Lipid-lowering therapy in older persons

Numerous randomized, double-blind, placebo-controlled studies and observational studies have shown that statins reduce mortality and major cardiovascular events in older high-risk persons with hypercholesterolemia. The Heart Protection Study showed that statins reduced mortality and major cardiovascular events in high-risk persons regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education Program III guidelines state that in very high-risk persons, a serum low-density lipoprotein (LDL) cholesterol level of < 70 mg/dl (1.8 mmol/l) is a reasonable clinical strategy for moderately high-risk persons (2 or more risk factors and a 10-year risk for coronary artery disease of 10% to 20%), and the serum LDL cholesterol should be reduced to < 100 mg/dl (2.6 mmol/l). When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the serum LDL cholesterol should be reduced by at least 30% to 40%. The serum LDL cholesterol should be decreased to less than 160 mg/dl in persons at low risk for cardiovascular disease. Addition of other lipid-lowering drugs to statin therapy has not been demonstrated to further reduce cardiovascular events and mortality.     

Clinical reasoning and prevention of cardiovascular disease

All the major lipid prevention guidelines agree that the 10-year risk of a cardiovascular event should be the primary method to select individuals for statin prevention of a cardiovascular event. They also all rely on LDL cholesterol (LDL-C) as the primary metric to monitor lipid lowering therapy. These two principles form the major instruments on which primary prevention of cardiovascular disease is based worldwide. Their application is based on decades of prospective observational studies and large numbers of randomized clinical trials. Their development and application are milestones in medical progress. But are there limits, which were unseen and unintended, that need to be identified and overcome so that cardiovascular prevention can improve?Based on new insights and old knowledge, this Viewpoint will apply Clinical Reasoning, the process by which we integrate all the relevant knowledge, including the knowledge we have gained from physiology, pathology, epidemiology, metabolism, experimental models of disease, and our clinical experience as well as the results of randomized clinical trials to the analysis of a single case to answer these questions. Moreover, this Viewpoint will challenge the universal practice of relating the clinical outcomes of the major successful lipid lowering trials to the decrease in LDL-C and argue that cardiovascular prevention should move from the Risk model to the Causal Benefit model. This Viewpoint will be framed around a single case because, as caregivers, we make decisions case by case and because, as caregivers, the individual is the true object of our concern.     

Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.

BACKGROUND: Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary heart disease is beneficial, there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein (HDL) cholesterol. METHODS: We conducted a double-blind trial comparing gemfibrozil (1200 mg per day) with placebo in 2531 men with coronary heart disease, an HDL cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or less, and an LDL cholesterol level of 140 mg per deciliter (3.6 mmol per liter) or less. The primary study outcome was nonfatal myocardial infarction or death from coronary causes. RESULTS: The median follow-up was 5.1 years. At one year, the mean HDL cholesterol level was 6 percent higher, the mean triglyceride level was 31 percent lower, and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group. LDL cholesterol levels did not differ significantly between the groups. A primary event occurred in 275 of the 1267 patients assigned to placebo (21.7 percent) and in 219 of the 1264 patients assigned to gemfibrozil (17.3 percent). The overall reduction in the risk of an event was 4.4 percentage points, and the reduction in relative risk was 22 percent (95 percent confidence interval, 7 to 35 percent; P=0.006). We observed a 24 percent reduction in the combined outcome of death from coronary heart disease, nonfatal myocardial infarction, and stroke (P< 0.001). There were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer. CONCLUSIONS: Gemfibrozil therapy resulted in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level. The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.     

National Lipid Association Scientific Statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high or very-high ASCVD risk

Representatives from the National Lipid Association (NLA) participated in the development of the 2018 American Heart Association/American College of Cardiology/Multisociety Guideline on the Management of Blood Cholesterol, which reaffirmed that lifestyle changes and statin treatment are therapeutic cornerstones for atherosclerotic cardiovascular disease (ASCVD) risk reduction. It also updated prior recommendations to incorporate newer data demonstrating ASCVD risk reduction with ezetimibe and proprotein convertase subtilisin kexin type 9 inhibitors as adjuncts to statin therapy for patients at high and very-high ASCVD risk. The 2018 Guideline was finalized shortly before full results were available from a randomized, placebo-controlled cardiovascular outcomes trial [Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT)] that examined the effects of icosapent ethyl (IPE) 4 g/d on major adverse cardiovascular events in selected high- or very high-risk, statin-treated patients with elevated triglycerides. The primary outcome variable of first major adverse cardiovascular event (cardiovascular death, myocardial infarction, stroke, coronary revascularization and hospitalization for unstable angina) was reduced by 25% (95% confidence interval 17%–32%, P < .001). REDUCE-IT served as the primary basis for the NLA's review of evidence for the use of IPE for ASCVD risk reduction. Based on this review, the NLA position is that for patients aged ≥45 years with clinical ASCVD, or aged ≥50 years with diabetes mellitus requiring medication plus ≥1 additional risk factor, with fasting triglycerides 135 to 499 mg/dL on high-intensity or maximally tolerated statin therapy (±ezetimibe), treatment with IPE is recommended for ASCVD risk reduction (evidence rating: class I; evidence level: B-R).     

Coronary artery calcium scoring in patients with statin associated muscle symptoms: Prescribing statins for those most likely to benefit

For primary prevention, statin therapy reduces the incidence of atherosclerotic cardiovascular disease (ASCVD) events in adults with intermediate or high estimated 10-year risk using traditional population-based risk calculators. While a variety of reported symptoms may limit statin adherence, muscle complaints, whether typical or atypical of that associated with statin therapy, are the most common reported by patients. Because additional testing, alteration in the patient's medical regimen and subsequent medical visits are often required, an informed clinician-patient discussion and shared decision making are necessary to achieve the best outcomes. The authors provide support for the perspective that coronary calcium scoring, by individualizing estimated risk and helping to identify those most likely to benefit, plays a vital role in preventive therapy decision-making for the primary prevention patient with troublesome muscle complaints attributed to statin therapy.     

Statin therapy for primary prevention in men: What is the role for coronary artery calcium?

Current cholesterol guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) base statin treatment decisions on multiple risk factor algorithms (e.g., Pooled Cohort Equations [PCEs]). By available PCEs, most older middle-aged men are statin eligible. But several studies cast doubt on predictive accuracy of available PCEs for ASCVD risk assessment. Recent studies suggest that accuracy can be improved by measurement of coronary artery calcium (CAC). This method has the advantage of identifying men at low risk in whom statin therapy can be delayed for several years, provided they are monitored periodically for progression of CAC. Thus, there are two approaches to statin therapy in men ≥ 55 years: first all men could be treated routinely, or second, treatment can be based on the extent of coronary calcium. The latter could allow a sizable fraction of men to avoid treatment for several years or indefinitely. Whether with initial CAC scan or with periodic rescanning, a CAC score ≥ 100 Agatston units is high enough to warrant statin therapy. In otherwise high-risk men (e.g., diabetes, severe hypercholesterolemia, 10-year risk by PCE ≥ 20%), a statin is generally indicated without the need for CAC; but in special cases, CAC measurement may aid in treatment decisions.     

Clinical commentary: Reaching new targets in monotherapy and combination therapy

Cardiovascular disease remains the most common cause of death in the United States. There has, however, been a decline in the age-adjusted death rate for coronary heart disease. This decline may be due, in part, to more aggressive treatment guidelines for treating cardiovascular risk factors, such as hypertension, diabetes, and dyslipidemia. The 2004 update to the National Cholesterol Education Program guidelines have recommended lower low-density lipoprotein cholesterol goals in high-risk patients. Based on the new targets for low-density lipoprotein cholesterol, clinicians will need more efficacious lipid-lowering therapies and improved options for combination therapy. Statin and statin-based combinations have been the mainstays of therapy during the last several years, and as statin utilization increases in the United States, more high-risk patients become exposed to potential statin intolerance. This commentary reviews statin-sparing combinations and use of cholesterol-absorption inhibitors.     

The importance of non-HDL cholesterol reporting in lipid management

Plasma levels of lipids and lipoproteins are essential to the management of lipid disorders by generalists and by practitioners of the emerging specialty of clinical lipidology. The routine lipid panel consists of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Several additional lipid parameters are emerging as potentially valuable adjuncts to the standard panel, including measurements of apolipoproteins and LDL particle size and concentration, but most of these serve mainly as research tools at present. One major exception is non-HDL-C, which is readily available for routine clinical use. This review outlines some of the numerous research studies that clearly establish the clinical utility and even preeminence of non-HDL-C as a comprehensive measure of atherogenic lipoproteins. Non-HDL-C was highlighted as a key secondary goal of therapy several years ago in the National Cholesterol Education Program Adult Treatment Panel III national lipid treatment guidelines and recently was further emphasized as a major goal of therapy in the consensus guidelines for lipoprotein management in patients with cardiometabolic risk from the American Diabetes Association and the American College of Cardiology. Non-HDL-C is superior to LDL-C for the prediction of cardiovascular events and has many other compelling advantages over LDL-C and other traditional lipid parameters. Importantly, it can be calculated directly from values in routine lipid panels, at no added expense. It is our opinion that non-HDL-C should be reported on all routine lipid profiles and used regularly in the management of dyslipidemia for optimal prevention of atherosclerosis and cardiovascular disease.     

Applying the Sheffield tables to data from general practice.

Lowering cholesterol with drugs of the statin class reduces the risk of a coronary event. Recent guidelines recommend use of the 'Sheffield tables' to detect individuals who might be offered drug treatment in whom the annual absolute risk of a first coronary event is > or = 3%. Using these tables in a general practice cohort aged 35-68 years, we found that 3% of men and 0.05% of women were above the treatment threshold. Smokers aged over 50 accounted for 85% of people recommended for statin therapy. Almost all smokers would fall below the treatment threshold if they quit smoking.     

Missed opportunity in the treatment of hyperlipidemia in patients with coronary heart disease: the primary care setting

BACKGROUND: Multiple clinical trials have established the benefits of controlling hyperlipidemia in patients with coronary heart disease (CHD). Nonetheless, many patients still remain untreated or not at goal low-density lipoprotein (LDL). There is limited data concerning the control of this risk factor in CHD patients in the primary care outpatient setting. METHODS: We evaluated the treatment of hyperlipidemia in the main primary care clinics of an academic, urban hospital. We identified 147 patients in a one-month period with a diagnosis of CHD and assessed the frequency of lipid-lowering therapy as well as the number of patients with LDL values that were at goal according to the National Cholesterol Education Program (NCEP) guidelines. RESULTS: A large proportion of patients were minorities and of low income, with 91.8% being African-American and 54.4% female. Although the frequency of statin therapy was relatively high (74.8%), only 55 patients (45.8%) were at goal LDL: < 100 mg/dl. The mean dose of statin prescribed (primarily simvastatin) was 33.3 +/- 17.1 mg. Only seven patients (6.5%) were on the maximum statin dose of 80 mg. CONCLUSIONS: These data show that while the frequency of lipid-lowering therapy in CHD patients in the primary care outpatient setting is relatively high, there remains a treatment gap. Specific areas for improvement are the initiation of higher doses of statins and more aggressive statin titration. The primary care outpatient setting may represent an ideal opportunity to improve control of hyperlipidemia in CHD patients.     

Regarding long-term statin therapy: Are we trading stronger hearts for weaker brains?

Ideally, the benefits of long-term statin therapy should outweigh the risks in all populations. However, some data suggest that long-term statin therapy might promote cerebral small vessel disease and impair myelination, perhaps resulting from cholesterol depletion and pleiotropic effects on amyloid-β metabolism and oligodendrocyte function. The clinical ramifications can be problematic and have a negative impact on the quality of life. Questions are proposed and the answers should be found by analysis of randomized prospective trials specifically investigating the effects of statin therapy on brain structure and function. Those trials should not be funded by drug companies and the investigators should not have financial ties to the pharmaceutical industry. The relevance of the aforementioned is amplified in light of the new cardiovascular guidelines that might culminate in more than a billion people receiving statin therapy worldwide.     

A lipidologist perspective of global lipid guidelines and recommendations,part 1: Lipid treatment targets and risk assessment

Having knowledge of worldwide lipid guidelines and recommendations may provide clinicians a more global perspective on lipid management. This perspective reviews 8 international scientific and/or medical organizations' lipid guidelines, recommendations, and position papers: the National Lipid Association (2014), National Institute for Health and Care Excellence (2014), International Atherosclerosis Society (2013), American College of Cardiology/American Heart Association (2013), Canadian Cardiovascular Society (2013), Japan Atherosclerosis Society (2012), European Society of Cardiology/European Atherosclerosis Society (2012), and Adult Treatment Panel III (2001/2004). Part 1 of this perspective focuses on sentinel components of these lipid guidelines and recommendations as applied to the role of atherogenic lipoprotein cholesterol levels, primary lipid target of therapy, other primary and secondary lipid treatment targets, and assessment of atherosclerotic cardiovascular disease (ASCVD) risk. Part 2 examines goals of lipid-altering therapy to reduce ASCVD events. Both parts 1 and 2 include the author's perspective on sentinel topics. In general, some guidelines and recommendations differ with regard to ASCVD risk assessment and lipid treatment goals. However, lipid guidelines and recommendations have significant concordance regarding the need to reduce atherogenic lipoprotein cholesterol levels, and are in general agreement on the primary lipid treatment targets. Finally, a substantial degree of agreement exists among guidelines and recommendations in their emphasis on the need for aggressive treatment of hypercholesterolemia, for which the predominance of ASCVD outcomes studies suggests statins as the first-line treatment of choice.     

Targeted screening for peripheral arterial disease in general practice: a pilot study in a high risk group

BACKGROUND: Screening of high-risk groups for peripheral arterial disease has been advocated because the condition underdiagnosed and secondary prevention can reduce cardiovascular event rates. AIM: To establish the feasibility of screening for peripheral arterial disease in people aged 60 years or over with hypertension, and to estimate the potential to improve secondary preventive treatment. DESIGN OF STUDY: Pilot study and cross-sectional survey. SETTING: Large general practice in north-east Scotland. METHOD: People aged 60 years or over with hypertension but no cardiovascular disease or diabetes were identified from computer records and invited to a screening clinic. Data were collected on ankle brachial pressure index (ABPI), preventive treatment, and risk factors. RESULTS: Of 705 potentially eligible patients, 443 (63%) agreed to participate. Sixty-four were excluded and 364 of 379 patients (96%) attended screening. Thirty patients had peripheral arterial disease (ABPI of 0.9 or less), of whom 24 (7%; 95% confidence interval [CI] = 4 to 10%) were previously undiagnosed. Fifteen (50%) patients took antiplatelets, 13 (45%) had cholesterol <5 mmol/l, and 16 (53%) had blood pressure below 140/85 mmHg. Twenty-two (73%) patients were non-smokers, 14 (47%) had low-fat diets, two (7%) were physically active, and three (10%) ate recommended amounts of fruit and vegetables. CONCLUSIONS: It is feasible to screen for peripheral arterial disease in primary care, but its prevalence is lower than anticipated. There is room for improvement in secondary preventive treatment and lifestyle, so a structured programme could still have important benefits for survival.     

Implications of recent statin trials for primary care practice

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are the first-line treatment for dyslipidemia and the results of large statin trials have a significant impact on guidelines for cardiovascular disease (CVD) management, such as those set by the National Cholesterol Education Program Adult Treatment Panel. The benefit of statin therapy in CVD prevention has traditionally been demonstrated in clinical trials by the superior efficacy of statins vs placebo in lowering low-density lipoprotein cholesterol (LDL-C) and preventing hard coronary heart disease (CHD) outcomes including myocardial infarction and CHD death. However, due to earlier and improved treatment of CVD, the clinical manifestations of atherosclerosis are changing and other forms of CVD are now thought to predominate (such as revascularization and stroke). These changes in how CVD manifests in the patient population may have consequences for selection of endpoints when designing future clinical trials. Recent statin trials have also demonstrated the early and improved clinical benefit of lowering LDL-C beyond traditional goals with intensive statin therapy vs more moderate lipid-lowering therapy. This review assesses the impact of early statin trials on current CVD management guidelines, summarizes results of recent landmark statin trials, and evaluates the potential implications of these studies for future clinical trials and CVD management guidelines.     

Are patients undergoing treatment of hyperlipidaemia with statins the best candidates for early cardiac rehabilitation?

The role of statins in the primary and secondary prevention of cardiovascular events is well known. An important adverse event associated with statin treatment is myopathy; intensive physical effort in patients treated with statins increases the risk of muscle injury/myopathy. In this article we discuss the benefits and risks associated with statin treatment in patients undergoing cardiac rehabilitation after acute coronary syndromes and/or coronary revascularization procedures. In our opinion, the benefits of the secondary prevention of coronary heart disease achieved with statins seem to outweigh the hazards associated with statin therapy. The careful selection of patients for both treatment with statins and the gradual intensification of physical training in the course of cardiac rehabilitation appears to constitute an important element of the therapeutic approach.     

Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease

To determine the associations of total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol with mortality from coronary heart disease and cardiovascular disease, we studied 2541 white men who were 40 to 69 years old at base line and followed them for an average of 10.1 years. Seventeen percent had some manifestation of cardiovascular disease at base line, whereas the others did not. Among the men who had cardiovascular disease at base line, we found, after multivariate adjustment, that those with "high" blood cholesterol levels (above 6.19 mmol per liter) had a risk of death from cardiovascular disease, including coronary heart disease, that was 3.45 times higher (95 percent confidence interval, 1.63 to 7.33) than that for men with "desirable" blood cholesterol levels (below 5.16 mmol per liter). The corresponding hazard ratios were 5.92 (95 percent confidence interval, 2.59 to 13.51) for LDL cholesterol levels above 4.13 mmol per liter as compared with those below 3.35 mmol per liter, and 6.02 (95 percent confidence interval, 2.73 to 13.28) for HDL cholesterol levels below 0.90 mmol per liter as compared with those above 1.16 mmol per liter. All three lipid levels were also significant predictors of death from coronary heart disease alone (P less than 0.005). Total cholesterol and LDL cholesterol levels were also significant predictors of death from cardiovascular and coronary heart disease in men without preexisting cardiovascular disease, although at a lower level of absolute risk of death. Thus, the 10-year risk of death from cardiovascular disease for a man with preexisting cardiovascular disease increased from 3.8 percent to almost 19.6 percent with increasing levels of total cholesterol from "desirable" to "high," whereas the corresponding risk for a man who was free of cardiovascular disease at base line increased from 1.7 percent to 4.9 percent. Our findings suggest that total, LDL, and HDL cholesterol levels predict subsequent mortality in men 40 to 69 years of age, especially those with preexisting cardiovascular disease.     

JCL Roundtable: Lipid-lowering drugs in those older than 75 years of age

Using drugs in the elderly requires some special considerations; however, there is no question that our older patients benefit tremendously from the use of agents that prevent and/or control many of the risk factors for vascular disease that are most prevalent in the latter years of life. Recently, the American College of Cardiology and the American Heart Association issued guidelines for the management of blood cholesterol elevations. For the first time, little specific guidance was given for the age group older than 75 years of age. The rationale given for this approach was primarily that the data from randomized trials comparing drug therapy to treatment with placebos were inadequate for such recommendations. There was also concern regarding safety in this group. This Roundtable will consider this lack of recommendations in a broader context than statin trials.     

Inclisiran—New hope in the management of lipid disorders?

Drugs reducing plasma concentrations of apolipoprotein B–containing lipoproteins have been demonstrated to reduce the risk of cardiovascular disease (CVD) in both primary and secondary prevention. Despite the demonstrated efficacy of statins and ezetimibe on low-density lipoprotein (LDL) concentration and long-term CVD risk, a large number of patients do not achieve their therapeutic goals. The introduction of monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) protein was a milestone in the treatment of lipid disorders, as their administration leads to unprecedentedly low LDL cholesterol concentrations. Inclisiran represents an entirely new mechanism of PSCK9 protein inhibition in hepatocytes, targeting the messenger RNA for PCSK9. Its administration is necessary only every 3 to 6 months, which is an essential advantage over statin and monoclonal antibody therapy. The infrequent administration regimen can increase the number of patients who maintain their therapeutic goals, especially in patients struggling to comply with daily or biweekly pharmacotherapy. Preclinical studies and Phase I and Phase II clinical trials of inclisiran have demonstrated its tolerability and efficacy in promoting long-term reduction of both PCSK9 protein and LDL cholesterol. The efficacy and safety of inclisiran will continue to be assessed in ongoing and forthcoming trials on larger patient groups. If the results of these trials reflect previously published data, they will add further evidence that inclisiran might be a revolutionary new tool in the pharmacologic management of plasma lipids. This review summarizes the currently available literature data on inclisiran with respect to its mechanism of action, effectiveness, and safety as a lipid-lowering drug for CVD prevention.