) <200 200-299 ≥ 300 Change from baseline (%) TG * Small LDL cholesterol Large LDL cholesterol LDL particle concentration * * TG † <200 mg/dl TG † ≥200 mg/dl † End-of-treatment TG level *p<0.03 vs. TG level ≥200 mg/dl Triglyceride reduction in metabolic syndrome (TRIMS) Significant inverse relationship p value for trend =0.019
Primary Prevention With Gemfibrozil The Helsinki Heart Study <ul><li>Adapted from Manninen V et al. Circulation 1992; 85: 37-45 </li></ul>Incidence of cardiac events per 1,000 person-years 0 5 10 15 20 HDL cholesterol 42 HDL cholesterol 42 TG 200 TG 200 TG 200 TG 200 mg/dl Gemfibrozil TG: triglycerides Placebo Incidence of coronary heart disease events
VA-HIT: Gemfibrozil Effect on Primary Endpoint - Lipids <ul><li>Adapted from Rubins HB et al. N Engl J Med 1999; 341: 410-8 </li></ul>LDL cholesterol TG HDL cholesterol Primary endpoint occurrence*† Change from baseline (%) % Placebo Gemfibrozil *Nonfatal myocardial infarction or death from coronary causes † 22% relative risk reduction (95% CI: 7%–35%, p=0.006) TG: triglycerides
VA-HIT: LDL and HDL Particle Subclasses Are Favourably Affected by Fibrate Treatment <ul><li>Adapted from Otvos JD et al. Circulation 2006; 113: 1556-63 </li></ul>IDL: intermediate-density lipoprotein B: baseline Placebo Fibrate 5% reduction 1364 1463 1352 1290* LDL particle number (nmol/l) B 7 months B 7 months 20% decrease 36% increase * * HDL particle number ( mol/l) 25.2 25.1 26.6 27.6* Placebo Fibrate B 7 months B 7 months 21% increase * * 10% increase *p≤0.0005 vs. placebo at 7 months IDL Large HDL Large LDL Medium HDL Small LDL Small HDL
VA-HIT: LDL and HDL Particle Numbers Are Significant, Independent Predictors of New Coronary Heart Disease Events <ul><li>Adapted from Otvos JD et al. Circulation 2006; 113: 1556-63 </li></ul>Relative odds ratio † LDL particle number LDL particle size * * Relative odds ratio † HDL particle number HDL particle size * * Baseline 7 months † Calculated for a 1-SD increment of each lipoprotein particle in separate logistic regression models adjusted for treatment group, age, hypertension, smoking, body mass index, and diabetes *p<0.05
VA-HIT: Cardiovascular Disease Risk Reduction in Nondiabetic Patients <ul><li>Adapted from Rubins HB et al. Arch Intern Med 2002; 162: 2597-604 </li></ul>Risk reduction ≤ 23 n=434 24-29 30-38 ≥ 39 n=431 n=426 n=442 Quartiles of fasting plasma insulin ( µU/ml) Favours gemfibrozil Favours placebo p=0.04 vs. placebo
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) <ul><li>Subjects: 9,795 (37% female) patients with type 2 diabetes aged 50-75 years with and without coronary heart disease (CHD) </li></ul><ul><li>Entry lipid criteria: cholesterol = 116-251 mg/dl (3.00-6.50 mmol/l), plus either </li></ul><ul><ul><li>Cholesterol/HDL cholesterol ratio >4 </li></ul></ul><ul><ul><li>or </li></ul></ul><ul><ul><li>Triglycerides >89 mg/dl (1.00 mmol/l) </li></ul></ul><ul><li>Treatment: fenofibrate 200 mg once daily or placebo for 5 years </li></ul><ul><li>Primary endpoint: CHD death plus nonfatal myocardial infarction </li></ul>Adapted from Keech AC and the FIELD Study Investigators Cardiovasc Diabetol 2004; 3: 9-24
FIELD: End of Study Lipid Results <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61 </li></ul>Placebo (P) Fenofibrate (F) 113 LDL cholesterol HDL cholesterol Triglycerides Baseline (mg/dl) 117 43 43 164 167 119 LDL cholesterol HDL cholesterol Triglycerides Baseline (mg/dl) 119 43 43 171 173 128 LDL cholesterol HDL cholesterol Baseline (mg/dl) 125 42 40 184 197 Triglycerides Did not start other lipid-lowering therapy n= 3,124 (P) 3,951 (F) Total population Started other lipid-lowering therapy n= 1,776 (P) 944 (F)
FIELD: Primary Endpoint of Coronary Heart Disease (CHD) Events* <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61 </li></ul>Event rate (%) 11% reduction p=0.16 *Nonfatal myocardial infarction or CHD death
FIELD: Primary Endpoint of Coronary Heart Disease (CHD) Events* <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61 </li></ul>24% reduction p=0.01 19% increase p=0.22 Placebo Fenofibrate *Nonfatal myocardial infarction or CHD death
FIELD Primary Prevention Population: Effects on Coronary Heart Disease (CHD) Events and Total Cardiovascular Disease (CVD) Events <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61 </li></ul>Risk reduction (%) (n=7,664) (n=7,664) p=0.014 p=0.004 CHD events Total CVD
FIELD: Microvascular Disease <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61 </li></ul>Progression Regression Patients (%) P F P F 14% reduction p<0.001 30% reduction p=0.0003 Placebo Fenofibrate Patients (%) *Progression of albuminuria was defined as the proportion of patients who progressed either from normoalbuminuria to microalbuminuria or from microalbuminuria to macroalbuminuria. Placebo (P) Fenofibrate (F) Laser treatment for retinopathy Progression and regression of albuminuria*
FIELD: Clinically Important Adverse Events ALT: alanine aminotransferase CPK: creatine phosphokinase ULN: upper limit of normal *Myositis was experienced by 1 placebo and 2 fenofibrate patients † Rhabdomyolysis was experienced by 1 placebo and 3 fenofibrate patients (none were taking a statin) ‡ p=0.022 § p=0.031 Adapted from Keech A et al. Lancet 2005; 366: 1849-61 Adverse Event Placebo, % n=4,900 Fenofibrate, % n=4,895 Newly diagnosed cancer 7.6 8.0 Deep-vein thrombosis 1.0 1.4 Pulmonary embolism 0.7 1.1 ‡ Pancreatitis 0.5 0.8 § Myositis* 0.02 0.04 Rhabdomyolysis † 0.02 0.06 Renal disease requiring dialysis 0.4 0.3 ALT 3-5x ULN 0.5 0.2 >5x ULN 0.2 0.2 CPK 5-10x ULN 0.1 0.2 >10x ULN 0.06 0.08 Creatinine increase >2.26 mg/dl 1.0 1.5
SAFARI: Effects on LDL Particle Subclasses <ul><li>Adapted from Grundy SM et al. Am J Cardiol 2005; 95: 462-8 </li></ul><ul><li>Reproduced with permission </li></ul>Simvastatin +Fenofibrate Simvastatin Simvastatin Change from baseline in LDL pattern (%) Baseline Week 12* Increased particle size n=618 *Significantly different pattern between the 2 treatment groups (p<0.001) B (Smaller, dense) AB (Intermediate) A (Larger, buoyant) Simvastatin +Fenofibrate
Atorvastatin and Fenofibrate Alone or in Combination in Patients With Type 2 Diabetes <ul><li>Adapted from Athyros VG et al. Diabetes Care 2002; 25: 1198-202 </li></ul>Triglycerides LDL cholesterol HDL cholesterol Change from baseline (%) * * * * ‡ * * * † Atorvastatin 20 mg Fenofibrate 200 mg Combination * † n=120 *p <0.0001 vs. baseline † p <0.05 vs. both monotherapies ‡ p <0.05 vs. atorvastatin
Statin-Fibrate Combination Therapy: Pharmacokinetic Interactions <ul><li>Adapted from: </li></ul><ul><li>TriCor [package insert]. Abbott Laboratories; 2004 </li></ul><ul><li>Kyrklund C et al. Clin Pharmacol Ther 2001; 69: 340-5 </li></ul><ul><li>Pan W J et al. J Clin Pharmacol 2000; 40: 316-23 </li></ul><ul><li>Backman JT et al. Clin Pharmacol Ther 2000; 68: 122-9 </li></ul><ul><li>Backman JT et al. Clin Pharmacol Ther 2002; 72: 685-91 </li></ul><ul><li>Abbott Laboratories. Data on file; 2005 </li></ul><ul><li>Davidson MH Am J Cardiol 2002; 90 (suppl): 50K-60K </li></ul><ul><li>Prueksaritanont T et al. Drug Metab Dispos 2002; 30: 1280-7 </li></ul><ul><li>Martin PD et al. Clin Ther 2003; 25: 459-71 </li></ul><ul><li>Bergman AJ et al. J Clin Pharmacol 2004; 44: 1054-62 </li></ul>Cmax: maximum concentrations Gemfibrozil Fenofibrate Atorvastatin Expected in C max No effect Simvastatin C max by 2-fold No effect Pravastatin C max by 2-fold No effect Rosuvastatin C max by 2-fold No effect Fluvastatin No effect No effect Lovastatin C max by 2.8-fold Not available Cerivastatin C max by 2-3 - fold No effect
Effects of Lovastatin or Lovastatin and Niaspan on Lipid Parameters <ul><li>Adapted from Hunninghake DB et al. Clin Cardiol 2003; 26: 112-8 </li></ul>Change from baseline (%) LDL cholesterol HDL cholesterol Triglycerides Lovastatin 40 mg Lovastatin 20 mg + 1,000 mg niaspan (Advicor)
Analysis of the HDL-Atherosclerosis Treatment Study (HATS): Angiographic and Clinical Endpoints After 3 Years – Simvastatin + Niacin vs. Placebo <ul><li>Adapted from Brown BG et al. N Engl J Med 2001; 345: 1583-92 </li></ul>Placebo Mean change in stenosis (%) *p<0.001 vs. placebo ‡ p=0.04 vs. placebo Coronary death, myocardial infarction, stroke or revascularization Simvastatin + Niacin Composite event rate (%) 3.9 23.7 89% reduction -0.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Nine proximal lesions 25 20 15 10 5 0 -0.4 2.6 * ‡
ARBITER 2: Statin Plus Placebo vs. Statin Plus Extended-Release Niacin (ERN) Values are mean SD BL: baseline Adapted from Taylor AJ et al. Circulation 2004; 110: 3512-7 12 months P value BL vs. 12 months Lipid (mg/dl) Statin + Placebo Statin + ERN P Value Statin + Placebo Statin + ERN n 71 78 LDL cholesterol 86 20 85 25 NS NS NS HDL cholesterol 40 9 47 16 0.003 NS <0.001 Triglycerides 164 83 134 87 0.03 NS 0.009 Non-HDL cholesterol 115 21 107 34 NS 0.03 0.02
ARBITER 2: Statin + Placebo vs. Statin + Extended-Release Niacin 1,000 mg/d Primary Endpoint – Carotid Intima-Media Thickness (CIMT) Change <ul><li>Adapted from Taylor AJ et al. Circulation 2004; 110: 3512-7 </li></ul>Statin + Placebo (n=71) Statin + Extended release niacin (n=78) Baseline CIMT (mm) Change in CIMT (mm) Statin + Extended release niacin (n=78) p=0.23* Statin + Placebo (n=71) p<0.001* *Within-group comparisons Baseline CIMT after 1 year