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Treatment of Dyslipidemia and Cardiovascular Outcomes: The Journey So Far—Is This the End for Statins? S Zoungas1,2, AJ Curtis1, JJ McNeil1 and AM Tonkin1 Dyslipidemia is common and is associated with the highest population-attributable risk for cardiovascular disease. Of various cardiovascular preventive therapies, the evidence from randomized controlled trials supporting the importance of aggressive lipid lowering is the most robust, particularly for statins. Despite the use of proven therapies, cardiovascular disease event rates remain relatively high, underpinning the development of novel therapies. In addition to testing new drugs to reduce low-density-lipoprotein cholesterol, there has been a major focus on treatments that can favorably influence high-density-lipoprotein cholesterol and triglyceride levels. This review provides an overview of the important relationship between lipids and cardiovascular disease, the lipid-modifying therapeutic approaches to reducing cardiovascular disease, new guidelines and recommendations, and the challenges ahead for the treatment of dyslipidemia, particularly whether statins will remain at the forefront of recommended therapies. EPIDEMIOLOGY: LIPIDS AND CARDIOVASCULAR DISEASE Global burden
Over the past few decades, mortality from atherosclerotic cardiovascular disease (CVD) in most developed countries has substantially declined. In northwestern Europe, North America, Australia, and other regions, treatment advances along with lower rates of smoking and better management of risk factors have led to major reductions in age-standardized death rates from CVD and coronary heart disease (CHD).1 Despite this, CVD remains the major cause of mortality globally, with 17.5 million deaths attributed to CVD in 2012. During the same period, CHD and stroke accounted for 7.4 and 6.7 million deaths, respectively.2 Two major global challenges are (i) the marked increase in the burden of CVD anticipated for low- and middle-income countries and in huge Asian populations such as those in China and India, and (ii) the slowing of the rate of decline in age-specific CHD mortality among those in younger age categories as seen in the United States.1 LIPID FRACTIONS AND CARDIOVASCULAR RISK Low-density-lipoprotein cholesterol
The continuous log-linear relationship between CVD risk and increasing levels of low-density-lipoprotein cholesterol (LDL-C) is well established.3 This relationship extends across age categories4 and pertains to different regions of the world.5
Non-high-density-lipoprotein cholesterol
Non-high-density-lipoprotein cholesterol (non-HDL-C) represents an alternative approach to quantifying total atherogenic particle number. It is calculated by subtraction of HDL-C from total cholesterol (TC) and encompasses low-, intermediate-, and very-low-density-lipoprotein (VLDL) cholesterol content. Similar to increasing levels of LDL-C, increasing levels of nonHDL-C have been associated with increased risk of CHD and ischemic stroke (Figure 1).6 High-density-lipoprotein cholesterol
Epidemiological studies, including the Framingham Heart Study, have demonstrated a strong and independent inverse relationship between levels of HDL-C and risk of CVD (Figure 1).6–8 Increases in HDL-C of 1 mg/l (0.03 mmol/l) have been associated with decreases in CVD risk of 2–3%.9 The relationship also holds in patients who are already taking a statin,10 although perhaps not when LDL-C levels are very low.11 In a meta-analysis of individual patient data from eight trials of statin therapy, higher HDL-C levels were strongly associated with reduced CVD risk.12 However, any in-trial incremental changes in HDL-C levels (i.e., increases) were not associated with reduced risk for CVD events.12 This uncertainty has led to the investigation of a role for functional quality of HDL rather than for its particle number.13
1School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia; 2The George Institute for Global Health, Sydney, Australia.
Correspondence: S Zoungas ([email protected])
Received 13 March 2014; accepted 7 April 2014; advance online publication 18 June 2014. doi:10.1038/clpt.2014.86 192
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state Triglycerides
Triglycerides (TGs) are still somewhat controversial. TG levels have been associated with risk of CVD, although less consistently than LDL-C and HDL-C levels.14–16 An independent role for TGs is supported by evidence from case–control studies14 as well as from numerous cohort studies and meta-analyses.17–20 In a recent meta-analysis of prospective studies, elevated blood TG levels were associated with an increased risk of CVD-related and all-cause mortality.18 In 22 studies the risk of CVD mortality was increased by 13% and the risk of all-cause mortality was increased by 12% per mmol/l increment in TG levels. Despite this evidence, a causative role for TGs in CVD has recently been challenged with new evidence suggesting that TG level is simply a marker for low HDL-C and increased LDL-C levels.6 Other lipid fractions and cardiovascular risk
Epidemiological evidence supports the importance of other lipid fractions in CVD/CHD. Apolipoprotein B. Apolipoprotein B (ApoB) is the major apolipoprotein and is an essential component of VLDL, LDL, intermediate-density lipoprotein, and lipoprotein(a). Like non-HDLC, it is a measure of total atherogenic particle number and is associated with CVD risk (Figure 1).6 For practical purposes, reporting of non-HDL-C levels is currently recommended over measurement of ApoB levels.6 Lipoprotein(a). Lipoprotein(a) (Lp(a)) is a cholesterol-rich LDL-
like particle bound to apolipoprotein (a) (Apo(a)), a plasminogen-like glycoprotein.21 Biologically plausible mechanisms for an effect of Lp(a) on CVD include induction of a prothrombotic/antifibrinolytic effect because Apo(a) resembles both plasminogen and plasmin but has no fibrinolytic activity and/ or causes no acceleration of atherosclerosis because Lp(a) is
cholesterol rich.22 Population studies have shown an association between high Lp(a) levels and CVD risk and with increased LDL-C levels this effect appears to be enhanced.23,24 Evidence from genetic studies also supports Lp(a) as a causal risk factor for CHD independent of other risk factors and LDL-C levels.25,26 In the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) trial, the levels of Lp(a) at baseline and during the study predicted CVD events, confirming an influence on residual risk.27 Despite this observation, there is little evidence that lowering Lp(a) levels reduces risk of CHD.27,28 Measurement of Lp(a) levels has been advocated for risk stratification, although this is not universally accepted.29 For example, the European Atherosclerosis Society22 has recently recommended Lp(a) screening (i) in people with intermediate or high CVD risk with premature CVD, familial hypercholesterolemia, a family history of premature CVD and/ or elevated Lp(a), and recurrent CVD despite statin treatment, and (ii) in people with a ≥3% 10-year risk of fatal CVD according to European guidelines and/or a ≥10% 10-year risk of CHD according to US guidelines.22 ESTABLISHED THERAPIES Therapies targeting LDL-C
Strategies to lower LDL-C levels have consistently been shown to reduce risk of major CVD events. Meta-regression of intervention studies has shown a clear linear relationship between the magnitude of the LDL-C reduction achieved and risk reduction observed (Figure 2).30 Of the LDL-lowering interventions studied (5 diet studies, 3 bile acid–sequestrant studies, 1 surgery study, and 10 statin trials that included a total of 81,859 patients), statins have the greatest evidence of benefits.
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Figure 1 Risks of CHD across fifths of non-HDL-C and HDL-C levels or apolipoprotein levels. CHD, coronary heart disease; HDL-C, high-densitylipoprotein cholesterol. Reprinted with permission from ref. 6. Clinical pharmacology & Therapeutics | VOLUME 96 NUMBER 2 | august 2014
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Figure 2 Correlation between LDL-C lowering and decreased CHD risk according to treatment modality in a meta-regression analysis. CHD, coronary heart disease; LDL-C, low-density-lipoprotein cholesterol. Reprinted with permission from ref. 30. 193
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Statins. Statins are the first-line therapeutic agents for reducing LDL-C levels. Many statins have been tested and overall have demonstrated reduction of major vascular events. Pharmacology/mechanism of action. Statins (3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors) inhibit the mevalonate pathway and biosynthesis of cholesterol and isoprenoids through displacement of HMG-CoA that is bound to HMG-CoA reductase. HMG-CoA reductase is prevented from attaining a functional conformation, which prevents the conversion of HMG-CoA to l-mevalonate and reduces the production of intracellular cholesterol. Induction of LDL receptor (LDL-R) gene expression and formation on the hepatocyte cell surface results in an increase in the clearance of LDL-C and its precursors, intermediate-density lipoprotein and VLDL, from the blood and an 18–55% decrease in the concentration of circulating LDL-C.31 Increased HDL-C levels (by 5–15%),32 decreased levels of atherogenic lipoproteins,33 decreased TG concentration (7–30%), and decreased synthesis and secretion of TG-rich lipoproteins,33 as well as reduced susceptibility of LDL-C to oxidation, have also been reported.31 Statins also exert a number of effects independent of their lipid-lowering properties,34 including improvement of endothelial function,35 inhibition of the thrombogenic response,36 a moderately powerful anti-inflammatory action,37 and a possible antihypertensive effect.38 These pleiotropic effects have been attributed to the inhibition of isoprenoid synthesis and isoprenylation of key cell signaling proteins such as the Rho, Ras, and Rac guanosine triphosphatases,39,40 an activation step important for multiple cell functions including maintenance of cell shape, factor secretion, differentiation, migration, and proliferation. Clinical trials. A meta-analysis of individual participant data from 27 statin trials reported a clear linear relationship between the degree of LDL-C lowering achieved with statins and benefits achieved, with reductions in major vascular events and allcause mortality of 21 and 10% per mmol/l reduction in LDL-C, respectively (Cholesterol Treatment Trialists’ Collaboration).41 This meta-analysis also confirmed the superiority of more intensive, as compared with less intensive, statin therapy. The benefits were broadly observed in people with CHD, stroke, and diabetes, as well as in younger people who were apparently healthy.41 Safety. Ongoing drug safety evaluation is particularly impor-
tant for widely prescribed drugs such as the statins, which are typically prescribed as lifelong therapies. Changes in metabolic processes, aging, and development of concomitant diseases requiring other pharmacotherapy, and hence having the potential for drug interactions, are also likely to occur and affect the overall safety of statins. Reported adverse events from randomized controlled trials (RCTs) and observational studies include skeletal myotoxicity, diabetes, cancer, cognitive impairment, and acute kidney injury.42 Myopathy: All statins have been reported to cause myopathy, with the severity ranging from asymptomatic increases in 194
creatine kinase to myalgia and myositis to fatal rhabdomyolysis commonly characterized by massive muscle necrosis, myoglobinuria, and acute renal failure.43–45 Rhabdomyolysis represents the least frequent, although potentially fatal, complication caused by skeletal muscle breakdown. The rates of rhabdomyolysis have been estimated from clinical trial and cohort data as 3 per 100,000 person-years during statin treatment.46 Myopathy is dose dependent and may occur even after therapy has been tolerated for up to 1 year.43 In routine practice, rates ranging from 0.3 to 33% have been reported.47 Diabetes: Statins may increase the risk of new-onset diabetes, particularly in patients already at risk of developing the disease, by disrupting a number of regulatory pathways including insulin signaling, which may affect insulin sensitivity, pancreatic β-cell function, and adipokine secretion. In a recently published metaanalysis of 13 randomized trials of statins including 91,140 participants, statin use was associated with a 9% increased risk for incident diabetes, with little heterogeneity between the individual trials.48 This represents one additional incident case of diabetes per 1,000 person-years of treatment or 1 additional patient developing diabetes for every 255 patients treated for 4 years.48 The risk of new-onset diabetes with statin use appears to be dose dependent but unrelated to the individual statin, its potency, or its lipophilic or hydrophilic properties.49,50 Meta-regression further indicated that the risk was highest in trials with older participants.48 Other groups at particular risk included women and Asian populations.51 Cancer: The West of Scotland Coronary Prevention Study (WOSCOPS) trial evaluating 40 mg/day pravastatin in men with hypercholesterolemia reported an increase in the overall incidence of cancer.52 The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial reported an increased risk of incident cancer and cancer mortality with pravastatin use among men and women older than 70 years of age.53 These findings have not been replicated in other statin trials. A meta-analysis by the Cholesterol Treatment Trialists’ Collaboration suggested no overall increased risk of cancer or cancer mortality.54 Cognitive impairment: The relationship between statin use and cognitive function is equivocal. Reports of postmarketing adverse events have generally described ill-defined memory loss that was reversible upon discontinuation of statin use. Most reports were from individuals older than 50 years of age. Time to onset of the impairment was highly variable, ranging from 1 day to years after statin exposure. An association between cognitive impairment and a specific statin, a specific age group, a particular statin dose, or concomitant medication use was not observed. Furthermore, the cognitive impairment did not appear to be associated with fixed or progressive dementia, such as Alzheimer’s disease, and was not detectable in controlled clinical trials measuring longer-term cognition.53,55,56 The absolute risk of such adverse events is relatively low. However, due to large-scale use of statins, even a small increase could have a significant public health impact. Cost-effectiveness. Statin therapy is cost effective in secondary
prevention or in populations with a high risk of CVD.57,58 In populations at intermediate or low absolute risk of CVD, VOLUME 96 NUMBER 2 | august 2014 | www.nature.com/cpt
state defined as less than 1% per year, statin therapy is not cost effective.57 As generic statins become more widely available, it is likely that statin therapy will become cost effective in lowerrisk populations,59,60 although it will be particularly important to address the balance of benefits and harms considering the smaller absolute effects in such population groups.61 Therapies targeting cholesterol absorption Ezetimibe. Ezetimibe can significantly lower LDL-C levels by up to about 20% when used alone or in combination with statin therapy. Pharmacology/mechanism of action. Ezetimibe targets the Niemann–Pick C1-like 1 protein (NPC1L1) that is expressed on the enterocyte (apical) intestinal cells.62 NPC1L1 has a sterolsensing domain that works in conjunction with the adapter protein 2 complex and clathrin to facilitate internalization of free cholesterol into the enterocyte (Figure 3). Cholesterol binds to the sterol-sensing domain of NPC1L1, and then the NPC1L1/ cholesterol complex is internalized or endocytosed by joining to the adaptor protein 2–clathrin complex, creating a vesicle complex that then translocates with the help of myosin along microfilaments in the cytosol to a storage endosome called the endocytic recycling compartment. When intracellular cholesterol levels become low, NPC1L1 is released from the endocytic recycling compartment and is trafficked back along microfilaments to the cell membrane.63 By reducing enterocyte cholesterol absorption, chylomicron formation and secretion, and the back flux of cholesterol from the bile, ezetimibe depletes hepatic pools of cholesterol and increases expression of the LDL-R on the surface of hepatocytes, resulting in reductions in serum levels of LDL-C. After being metabolized in the small intestine and liver, ezetimibe is excreted in the bile back into the intestinal lumen, where it can again inhibit the NPC1L1 protein or be excreted in the feces. A small amount (10%) of ezetimibe is excreted in the urine. Clinical trials. Pooled analyses of trials of monotherapy with ezetimibe (10 mg daily) in hypercholesterolemic subjects for a minimum of 12 weeks have reported an 18.5% reduction in LDL-C, an 8% reduction in TGs, and a 3% increase in HDL-C
Ezetimibe
High cholesterol
Extracellular Cell membrane Intracellular
as compared with the effects of placebo.64 Combinationtherapy trials comparing ezetimibe plus statin to ezetimibe alone or statin alone have shown greater LDL-C-lowering efficacy.65 This may reflect potential synergy of the agents because statins can upregulate cholesterol absorption. However, the results of clinical trials evaluating effects on atheroma burden have been disappointing. The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial reported no difference in carotid intimamedia thickness in patients with heterozygous familial hypercholesterolemia who were treated with simvastatin and ezetimibe or with simvastatin and placebo, despite significantly greater LDL-C lowering with the combination.66 In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study,67 1,873 subjects with mild to moderate aortic stenosis were randomized to ezetimibe 10 mg/day and simvastatin or to placebo. After 4 years, combination therapy with ezetimibe reduced LDL-C by 61% as compared with the effect of placebo administration. Although there was no effect on requirement for aortic valve surgery, major CVD events were reduced by 41% in the statin plus ezetimibe group but only in those with less severe aortic stenosis at baseline. In the Study of Heart and Renal Protection (SHARP) trial, subjects with chronic kidney disease (about a third of whom were dialysis dependent) were randomized to a combination of ezetimibe (10 mg/day) and simvastatin or to placebo.68 After 5 years of therapy, a significant 17% reduction in major atherosclerotic events was observed in those on ezetimibe as compared with those on placebo. Notably, no increased risk for adverse events was reported, including for myopathy and for rhabdomyolysis. The CVD risk reductions observed in both the SEAS and SHARP trials were proportional to the degree of LDL-C lowering achieved. Considering that both trials compared the combination of ezetimibe and statin with placebo, the effect of ezetimibe beyond that of the statin remains uncertain. Further important evidence will be provided by the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial, which has recruited more than 18,000 patients with acute coronary syndrome and is comparing the combination of ezetimibe and simvastatin (target LDL-C: 1.4 mmol/l) with simvastatin alone (target LDL-C: 1.8 mmol/l).69 The trial is expected to report in 2014 and will also provide important safety data concerning very low LDL-C levels. Therapies targeting cholesterol synthesis Niacin (nicotinic acid). Pooled studies of niacin use have reported
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reductions in LDL-C and TGs by about 14 and 20%, respectively, and increases in HDL-C by 16% (ref. 70). Reductions in Lp(a) levels have also been reported.71
AP2
Figure 3 Effect of ezetimibe on Niemann–Pick C1-like 1 protein (NPC1L1)mediated internalization of cholesterol. Reprinted with permission from ref. 63. Clinical pharmacology & Therapeutics | VOLUME 96 NUMBER 2 | august 2014
Pharmacology/mechanism of action. Niacin reduces LDL-C and TGs by decreasing fatty acid mobilization from adipose tissue TG stores and by inhibiting hepatocyte diacylglycerol acyltransferase and TG synthesis, leading to increased intracellular ApoB degradation and subsequent decreased secretion of VLDL and LDL-C particles.72 It increases HDL-C by decreasing the catabolism of HDL–ApoAI particles.72 This increases 195
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cholesterol efflux through the reverse cholesterol transport pathway. Side effects, particularly flushing, have limited the use of niacin. Flushing is produced by the stimulation of prostaglandins D(2) and E(2) by subcutaneous Langerhans cells through the G-protein-coupled niacin receptor.72 Clinical trials. A meta-analysis of 11 RCTs evaluated the effect of lipid-modifying strategies containing niacin therapy on CVD outcomes.73 Niacin-containing strategies reduced major coronary events by 25%, stroke by 26%, and all cardiovascular events by 27%.73 However, the effect of niacin alone could not be determined.73 The AIM-HIGH trial in 3,300 subjects with vascular disease and atherogenic dyslipidemia showed no reduction in vascular events with use of a niacin–statin combination as compared with the effect of a statin alone.74 However, the trial was probably underpowered, considering the small differences in achieved HDL-C and LDL-C levels (only +4 and −5 mg/dl, respectively). Moreover, efforts to develop longer-acting niacin formulations that might also incorporate prostaglandin inhibition to minimize side effects have not produced demonstrable CVD benefits. The Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial in 27,000 patients with vascular disease and/or diabetes also showed no reduction in vascular events beyond that observed with statin therapy alone.75 Again, differences in lipid subfractions between the randomized treatment groups were small. In addition, more side effects were reported in patients assigned to niacin–laropiprant (a true prostaglandin inhibitor) than in those assigned to placebo.
Therapies targeting bile acid synthesis Bile acid sequestrants. The bile acid sequestrants cholestyramine
and colestipol have long been recognized to lower LDL-C levels. However, palatability issues and gastrointestinal side effects have limited their use. More recently, colesevelam (and colestimide) have been investigated. Colesevelam HCl is a tablet-form nonabsorbed hydrogel with bile acid–binding properties.
Pharmacology/mechanism of action. Bile acid sequestrants bind negatively charged bile acids and bile salts in the small intestine. This binding interrupts the enterohepatic circulation to increase conversion of cholesterol into bile within the liver. The resulting decrease in hepatocyte cholesterol promotes increased clearance of LDL-C from the circulation. However, hepatocyte synthesis of cholesterol also increases, limiting the LDL-C lowering effect and increasing TG levels.76 Refs. 76–163 are listed in the Supplementary Data online. Clinical trials. In the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), 3,806 men with elevated cholesterol levels but no CHD were randomized to cholestyramine or placebo. Treatment with cholestyramine reduced LDL-C levels by 12% and major CVD events (CHD death and nonfatal myocardial infarction) by 19% (ref. 77). In other trials of cholestyramine and colestipol used alone or in combination with other agents, reduced atheroma progression and coronary disease were reported.78,79 In clinical trials of colesevelam, the 196
LDL-C-lowering effect was similar to or slightly less than that of cholestyramine or colestipol.80 LDL-C reductions of up to 20% (with 3.75–4.5 g/day of colesevelam), as well as increases in HDL-C of up to 9%, were noted. However, the safety and tolerability of colesevelam were superior to those of the older bile acid sequestrants. In patients with type 2 diabetes mellitus, colesevelam also reduced hemoglobin A1c.81 The effects of colesevelam on major CVD events have not been studied. Fibrates. The role of fibrates in the prevention of CVD is much less clear than that of statins. Pharmacology/mechanism of action. Fibrates are weak agonists of peroxisome proliferator–activated receptor α. Fenofibrate is the fibrate of choice because it has no pharmacokinetic interaction with statins.
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial randomized 9,795 patients with type 2 diabetes to fenofibrate or placebo.82,83 The primary CVD outcome, a composite of coronary death or nonfatal myocardial infarction, was not significantly reduced in the active treatment group. This may be due to opposing effects on the individual components of the composite outcome (that is, an observed reduction in nonfatal MI but increase in coronary death) in the active treatment group. The study was limited by a substantial “drop-in” of statin therapy during follow-up, which was greater in the placebo group. Similarly, the lipid arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial randomized 5,518 people with diabetes taking open-label simvastatin to fenofibrate or placebo and reported no significant difference in the primary CVD outcome between the randomized groups.84 However, it is notable that analyses of both the FIELD and ACCORD studies have shown a reduction in microvascular events, including need for laser therapy for diabetic retinopathy, progression in renal impairment, and microfilament mononeuropathy.85–87 Although FIELD and ACCORD represent the largest trials of fibrates, a number of studies with agents other than fenofibrate have been conducted in populations at high risk of future CVD events. A systematic overview of all these trials reported that fibrates were associated with modest but significant reductions in major CVD events and CHD events, but no significant reductions in CVD death or all-cause mortality were found.88 These benefits particularly accrue in individuals who have low HDL-C and high TG levels.88 Clinical trials.
Cholesterylester transfer protein inhibitors. Cholesterylester trans-
fer protein (CETP) inhibition appeared to offer great potential for the treatment of dyslipidemia.
Pharmacology/mechanism of action. CETP is associated with the
transfer of cholesterol between antiatherogenic apoA-containing particles and proatherogenic apoB particles.32 CETP gene variants have been reported to affect CHD event rates, VOLUME 96 NUMBER 2 | august 2014 | www.nature.com/cpt
state but whether these effects reflect changes in HDL-C and/or LDL-C levels is unclear.
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WHY ARE NOVEL THERAPEUTICS NEEDED?
There are three main reasons for the development of novel lipid-lowering agents. First, in people at a very high risk of CVD events, guidelines recommend aiming for a target LDL-C level of 6 years) with familial hypercholesterolemia.141
TREATMENT GUIDELINES
Table 1 summarizes and compares the recently published international treatment guidelines for the management of lipids to reduce CVD.101–103,142 It is of interest that the new ACC/AHA guidelines have been received with great applause but also great consternation. The 2013 ACC/AHA guidelines recommend the use of statins while discouraging the use of other lipid-modifying therapies in high-risk patients.100 Either moderate-intensity or high-intensity statin therapy is recommended for patients with clinical CVD; patients with LDL-C levels ≥ 190 mg/dl (4.9 mmol/l); patients with diabetes aged 40–75 years with LDL-C levels of 70–189 mg/dl (1.8–4.8 mmol/l) and an estimated 10-year CVD risk of ≥7.5%; and finally, patients without clinical CVD or diabetes but with LDL cholesterol levels of 70–189 mg/dl and an estimated 10-year CVD risk of ≥7.5%. In addition, LDL-C treatment targets are no longer 200
recommended, obviating the need for statin therapy to be titrated.100 Clearly, the move away from the treat-to-target approach toward the fixed-dose approach will simplify the treatment of patients.143 However, the lower recommended cardiovascular risk score at which to commence therapy will substantially increase treatment and possibly overtreat people from the age of 40 years.143 Indeed, the confidence that clinicians and healthcare systems have in implementing these guidelines will largely depend on their ability to understand and adequately communicate net treatment benefits (benefits minus harms) to patients. THE CLINICAL AND POPULATION HEALTH CONTEXT Is this the end for statins?
The nadir in terms of reduction of cardiovascular outcomes and the benefits of treatment of dyslipidemia has not been reached. The current evidence is robust and suggests that statins will remain a cornerstone of therapy, together with lifestyle approaches. However, from both the theoretical and practical viewpoint, there is still much to be achieved. In the context of current statin use, the key issues that need to be addressed are as follows: the emergence of new treatment indications, the role of biomarkers for risk stratification and treatment initiation, the improvement of utilization, and, finally, the development of novel therapeutics. EMERGING TREATMENT INDICATIONS FOR STATINS New vascular indications for statins
Concerning new treatment indications, meta-analyses have recently reported a reduction in markers of periprocedural myocardial injury with statin use following percutaneous coronary intervention144 and reduction in postoperative and recurrent atrial fibrillation.145 Furthermore, observational data now suggest benefit with statin use before stroke but also with statin initiation in the hospital at the time of stroke.146 Although these data would ideally be supplemented by large-scale RCTs, they should be seen at this time as extending the results of trials in stable CHD patients, or following acute coronary syndromes, and in patients following a stroke (Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)). Earlier commencement of statins
One particularly important question is whether statin use should be commenced earlier in subjects who are apparently healthy. Estimates of absolute risk are driven particularly by age rather than by modifiable risk factors, including lipid levels. The Global Burden of Disease Study Group has shown that the maximum impact in terms of healthy life-years gained or disability-adjusted life-years averted with CVD interventions such as LDL-C lowering is observed in the decade between 55 and 64 years of age.147 However, atherosclerotic CVD develops over a period of decades from a young age,148 with a long latent period before a presentation with a potentially fatal first clinical event. Moreover, younger individuals and particularly women have higher modifiable risk and longer future lifetime exposure for any particular absolute risk level as compared with older people. The case for earlier initiation of statins is supported by VOLUME 96 NUMBER 2 | august 2014 | www.nature.com/cpt
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Table 1 Comparison of recent guidelines for lipid management Guideline Very high risk Established CVD; type 2 diabetes; type 1 diabetes with organ damage; moderate to severe CKD; 10 year SCORE level ≥ 10%;
High risk Markedly elevated single risk factors; 10 year SCORE level ≥5 to < 10%;
Moderate risk 10 year SCORE level ≥ 1 to ≤5%;
Low risk 10 year SCORE level 4.9 mmol/l;
Lifestyle intervention if LDL-C < 2.5 mmol/l; Lifestyle intervention if LDL-C = 2.5 to >4.9 mmol/l (consider drugs if uncontrolled);
No intervention if LDL-C < 2.5 mmol/l; Lifestyle intervention if LDL-C = 2.5 to 4.9 mmol/l (consider drugs if uncontrolled)
Target LDL-C < 1.8 mmol/l, and/or ≥50% reduction if target not reached
Target LDL-C = 15 years duration and age ≥ 30 years or microvascular disease; CKD; high-risk hypertension;
Intervention
Treatment (Health behavior Treatment (Health behavior modification and statin therapy) modification and statin therapy) if LDL-C ≥ 3.5 in all high-risk individuals; mmol/l; If LDL-C < 3.5 mmol/l health behavior modification or additional risk stratification based on, ApoB (≥ 1.2 g/l), or non-HDL-C ( ≥ 4.3 mmol/l) is suggested to identify patients who might benefit from pharmacotherapy;
Targets
LDL-C ≤ 2.0 mmol/l or ≥50% reduction of LDL-C; alternative targets are ApoB ≤0.8 g/l or non-HDL-C ≤ 2.6 mmol/l
EAS/ESC 2011 Risk stratification (Europe)
Intervention
Targets
NVDPA 2012 (Australia)
CCS 2012 (Canada)
Intermediate risk No high-risk features; FRE score: 10–19%;
LDL-C ≤ 2.0 mmol/l or ≥50% reduction of LDL-C; Alternative targets are ApoB ≤ 0.8 g/l or non-HDL-C ≤ 2.6 mmol/l
Low risk FRE as
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nature publishing group
Treatment of Dyslipidemia and Cardiovascular Outcomes: The Journey So Far—Is This the End for Statins? S Zoungas1,2, AJ Curtis1, JJ McNeil1 and AM Tonkin1 Dyslipidemia is common and is associated with the highest population-attributable risk for cardiovascular disease. Of various cardiovascular preventive therapies, the evidence from randomized controlled trials supporting the importance of aggressive lipid lowering is the most robust, particularly for statins. Despite the use of proven therapies, cardiovascular disease event rates remain relatively high, underpinning the development of novel therapies. In addition to testing new drugs to reduce low-density-lipoprotein cholesterol, there has been a major focus on treatments that can favorably influence high-density-lipoprotein cholesterol and triglyceride levels. This review provides an overview of the important relationship between lipids and cardiovascular disease, the lipid-modifying therapeutic approaches to reducing cardiovascular disease, new guidelines and recommendations, and the challenges ahead for the treatment of dyslipidemia, particularly whether statins will remain at the forefront of recommended therapies. EPIDEMIOLOGY: LIPIDS AND CARDIOVASCULAR DISEASE Global burden
Over the past few decades, mortality from atherosclerotic cardiovascular disease (CVD) in most developed countries has substantially declined. In northwestern Europe, North America, Australia, and other regions, treatment advances along with lower rates of smoking and better management of risk factors have led to major reductions in age-standardized death rates from CVD and coronary heart disease (CHD).1 Despite this, CVD remains the major cause of mortality globally, with 17.5 million deaths attributed to CVD in 2012. During the same period, CHD and stroke accounted for 7.4 and 6.7 million deaths, respectively.2 Two major global challenges are (i) the marked increase in the burden of CVD anticipated for low- and middle-income countries and in huge Asian populations such as those in China and India, and (ii) the slowing of the rate of decline in age-specific CHD mortality among those in younger age categories as seen in the United States.1 LIPID FRACTIONS AND CARDIOVASCULAR RISK Low-density-lipoprotein cholesterol
The continuous log-linear relationship between CVD risk and increasing levels of low-density-lipoprotein cholesterol (LDL-C) is well established.3 This relationship extends across age categories4 and pertains to different regions of the world.5
Non-high-density-lipoprotein cholesterol
Non-high-density-lipoprotein cholesterol (non-HDL-C) represents an alternative approach to quantifying total atherogenic particle number. It is calculated by subtraction of HDL-C from total cholesterol (TC) and encompasses low-, intermediate-, and very-low-density-lipoprotein (VLDL) cholesterol content. Similar to increasing levels of LDL-C, increasing levels of nonHDL-C have been associated with increased risk of CHD and ischemic stroke (Figure 1).6 High-density-lipoprotein cholesterol
Epidemiological studies, including the Framingham Heart Study, have demonstrated a strong and independent inverse relationship between levels of HDL-C and risk of CVD (Figure 1).6–8 Increases in HDL-C of 1 mg/l (0.03 mmol/l) have been associated with decreases in CVD risk of 2–3%.9 The relationship also holds in patients who are already taking a statin,10 although perhaps not when LDL-C levels are very low.11 In a meta-analysis of individual patient data from eight trials of statin therapy, higher HDL-C levels were strongly associated with reduced CVD risk.12 However, any in-trial incremental changes in HDL-C levels (i.e., increases) were not associated with reduced risk for CVD events.12 This uncertainty has led to the investigation of a role for functional quality of HDL rather than for its particle number.13
1School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia; 2The George Institute for Global Health, Sydney, Australia.
Correspondence: S Zoungas ([email protected])
Received 13 March 2014; accepted 7 April 2014; advance online publication 18 June 2014. doi:10.1038/clpt.2014.86 192
VOLUME 96 NUMBER 2 | august 2014 | www.nature.com/cpt
state Triglycerides
Triglycerides (TGs) are still somewhat controversial. TG levels have been associated with risk of CVD, although less consistently than LDL-C and HDL-C levels.14–16 An independent role for TGs is supported by evidence from case–control studies14 as well as from numerous cohort studies and meta-analyses.17–20 In a recent meta-analysis of prospective studies, elevated blood TG levels were associated with an increased risk of CVD-related and all-cause mortality.18 In 22 studies the risk of CVD mortality was increased by 13% and the risk of all-cause mortality was increased by 12% per mmol/l increment in TG levels. Despite this evidence, a causative role for TGs in CVD has recently been challenged with new evidence suggesting that TG level is simply a marker for low HDL-C and increased LDL-C levels.6 Other lipid fractions and cardiovascular risk
Epidemiological evidence supports the importance of other lipid fractions in CVD/CHD. Apolipoprotein B. Apolipoprotein B (ApoB) is the major apolipoprotein and is an essential component of VLDL, LDL, intermediate-density lipoprotein, and lipoprotein(a). Like non-HDLC, it is a measure of total atherogenic particle number and is associated with CVD risk (Figure 1).6 For practical purposes, reporting of non-HDL-C levels is currently recommended over measurement of ApoB levels.6 Lipoprotein(a). Lipoprotein(a) (Lp(a)) is a cholesterol-rich LDL-
like particle bound to apolipoprotein (a) (Apo(a)), a plasminogen-like glycoprotein.21 Biologically plausible mechanisms for an effect of Lp(a) on CVD include induction of a prothrombotic/antifibrinolytic effect because Apo(a) resembles both plasminogen and plasmin but has no fibrinolytic activity and/ or causes no acceleration of atherosclerosis because Lp(a) is
cholesterol rich.22 Population studies have shown an association between high Lp(a) levels and CVD risk and with increased LDL-C levels this effect appears to be enhanced.23,24 Evidence from genetic studies also supports Lp(a) as a causal risk factor for CHD independent of other risk factors and LDL-C levels.25,26 In the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) trial, the levels of Lp(a) at baseline and during the study predicted CVD events, confirming an influence on residual risk.27 Despite this observation, there is little evidence that lowering Lp(a) levels reduces risk of CHD.27,28 Measurement of Lp(a) levels has been advocated for risk stratification, although this is not universally accepted.29 For example, the European Atherosclerosis Society22 has recently recommended Lp(a) screening (i) in people with intermediate or high CVD risk with premature CVD, familial hypercholesterolemia, a family history of premature CVD and/ or elevated Lp(a), and recurrent CVD despite statin treatment, and (ii) in people with a ≥3% 10-year risk of fatal CVD according to European guidelines and/or a ≥10% 10-year risk of CHD according to US guidelines.22 ESTABLISHED THERAPIES Therapies targeting LDL-C
Strategies to lower LDL-C levels have consistently been shown to reduce risk of major CVD events. Meta-regression of intervention studies has shown a clear linear relationship between the magnitude of the LDL-C reduction achieved and risk reduction observed (Figure 2).30 Of the LDL-lowering interventions studied (5 diet studies, 3 bile acid–sequestrant studies, 1 surgery study, and 10 statin trials that included a total of 81,859 patients), statins have the greatest evidence of benefits.
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Figure 1 Risks of CHD across fifths of non-HDL-C and HDL-C levels or apolipoprotein levels. CHD, coronary heart disease; HDL-C, high-densitylipoprotein cholesterol. Reprinted with permission from ref. 6. Clinical pharmacology & Therapeutics | VOLUME 96 NUMBER 2 | august 2014
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Figure 2 Correlation between LDL-C lowering and decreased CHD risk according to treatment modality in a meta-regression analysis. CHD, coronary heart disease; LDL-C, low-density-lipoprotein cholesterol. Reprinted with permission from ref. 30. 193
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Statins. Statins are the first-line therapeutic agents for reducing LDL-C levels. Many statins have been tested and overall have demonstrated reduction of major vascular events. Pharmacology/mechanism of action. Statins (3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors) inhibit the mevalonate pathway and biosynthesis of cholesterol and isoprenoids through displacement of HMG-CoA that is bound to HMG-CoA reductase. HMG-CoA reductase is prevented from attaining a functional conformation, which prevents the conversion of HMG-CoA to l-mevalonate and reduces the production of intracellular cholesterol. Induction of LDL receptor (LDL-R) gene expression and formation on the hepatocyte cell surface results in an increase in the clearance of LDL-C and its precursors, intermediate-density lipoprotein and VLDL, from the blood and an 18–55% decrease in the concentration of circulating LDL-C.31 Increased HDL-C levels (by 5–15%),32 decreased levels of atherogenic lipoproteins,33 decreased TG concentration (7–30%), and decreased synthesis and secretion of TG-rich lipoproteins,33 as well as reduced susceptibility of LDL-C to oxidation, have also been reported.31 Statins also exert a number of effects independent of their lipid-lowering properties,34 including improvement of endothelial function,35 inhibition of the thrombogenic response,36 a moderately powerful anti-inflammatory action,37 and a possible antihypertensive effect.38 These pleiotropic effects have been attributed to the inhibition of isoprenoid synthesis and isoprenylation of key cell signaling proteins such as the Rho, Ras, and Rac guanosine triphosphatases,39,40 an activation step important for multiple cell functions including maintenance of cell shape, factor secretion, differentiation, migration, and proliferation. Clinical trials. A meta-analysis of individual participant data from 27 statin trials reported a clear linear relationship between the degree of LDL-C lowering achieved with statins and benefits achieved, with reductions in major vascular events and allcause mortality of 21 and 10% per mmol/l reduction in LDL-C, respectively (Cholesterol Treatment Trialists’ Collaboration).41 This meta-analysis also confirmed the superiority of more intensive, as compared with less intensive, statin therapy. The benefits were broadly observed in people with CHD, stroke, and diabetes, as well as in younger people who were apparently healthy.41 Safety. Ongoing drug safety evaluation is particularly impor-
tant for widely prescribed drugs such as the statins, which are typically prescribed as lifelong therapies. Changes in metabolic processes, aging, and development of concomitant diseases requiring other pharmacotherapy, and hence having the potential for drug interactions, are also likely to occur and affect the overall safety of statins. Reported adverse events from randomized controlled trials (RCTs) and observational studies include skeletal myotoxicity, diabetes, cancer, cognitive impairment, and acute kidney injury.42 Myopathy: All statins have been reported to cause myopathy, with the severity ranging from asymptomatic increases in 194
creatine kinase to myalgia and myositis to fatal rhabdomyolysis commonly characterized by massive muscle necrosis, myoglobinuria, and acute renal failure.43–45 Rhabdomyolysis represents the least frequent, although potentially fatal, complication caused by skeletal muscle breakdown. The rates of rhabdomyolysis have been estimated from clinical trial and cohort data as 3 per 100,000 person-years during statin treatment.46 Myopathy is dose dependent and may occur even after therapy has been tolerated for up to 1 year.43 In routine practice, rates ranging from 0.3 to 33% have been reported.47 Diabetes: Statins may increase the risk of new-onset diabetes, particularly in patients already at risk of developing the disease, by disrupting a number of regulatory pathways including insulin signaling, which may affect insulin sensitivity, pancreatic β-cell function, and adipokine secretion. In a recently published metaanalysis of 13 randomized trials of statins including 91,140 participants, statin use was associated with a 9% increased risk for incident diabetes, with little heterogeneity between the individual trials.48 This represents one additional incident case of diabetes per 1,000 person-years of treatment or 1 additional patient developing diabetes for every 255 patients treated for 4 years.48 The risk of new-onset diabetes with statin use appears to be dose dependent but unrelated to the individual statin, its potency, or its lipophilic or hydrophilic properties.49,50 Meta-regression further indicated that the risk was highest in trials with older participants.48 Other groups at particular risk included women and Asian populations.51 Cancer: The West of Scotland Coronary Prevention Study (WOSCOPS) trial evaluating 40 mg/day pravastatin in men with hypercholesterolemia reported an increase in the overall incidence of cancer.52 The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial reported an increased risk of incident cancer and cancer mortality with pravastatin use among men and women older than 70 years of age.53 These findings have not been replicated in other statin trials. A meta-analysis by the Cholesterol Treatment Trialists’ Collaboration suggested no overall increased risk of cancer or cancer mortality.54 Cognitive impairment: The relationship between statin use and cognitive function is equivocal. Reports of postmarketing adverse events have generally described ill-defined memory loss that was reversible upon discontinuation of statin use. Most reports were from individuals older than 50 years of age. Time to onset of the impairment was highly variable, ranging from 1 day to years after statin exposure. An association between cognitive impairment and a specific statin, a specific age group, a particular statin dose, or concomitant medication use was not observed. Furthermore, the cognitive impairment did not appear to be associated with fixed or progressive dementia, such as Alzheimer’s disease, and was not detectable in controlled clinical trials measuring longer-term cognition.53,55,56 The absolute risk of such adverse events is relatively low. However, due to large-scale use of statins, even a small increase could have a significant public health impact. Cost-effectiveness. Statin therapy is cost effective in secondary
prevention or in populations with a high risk of CVD.57,58 In populations at intermediate or low absolute risk of CVD, VOLUME 96 NUMBER 2 | august 2014 | www.nature.com/cpt
state defined as less than 1% per year, statin therapy is not cost effective.57 As generic statins become more widely available, it is likely that statin therapy will become cost effective in lowerrisk populations,59,60 although it will be particularly important to address the balance of benefits and harms considering the smaller absolute effects in such population groups.61 Therapies targeting cholesterol absorption Ezetimibe. Ezetimibe can significantly lower LDL-C levels by up to about 20% when used alone or in combination with statin therapy. Pharmacology/mechanism of action. Ezetimibe targets the Niemann–Pick C1-like 1 protein (NPC1L1) that is expressed on the enterocyte (apical) intestinal cells.62 NPC1L1 has a sterolsensing domain that works in conjunction with the adapter protein 2 complex and clathrin to facilitate internalization of free cholesterol into the enterocyte (Figure 3). Cholesterol binds to the sterol-sensing domain of NPC1L1, and then the NPC1L1/ cholesterol complex is internalized or endocytosed by joining to the adaptor protein 2–clathrin complex, creating a vesicle complex that then translocates with the help of myosin along microfilaments in the cytosol to a storage endosome called the endocytic recycling compartment. When intracellular cholesterol levels become low, NPC1L1 is released from the endocytic recycling compartment and is trafficked back along microfilaments to the cell membrane.63 By reducing enterocyte cholesterol absorption, chylomicron formation and secretion, and the back flux of cholesterol from the bile, ezetimibe depletes hepatic pools of cholesterol and increases expression of the LDL-R on the surface of hepatocytes, resulting in reductions in serum levels of LDL-C. After being metabolized in the small intestine and liver, ezetimibe is excreted in the bile back into the intestinal lumen, where it can again inhibit the NPC1L1 protein or be excreted in the feces. A small amount (10%) of ezetimibe is excreted in the urine. Clinical trials. Pooled analyses of trials of monotherapy with ezetimibe (10 mg daily) in hypercholesterolemic subjects for a minimum of 12 weeks have reported an 18.5% reduction in LDL-C, an 8% reduction in TGs, and a 3% increase in HDL-C
Ezetimibe
High cholesterol
Extracellular Cell membrane Intracellular
as compared with the effects of placebo.64 Combinationtherapy trials comparing ezetimibe plus statin to ezetimibe alone or statin alone have shown greater LDL-C-lowering efficacy.65 This may reflect potential synergy of the agents because statins can upregulate cholesterol absorption. However, the results of clinical trials evaluating effects on atheroma burden have been disappointing. The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial reported no difference in carotid intimamedia thickness in patients with heterozygous familial hypercholesterolemia who were treated with simvastatin and ezetimibe or with simvastatin and placebo, despite significantly greater LDL-C lowering with the combination.66 In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study,67 1,873 subjects with mild to moderate aortic stenosis were randomized to ezetimibe 10 mg/day and simvastatin or to placebo. After 4 years, combination therapy with ezetimibe reduced LDL-C by 61% as compared with the effect of placebo administration. Although there was no effect on requirement for aortic valve surgery, major CVD events were reduced by 41% in the statin plus ezetimibe group but only in those with less severe aortic stenosis at baseline. In the Study of Heart and Renal Protection (SHARP) trial, subjects with chronic kidney disease (about a third of whom were dialysis dependent) were randomized to a combination of ezetimibe (10 mg/day) and simvastatin or to placebo.68 After 5 years of therapy, a significant 17% reduction in major atherosclerotic events was observed in those on ezetimibe as compared with those on placebo. Notably, no increased risk for adverse events was reported, including for myopathy and for rhabdomyolysis. The CVD risk reductions observed in both the SEAS and SHARP trials were proportional to the degree of LDL-C lowering achieved. Considering that both trials compared the combination of ezetimibe and statin with placebo, the effect of ezetimibe beyond that of the statin remains uncertain. Further important evidence will be provided by the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial, which has recruited more than 18,000 patients with acute coronary syndrome and is comparing the combination of ezetimibe and simvastatin (target LDL-C: 1.4 mmol/l) with simvastatin alone (target LDL-C: 1.8 mmol/l).69 The trial is expected to report in 2014 and will also provide important safety data concerning very low LDL-C levels. Therapies targeting cholesterol synthesis Niacin (nicotinic acid). Pooled studies of niacin use have reported
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reductions in LDL-C and TGs by about 14 and 20%, respectively, and increases in HDL-C by 16% (ref. 70). Reductions in Lp(a) levels have also been reported.71
AP2
Figure 3 Effect of ezetimibe on Niemann–Pick C1-like 1 protein (NPC1L1)mediated internalization of cholesterol. Reprinted with permission from ref. 63. Clinical pharmacology & Therapeutics | VOLUME 96 NUMBER 2 | august 2014
Pharmacology/mechanism of action. Niacin reduces LDL-C and TGs by decreasing fatty acid mobilization from adipose tissue TG stores and by inhibiting hepatocyte diacylglycerol acyltransferase and TG synthesis, leading to increased intracellular ApoB degradation and subsequent decreased secretion of VLDL and LDL-C particles.72 It increases HDL-C by decreasing the catabolism of HDL–ApoAI particles.72 This increases 195
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cholesterol efflux through the reverse cholesterol transport pathway. Side effects, particularly flushing, have limited the use of niacin. Flushing is produced by the stimulation of prostaglandins D(2) and E(2) by subcutaneous Langerhans cells through the G-protein-coupled niacin receptor.72 Clinical trials. A meta-analysis of 11 RCTs evaluated the effect of lipid-modifying strategies containing niacin therapy on CVD outcomes.73 Niacin-containing strategies reduced major coronary events by 25%, stroke by 26%, and all cardiovascular events by 27%.73 However, the effect of niacin alone could not be determined.73 The AIM-HIGH trial in 3,300 subjects with vascular disease and atherogenic dyslipidemia showed no reduction in vascular events with use of a niacin–statin combination as compared with the effect of a statin alone.74 However, the trial was probably underpowered, considering the small differences in achieved HDL-C and LDL-C levels (only +4 and −5 mg/dl, respectively). Moreover, efforts to develop longer-acting niacin formulations that might also incorporate prostaglandin inhibition to minimize side effects have not produced demonstrable CVD benefits. The Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial in 27,000 patients with vascular disease and/or diabetes also showed no reduction in vascular events beyond that observed with statin therapy alone.75 Again, differences in lipid subfractions between the randomized treatment groups were small. In addition, more side effects were reported in patients assigned to niacin–laropiprant (a true prostaglandin inhibitor) than in those assigned to placebo.
Therapies targeting bile acid synthesis Bile acid sequestrants. The bile acid sequestrants cholestyramine
and colestipol have long been recognized to lower LDL-C levels. However, palatability issues and gastrointestinal side effects have limited their use. More recently, colesevelam (and colestimide) have been investigated. Colesevelam HCl is a tablet-form nonabsorbed hydrogel with bile acid–binding properties.
Pharmacology/mechanism of action. Bile acid sequestrants bind negatively charged bile acids and bile salts in the small intestine. This binding interrupts the enterohepatic circulation to increase conversion of cholesterol into bile within the liver. The resulting decrease in hepatocyte cholesterol promotes increased clearance of LDL-C from the circulation. However, hepatocyte synthesis of cholesterol also increases, limiting the LDL-C lowering effect and increasing TG levels.76 Refs. 76–163 are listed in the Supplementary Data online. Clinical trials. In the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), 3,806 men with elevated cholesterol levels but no CHD were randomized to cholestyramine or placebo. Treatment with cholestyramine reduced LDL-C levels by 12% and major CVD events (CHD death and nonfatal myocardial infarction) by 19% (ref. 77). In other trials of cholestyramine and colestipol used alone or in combination with other agents, reduced atheroma progression and coronary disease were reported.78,79 In clinical trials of colesevelam, the 196
LDL-C-lowering effect was similar to or slightly less than that of cholestyramine or colestipol.80 LDL-C reductions of up to 20% (with 3.75–4.5 g/day of colesevelam), as well as increases in HDL-C of up to 9%, were noted. However, the safety and tolerability of colesevelam were superior to those of the older bile acid sequestrants. In patients with type 2 diabetes mellitus, colesevelam also reduced hemoglobin A1c.81 The effects of colesevelam on major CVD events have not been studied. Fibrates. The role of fibrates in the prevention of CVD is much less clear than that of statins. Pharmacology/mechanism of action. Fibrates are weak agonists of peroxisome proliferator–activated receptor α. Fenofibrate is the fibrate of choice because it has no pharmacokinetic interaction with statins.
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial randomized 9,795 patients with type 2 diabetes to fenofibrate or placebo.82,83 The primary CVD outcome, a composite of coronary death or nonfatal myocardial infarction, was not significantly reduced in the active treatment group. This may be due to opposing effects on the individual components of the composite outcome (that is, an observed reduction in nonfatal MI but increase in coronary death) in the active treatment group. The study was limited by a substantial “drop-in” of statin therapy during follow-up, which was greater in the placebo group. Similarly, the lipid arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial randomized 5,518 people with diabetes taking open-label simvastatin to fenofibrate or placebo and reported no significant difference in the primary CVD outcome between the randomized groups.84 However, it is notable that analyses of both the FIELD and ACCORD studies have shown a reduction in microvascular events, including need for laser therapy for diabetic retinopathy, progression in renal impairment, and microfilament mononeuropathy.85–87 Although FIELD and ACCORD represent the largest trials of fibrates, a number of studies with agents other than fenofibrate have been conducted in populations at high risk of future CVD events. A systematic overview of all these trials reported that fibrates were associated with modest but significant reductions in major CVD events and CHD events, but no significant reductions in CVD death or all-cause mortality were found.88 These benefits particularly accrue in individuals who have low HDL-C and high TG levels.88 Clinical trials.
Cholesterylester transfer protein inhibitors. Cholesterylester trans-
fer protein (CETP) inhibition appeared to offer great potential for the treatment of dyslipidemia.
Pharmacology/mechanism of action. CETP is associated with the
transfer of cholesterol between antiatherogenic apoA-containing particles and proatherogenic apoB particles.32 CETP gene variants have been reported to affect CHD event rates, VOLUME 96 NUMBER 2 | august 2014 | www.nature.com/cpt
state but whether these effects reflect changes in HDL-C and/or LDL-C levels is unclear.
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WHY ARE NOVEL THERAPEUTICS NEEDED?
There are three main reasons for the development of novel lipid-lowering agents. First, in people at a very high risk of CVD events, guidelines recommend aiming for a target LDL-C level of 6 years) with familial hypercholesterolemia.141
TREATMENT GUIDELINES
Table 1 summarizes and compares the recently published international treatment guidelines for the management of lipids to reduce CVD.101–103,142 It is of interest that the new ACC/AHA guidelines have been received with great applause but also great consternation. The 2013 ACC/AHA guidelines recommend the use of statins while discouraging the use of other lipid-modifying therapies in high-risk patients.100 Either moderate-intensity or high-intensity statin therapy is recommended for patients with clinical CVD; patients with LDL-C levels ≥ 190 mg/dl (4.9 mmol/l); patients with diabetes aged 40–75 years with LDL-C levels of 70–189 mg/dl (1.8–4.8 mmol/l) and an estimated 10-year CVD risk of ≥7.5%; and finally, patients without clinical CVD or diabetes but with LDL cholesterol levels of 70–189 mg/dl and an estimated 10-year CVD risk of ≥7.5%. In addition, LDL-C treatment targets are no longer 200
recommended, obviating the need for statin therapy to be titrated.100 Clearly, the move away from the treat-to-target approach toward the fixed-dose approach will simplify the treatment of patients.143 However, the lower recommended cardiovascular risk score at which to commence therapy will substantially increase treatment and possibly overtreat people from the age of 40 years.143 Indeed, the confidence that clinicians and healthcare systems have in implementing these guidelines will largely depend on their ability to understand and adequately communicate net treatment benefits (benefits minus harms) to patients. THE CLINICAL AND POPULATION HEALTH CONTEXT Is this the end for statins?
The nadir in terms of reduction of cardiovascular outcomes and the benefits of treatment of dyslipidemia has not been reached. The current evidence is robust and suggests that statins will remain a cornerstone of therapy, together with lifestyle approaches. However, from both the theoretical and practical viewpoint, there is still much to be achieved. In the context of current statin use, the key issues that need to be addressed are as follows: the emergence of new treatment indications, the role of biomarkers for risk stratification and treatment initiation, the improvement of utilization, and, finally, the development of novel therapeutics. EMERGING TREATMENT INDICATIONS FOR STATINS New vascular indications for statins
Concerning new treatment indications, meta-analyses have recently reported a reduction in markers of periprocedural myocardial injury with statin use following percutaneous coronary intervention144 and reduction in postoperative and recurrent atrial fibrillation.145 Furthermore, observational data now suggest benefit with statin use before stroke but also with statin initiation in the hospital at the time of stroke.146 Although these data would ideally be supplemented by large-scale RCTs, they should be seen at this time as extending the results of trials in stable CHD patients, or following acute coronary syndromes, and in patients following a stroke (Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)). Earlier commencement of statins
One particularly important question is whether statin use should be commenced earlier in subjects who are apparently healthy. Estimates of absolute risk are driven particularly by age rather than by modifiable risk factors, including lipid levels. The Global Burden of Disease Study Group has shown that the maximum impact in terms of healthy life-years gained or disability-adjusted life-years averted with CVD interventions such as LDL-C lowering is observed in the decade between 55 and 64 years of age.147 However, atherosclerotic CVD develops over a period of decades from a young age,148 with a long latent period before a presentation with a potentially fatal first clinical event. Moreover, younger individuals and particularly women have higher modifiable risk and longer future lifetime exposure for any particular absolute risk level as compared with older people. The case for earlier initiation of statins is supported by VOLUME 96 NUMBER 2 | august 2014 | www.nature.com/cpt
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Table 1 Comparison of recent guidelines for lipid management Guideline Very high risk Established CVD; type 2 diabetes; type 1 diabetes with organ damage; moderate to severe CKD; 10 year SCORE level ≥ 10%;
High risk Markedly elevated single risk factors; 10 year SCORE level ≥5 to < 10%;
Moderate risk 10 year SCORE level ≥ 1 to ≤5%;
Low risk 10 year SCORE level 4.9 mmol/l;
Lifestyle intervention if LDL-C < 2.5 mmol/l; Lifestyle intervention if LDL-C = 2.5 to >4.9 mmol/l (consider drugs if uncontrolled);
No intervention if LDL-C < 2.5 mmol/l; Lifestyle intervention if LDL-C = 2.5 to 4.9 mmol/l (consider drugs if uncontrolled)
Target LDL-C < 1.8 mmol/l, and/or ≥50% reduction if target not reached
Target LDL-C = 15 years duration and age ≥ 30 years or microvascular disease; CKD; high-risk hypertension;
Intervention
Treatment (Health behavior Treatment (Health behavior modification and statin therapy) modification and statin therapy) if LDL-C ≥ 3.5 in all high-risk individuals; mmol/l; If LDL-C < 3.5 mmol/l health behavior modification or additional risk stratification based on, ApoB (≥ 1.2 g/l), or non-HDL-C ( ≥ 4.3 mmol/l) is suggested to identify patients who might benefit from pharmacotherapy;
Targets
LDL-C ≤ 2.0 mmol/l or ≥50% reduction of LDL-C; alternative targets are ApoB ≤0.8 g/l or non-HDL-C ≤ 2.6 mmol/l
EAS/ESC 2011 Risk stratification (Europe)
Intervention
Targets
NVDPA 2012 (Australia)
CCS 2012 (Canada)
Intermediate risk No high-risk features; FRE score: 10–19%;
LDL-C ≤ 2.0 mmol/l or ≥50% reduction of LDL-C; Alternative targets are ApoB ≤ 0.8 g/l or non-HDL-C ≤ 2.6 mmol/l
Low risk FRE as
