Low-density lipoprotein cholesterol lowering in the prevention of CHD: How low should we go?

Opinion statement The past 12 years have seen the publication of numerous randomized placebo-controlled studies using statins to lower low-density lipoprotein cholesterol (LDLC) to assess the efficacy of cholesterol lowering on cardiovascular events. Initial studies predominantly evaluated mortality or nonfatal myocardial infarctions and coronary heart disease (CHD) death in patients with known or presumed established coronary disease and moderately elevated to very elevated serum cholesterol concentrations. Subsequent investigations studied a broader spectrum of cardiovascular events as a composite primary end point in both primary and secondary prevention strategies in subjects with lower mean entry serum LDLC concentrations. These studies have generally shown a reduction in a composite end point of cardiovascular events, although not necessarily the more restricted end points used in previous studies. Although the LDLC mantra "lower is better" has been popularized in advertising and continuing medical education and suggested as an option in "very high risk" patients by the National Cholesterol Education Program Adult Treatment Panel, the precise target level for LDLC for optimal treatment has not been rigorously defined. Serum LDLC less than 100 mg/dL seems reasonable for patients with known atherosclerosis or at high risk for atherosclerosis (diabetes or presence of multiple risk factors). Serum LDLC less than 70 mg/dL may be a reasonable goal in the setting of acute coronary syndromes, but there are many problems with the data on which this recommendation is made. Furthermore, many advocates of "lower is better" seem oblivious to the potential downsides of more aggressive lipid-lowering therapy. The LDLC target in lower risk primary prevention is less clear. What is obvious is that moderate-dose statin therapy can lower CHD risk in primary prevention and secondary prevention with minimal side effects, and with the imminent availability of several generic statins, with great costeffectiveness.     

Hypolipemic agents for stroke prevention

An important issue for stroke prevention is identification and treatment of risk factors such as hypercholesterolemia. The four reasons to test hypolipidemic agents in stroke prevention are: (i) a statistical link between elevated low-density lipoprotein cholesterol (LDL-c) or decreased high-density lipoprotein cholesterol (HDL-c) and ischemic stroke; (ii) a reduction in vascular risk in randomized trials in patients with coronary heart disease; (iii) evidence of a decreased plaque progression under statins, (iv) pooled analyses of primary and secondary prevention trials showing that reduction of total serum cholesterol reduces the incidence of stroke, especially with the highest rate of cholesterol reduction, and in patients with the highest risk of stroke (i.e., with statins in secondary prevention trials), and (v) prophylactic neuroprotection induced by hypolipidemic agents in animal models of cerebral ischemia. Data provided by trials conducted in subjects with coronary heart disease and in asymptomatic individuals should now be confirmed in stroke patient.     

HYPOLIPEMIC AGENTS FOR STROKE PREVENTION

An important issue for stroke prevention is identification and treatment of risk factors such as hypercholesterolemia. The four reasons to test hypolipidemic agents in stroke prevention are: (i) a statistical link between elevated low-density lipoprotein cholesterol (LDL-c) or decreased high-density lipoprotein cholesterol (HDL-c) and ischemic stroke; (ii) a reduction in vascular risk in randomized trials in patients with coronary heart disease; (iii) evidence of a decreased plaque progression under statins, (iv) pooled analyses of primary and secondary prevention trials showing that reduction of total serum cholesterol reduces the incidence of stroke, especially with the highest rate of cholesterol reduction, and in patients with the highest risk of stroke (i.e., with statins in secondary prevention trials), and (v) prophylactic neuroprotection induced by hypolipidemic agents in animal models of cerebral ischemia. Data provided by trials conducted in subjects with coronary heart disease and in asymptomatic individuals should now be confirmed in stroke patient.     

Miscellaneous non-inflammatory musculoskeletal conditions. Rare thesaurismosis and xanthomatosis

The focus will be on xanthomatosis, a tissue danger signal which needs to be recognized by the clinician, and its relationship with monogenetic lipoprotein disorders (cholesterol, triglycerides), bile acid and sterol metabolism, particularly on metabolic pathways and genetics as well as on musculoskeletal and cardiovascular involvement, and their implications for clinical management. The critical question is to assess coronary heart disease risk, requiring correct identification of the pattern of lipoprotein disorders and of the causes (primary or secondary). Familial hypercholesterolemia must be suspected in adults and children with raised total cholesterol, especially when there is a personal or a family history of premature coronary heart disease, usually requiring potent statins to achieve adequate LDL-cholesterol lowering, even if we do not know safety of long-term therapy and whether treatments of dyslipidemia early in life prevent cardiovascular diseases in adulthood. Cerebrotendinous xanthomatosis is a treatable disease and must be suspected if there is a history of infantile chronic diarrhea and/or juvenile cataracts, even in the absence of tendon xanthomas. Current evidence for the prevention and screening, diagnosis, and treatment of dyslipidemia are available for the clinicians.     

Lipid management: Considerations in acute coronary syndrome

Managing dyslipidemia is an important part of the primary and secondary prevention of coronary heart disease. Low-density lipoprotein cholesterol reduction remains the primary lipid goal. Patients who have experienced an acute coronary syndrome (ACS) are at very high risk of recurrent adverse cardiovascular events. A growing body of literature supports the concept that early and intensive treatment with statins after an ACS event decreases recurrent adverse cardiovascular events. We review available evidence pertaining to lipid alterations in ACS.     

Lipid management: Considerations in acute coronary syndrome

Managing dyslipidemia is an important part of the primary and secondary prevention of coronary heart disease. Low-density lipoprotein cholesterol reduction remains the primary lipid goal. Patients who have experienced an acute coronary syndrome (ACS) are at very high risk of recurrent adverse cardiovascular events. A growing body of literature supports the concept that early and intensive treatment with statins after an ACS event decreases recurrent adverse cardiovascular events. We review available evidence pertaining to lipid alterations in ACS.     

Lipids in type 2 diabetes

Type 2 diabetes increases the risk of cardiovascular disease two- to fourfold compared to the risk in nondiabetic subjects. Although type 2 diabetes is associated with a clustering of risk factors, the cause for an excess risk of cardiovascular disease remains unknown. Lipid and lipoprotein abnormalities in type 2 diabetes include particularly elevated levels of total and very low-density lipoprotein triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol. Total and low-density lipoprotein (LDL) cholesterol levels are usually normal if glycemic control is adequate but LDL particles are small and dense. According to prospective population-based studies, total cholesterol is a similar risk factor for coronary heart disease (CHD) in patients with type 2 diabetes as it is in nondiabetic subjects. High total triglycerides and low HDL cholesterol may be even stronger risk factors for CHD in patients with type 2 diabetes than in nondiabetic subjects. Recent drug treatment trials have indicated that the lowering of total and LDL cholesterol by statins, and the lowering of total triglycerides and the raising of HDL cholesterol by fibrates, are at least as beneficial in diabetic patients as in nondiabetic subjects in the prevention of cardiovascular disease.     

Use of statins for secondary prevention

Opinion statement The causal role of hyperlipidemia in the pathogenesis of atherosclerosis is beyond dispute. The principal lipid abnormality responsible for coronary heart disease (CHD) is considered to be the elevation of the low-density lipoprotein cholesterol (LDL-C), although reduced levels of high-density lipoprotein cholesterol, and most recently elevated triglyceride levels, have also been associated with increased risk for CHD. The risk with these lipid abnormalities exists both in the asymptomatic population as well as in individuals with clinical evidence of atherosclerosis. Most patients with established CHD, and noncoronary atherosclerosis, will need drug therapy to achieve their National Cholesterol Education Program Adult Treatment Panel LDL-C goal of less than 100 mg/dL; the most efficacious, safe, and well-tolerated drugs for this purpose are the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins. The role of statins for secondary cardiovascular disease prevention has been well established in several large randomized clinical trials. New data now suggest that statins offer significant benefits to a broad range of patients at high global CHD risk, and should be regarded as an integral part of the management of acute coronary syndromes.     

Efficacy and safety of intensive statin therapy in the elderly

Numerous epidemiologic and intervention trials, including many studying elderly cohorts, have demonstrated the importance of lipids in primary and secondary preventions of cardiovascular diseases, including coronary heart disease (CHD) and stroke. More recent studies have demonstrated that more intensive statin therapy that reduces low-density lipoprotein cholesterol levels to <70 to 80 mg/dL have resulted in more marked cardiovascular event reduction than less intensive statin treatment. The authors review the efficacy and safety of intensive vs less intensive statin therapy. Specifically, 4 such studies with sufficient data in elderly patients, including 2 trials of patients with stable CHD and 2 with acute coronary syndrome, demonstrating the efficacy and safety of intensive statin therapy with high-dose (80 mg) atorvastatin are reviewed in detail. Although elderly patients may be more susceptible to drug interactions when receiving high doses of statins, the present evidence supports the use of intensive statin therapy in most high-risk elderly patients both with stable CHD and following acute coronary syndrome.     

Hypercholesterolemia. The evidence supports use of statins

Using statins to treat older men and women with coronary artery disease (CAD) and hypercholesterolemia reduces the risk of all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, Intermittent claudication, and congestive heart failure. The target serum low-density lipoprotein (LDL) cholesterol level is < 100 mg in older patients with CAD, prior stroke, peripheral arterial disease, extracranial carotid arterial disease, abdominal aortic aneurysm, diabetes meilitus, and the metabolic syndrome. Statins are also effective in reducing cardiovascular events in older persons with hypercholesterolemia without cardiovascular disease. Consider using statins in older persons without cardiovascular disease but with a serum LDL cholesterol > or = 130 mg/dL, or a serum high-density lipoprotein cholesterol < 50 mg/dL. Data from the Heart Protection Study favor treating patients at high risk for vascular events with statins regardless of age or initial serum lipids.     

Statins and the primary prevention of cardiovascular events

Cardiovascular disease remains the leading cause of death in both men and women in the United States. Treating elevated low-density lipoprotein (LDL) cholesterol has been shown to be very effective in reducing the rate of coronary heart disease (CHD) in primary prevention trials; however, the data are not as robust for treating individuals categorized at either lower risk for CHD or with below-average LDL cholesterol levels. The next frontier for investigation will include strategies to determine who in these lower risk categories should be treated with statins. The growing epidemics of obesity, diabetes, and metabolic syndrome also loom as major problems that need to be incorporated into any strategy that focuses on the prevention of cardiovascular disease. In individuals with multiple cardiovascular risk factors, combination therapies tailored to address each individual’s risk profile need to be considered to best decrease the likelihood of their first coronary event.     

New and Emerging Therapies for Reduction of LDL-Cholesterol and Apolipoprotein B: JACC Focus Seminar 1/4

Adding to the foundation of statins, ezetimibe and proprotein convertase subtilisin–kexin type 9 inhibitors (PCSK9i), novel, emerging low-density lipoprotein cholesterol (LDL-C)–lowering therapies are under development for the prevention of cardiovascular disease. Inclisiran, a small interfering RNA molecule that inhibits PCSK9, only needs to be dosed twice a year and has the potential to help overcome current barriers to persistence and adherence to lipid-lowering therapies. Bempedoic acid, which lowers LDL-C upstream from statins, provides a novel alternative for patients with statin intolerance. Angiopoetin-like 3 protein (ANGPTL3) inhibitors have been shown to provide potent LDL-C lowering in patients with homozygous familial hypercholesterolemia without major adverse effects as seen with lomitapide and mipomersen, and may reduce the need for apheresis. Finally, CETP inhibitors may yet be effective with the development of obicetrapib. These novel agents provide the clinician the tools to effectively lower LDL-C across the entire range of LDL-C–induced elevation of cardiovascular risk, from primary prevention and secondary prevention to null-null homozygous familial hypercholesterolemia patients.     

Prevalence of low high-density lipoprotein cholesterol in patients with documented coronary heart disease or risk equivalent and controlled low-density lipoprotein cholesterol

Current guidelines identify low-density lipoprotein (LDL) cholesterol as the primary target for cardiovascular prevention but also recognize low high-density lipoprotein (HDL) cholesterol as an important secondary target. This study was conducted to determine the prevalence of low HDL cholesterol in a contemporary ambulatory high-risk population across various LDL cholesterol levels, including patients taking statins. Screening of 44,052 electronic medical records from a primary care practice identified 1,512 high-risk patients with documented coronary heart disease (CHD) or CHD risk equivalents. Low HDL cholesterol (< or =40 mg/dl in men, < or =50 mg/dl in women) was present in 66% of the 1,512 patients. Low HDL cholesterol was prevalent across all LDL cholesterol levels but most prevalent in patients with LDL cholesterol < or =70 mg/dl (79% vs 66% in those with LDL cholesterol 71 to 100 mg/dl and 64% in patients with LDL cholesterol >100 mg/dl, p <0.01). Low HDL cholesterol was equally and highly prevalent in patients taking statins (67%) and those not taking statins (64%) (p = NS). HDL cholesterol and LDL cholesterol levels correlated poorly (R(2) = 0.01), and this was unaffected by gender or statin treatment. In conclusion, in high-risk patients with CHD or CHD risk equivalents, low HDL cholesterol levels remain prevalent despite statin treatment and the achievement of aggressive LDL cholesterol goals.     

The evolving role of statins in the management of atherosclerosis

Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.     

Therapy to reduce risk of coronary heart disease

Recent primary and secondary intervention studies have shown that reduction of low-density lipoprotein cholesterol (LDL-C) with statins significantly reduced coronary heart disease (CHD) morbidity and mortality. However, many patients with dyslipidemia who have or are at risk for CHD do not reach target LDL-C goals. The recently updated National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines identify a group of patients at very high risk for CHD for more aggressive LDL-C reduction and reaffirm the importance of high-density lipoprotein cholesterol (HDL-C) by raising the categorical threshold to 40 mg/dl. Lipid-lowering therapy needs to be more aggressive in both primary and secondary prevention settings, and therapy should be considered to increase HDL-C as well as lower LDL-C in order to improve patient outcomes. Both combination therapy and the next generation of statins may provide improved efficacy across the dyslipidemia spectrum.     

The benefit of aggressive lipid lowering

The beneficial effects of lipid-lowering therapy for the primary and secondary prevention of coronary heart disease (CHD) have been conclusively demonstrated in large-scale clinical trials. Does more aggressive lipid lowering provide even greater clinical benefit? The post coronary artery bypass graft (post-CABG) study was the first angiographic trial to show that aggressive lipid-lowering therapy was more effective at reducing disease progression than conventional approaches to cholesterol management. Recently, the results of the atorvastatin versus revascularization treatments (AVERT) trial have also shown significant benefit on clinical events with aggressive lipid lowering. A total of 341 patients with stable CHD were randomly assigned to receive medical therapy with atorvastatin 80 mg/day plus conventional treatment or angioplasty followed by usual care. Atorvastatin therapy resulted in a 46% reduction in the mean low-density lipoprotein cholesterol level compared with an 18% decrease for patients in the angioplasty/usual care group. Patients treated with atorvastatin had fewer ischemic events compared with those who had angioplasty (13 vs. 21%, P = 0.048) and a significantly greater time to first ischemic event (P = 0.027). AVERT is the first clinical study demonstrating that patients with stable CHD achieve significant cardiovascular benefit by aggressively lowering cholesterol levels with atorvastatin. It would therefore appear that an aggressive approach to lipid-lowering therapy is beneficial in patients with existing CHD.     

Therapeutic implications of recent ATP III guidelines and the important role of combination therapy in total dyslipidemia management

The Adult Treatment Panel III report reemphasized the importance of reducing elevated levels of low-density lipoprotein cholesterol as the most efficacious treatment target to reducing coronary heart disease morbidity and mortality, which is the leading cause of disability and death in the United States. Although the etiologic role of elevated levels of low-density lipoprotein cholesterol in atherosclerosis is well established, treatment with statins still leaves a large proportion of patients vulnerable to cardiovascular events. The role of high-density lipoprotein cholesterol in atherosclerosis is increasingly recognized because of its strong inverse association with coronary heart disease in epidemiologic studies, and the observed high prevalence of low high-density lipoprotein cholesterol that occurs in populations with coronary heart disease, with or without elevated low-density lipoprotein cholesterol, especially among patients with diabetes and metabolic syndrome. This report highlights some of the therapeutic implications of the Adult Treatment Panel III report and various therapeutic approaches to both lowering elevated low-density lipoprotein cholesterol and triglycerides as well as increasing low levels of high-density lipoprotein cholesterol to optimize clinical event rate reduction in patients with coronary heart disease. Among available dyslipidemic therapies, although statins remain the mainstay for lowering low-density lipoprotein cholesterol and clinical events, niacin is currently the most effective agent for increasing low high-density lipoprotein cholesterol levels. The importance of combination dyslipidemic therapy, such as a statin plus niacin, in treating more optimally the entire lipid profile has been demonstrated not only to decrease progression and increase regression of atherosclerotic lesions, but to enhance event-free survival compared with statin monotherapy. Combination dyslipidemic therapy affords the most efficacious approach to controlling the multiple lipid abnormalities associated with atherosclerotic cardiovascular disease and optimizing cardiovascular event rate reduction in patients with coronary heart disease.     

Women do benefit from lipid lowering: latest clinical trial data

Cardiovascular disease is the leading cause of morbidity and mortality among women in industrialized nations. Optimizing cardiovascular risk reduction is therefore of paramount importance, particularly among postmenopausal women, in whom the incidence of cardiovascular disease is highest. Accumulated data from a series of landmark trials unequivocally demonstrate the efficacy of statin therapy in the primary and secondary prevention of cardiovascular outcomes in both men and women. Moreover, the recently released Heart Protection Study provides substantive evidence that lowering low-density lipoprotein cholesterol below levels currently defined as optimal by National Cholesterol Educational Program guidelines is strongly associated with further cardiovascular risk reduction, and that this benefit accrues in all subgroups of patients, including women and the elderly. Despite the ability of hormone replacement therapy to improve serum lipid profiles, randomized trials of hormone therapy have demonstrated no benefit in reducing coronary outcomes among postmenopausal women. In contrast, data from over 8,000 women enrolled in the statin trials demonstrate that lipid lowering with statins is as effective at reducing cardiovascular outcomes in women as it is in men and suggest that statins should be considered standard of care for the prevention of adverse cardiovascular events in women at risk for coronary heart disease.     

Women Versus Men: Is There Equal Benefit and Safety from Statins?

Coronary heart disease (CHD) is the leading cause of death in the United States. CHD risk differs between genders, with coronary events lagging behind ten years for women in comparison to men. Low-density lipoprotein cholesterol lowering with statin therapy is a major target for cardiovascular risk reduction. The benefit of statin therapy has been well established in men, for both primary and secondary prevention. However, the same has not been shown for women. While studies have demonstrated benefit in women for secondary prevention, their role in primary prevention of cardiovascular disease remains controversial. Data released over the past several years regarding statin efficacy and safety in men and women has been inconsistent, given that these studies had small sample sizes with numerous study limitations. A recent large scale meta-analysis of both primary and secondary statin prevention trials with sex-specific outcomes demonstrated a similar benefit in both men and women. Statins demonstrated a decrease in cardiovascular events and all-cause mortality in both sexes. In regards to statin safety, additional trials investigating the difference in adverse events of statins in men versus women, particularly new onset of diabetes, myalgias, and liver dysfunction, are warranted. Increased awareness and monitoring of female patients for myalgias and hyperglycemia should be considered as a precaution. Overall, women need to be better represented in prospective clinical trials powered to evaluate gender-specific differences in statin safety and efficacy in the management of cardiovascular disease.     

Meaning of Low‐Density Lipoprotein‐Apheresis for Hypercholesterolemic Patients at High Risk for Recurrence of Coronary Heart Disease

Abstract: The goal of cholesterol‐lowering therapy in hypercholesterolemic patients at high risk for recurrence of coronary heart disease (CHD) is the prevention of acute coronary syndrome by stabilization of coronary atheromatous plaque. We often encounter patients in whom it is difficult to maintain the serum cholesterol level at a desirable level with dietary therapy and drug treatment, despite the development and use of statins. For secondary prevention in patients who are at high risk for the recurrence of CHD and whose cholesterol level cannot be controlled by drugs alone, low‐density lipoprotein (LDL)‐apheresis therapy, which involves removal of LDL through extracorporeal circulation, is now available. Many reports concerning improvement of vascular endothelial function, improvement of myocardial ischemia, regression of coronary atherosclerotic lesions, stabilization of coronary plaque, and reduction in the incidence of cardiac events as a result of LDL‐apheresis treatment have been published in various countries. We believe that LDL‐apheresis should be performed on hypercholesterolemic patients with existing CHD for whom diet and maximum cholesterol‐lowering drug therapies have been ineffective or not tolerated and whose LDL cholesterol level is 160 mg/dL or higher.