Trials Of Lipid-lowering Therapy Research Articles

Relationship between the non-HDLc-to-HDLc ratio and carotid plaques in a high stroke risk population: a cross-sectional study in China

BackgroundEvidence on the association between the non-high-density lipoprotein cholesterol (non-HDLc)-to-high-density lipoprotein cholesterol (HDLc) ratio (non-HDLc/HDLc) and carotid plaques is still limited. This study aims to assess the relationship between the non-HDLc/HDLc and carotid plaques in a population with a high risk of stroke.MethodsA cross-sectional study based on the community was conducted in Yangzhou, China. Residents (no younger than 40 years old) underwent questionnaire interviews, physical examinations, and laboratory testing during 2013–2014. The subjects with a high risk of stroke were further selected (at least three of eight risk factors including hypertension, atrial fibrillation, type 2 diabetes mellitus, dyslipidaemia, smoking, lack of exercise, overweight, and family history of stroke) or a transient ischaemic attack (TIA) or stroke history. Carotid ultrasonography was then performed on the high stroke risk participants. Carotid plaque was defined as a focal carotid intima-media thickness (cIMT) ≥1.5 cm or a discrete structure protruding into the arterial lumen at least 50% of the surrounding cIMT. Logistic regression was employed to evaluate the relationship between the non-HDLc/HDLc and carotid plaques.ResultsOverall, 839 subjects with a high risk of stroke were ultimately included in the analysis, and carotid plaques were identified in 341 (40.6%) of them. Participants in the highest non-HDLc/HDLc tertile group presented a higher proportion of carotid plaques than did those in the other two groups. After adjustment for other confounders, each unit increase in the non-HDLc/HDLc was significantly associated with carotid plaques (OR 1.55, 95%CI 1.28–1.88). In the subgroup analysis, the non-HDLc/HDLc was positively and significantly associated with the presence of carotid plaques in most subgroups. Additionally, the non-HDLc/HDLc interacted significantly with three stratification variables, including sex (OR 1.31 for males vs. OR 2.37 for females, P interaction = 0.016), exercise (OR 1.18 for subjects without lack of exercise vs. OR 1.99 for subjects with lack of exercise, P interaction = 0.004) and heart diseases (OR 1.40 for subjects without heart diseases vs. OR 3.12 for subjects with heart diseases, P interaction = 0.033).ConclusionThe non-HDLc/HDLc was positively associated with the presence of carotid plaques in a Chinese high stroke risk population. A prospective study or randomized clinical trial of lipid-lowering therapy in the Chinese population is needed to evaluate their causal relationship.

Abstract 208: Trends of Comorbidities in Clinical Trials of Lipid Lowering Therapies: A Systematic Review

Background: Prevalence of coexisting comorbidities in clinical trials of lipid lowering therapies remains uncertain. Methods: We selected 61 trials ( n = 485,678) with follow-up of ≥3 months from databases of MEDLINE and ClinicalTrials.gov through December 2018. Trends in the prevalence of comorbid conditions across study period were tested using simple linear regression. Results: There was a downtrend in enrollment of patients with coronary artery disease (CAD) (57.1% [18,968 of 33,230] to 30.9% [59,078 of 190,930]) from 1993-1998 period to 2014-2018 and peripheral artery disease (PAD) (11.6% [9062 of 78,249] to 4.2% [7996 of 190,930]) from 1999-2003 period to 2014-2018; however, there was a significant increase in enrollment of hypertensives from 23.8% (7897 of 33,230) to 59.2% (112,978 of 190930) from 1993-1998 period to 2014-2018. Enrollment of cerebrovascular accident (CVA) improved from 2.1% (701 of 33,230) to 7.2% (13,836 of 190,930) during the same periods. Enrollment of patients with chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD) and cancer remained consistently low. The overall recruitment of patients with smoking (20.6% [55004 of 267631]) and heart failure (HF) (7.6% [20395 of 267631]) was higher among industry sponsored trials and PAD (10.2% [2279 of 22340) among university funded trials. The reporting on cancer, COPD and CKD was provided only by industry sponsored trials. Conclusion: Overall reporting on comorbidity was consistently low across trials of lipid lowering therapy.

Statins May Contribute to Cognitive Decline

CHICAGO – More liberal lipid targets in elderly patients and lower statin doses might offset the risk of memory decline associated with statin use in these patients, Australian investigators suggested. Katherine Samaras, PhD, and her associates did neuropsychometric testing on 377 subjects 70-90 years old who had been on statins for 2-22 years, and 301 controls who had not taken the drugs. They then repeated the assessments at 2 and 4 years, and they calculated composite, normalized z scores for various cognitive functions. The team found a significantly greater decline in memory z score from baseline among statin users at both 2 and 4 years (4-year z score −0.27 vs. −0.07). However, statin use was not associated with greater 4-year declines in language, processing speed, or visuospatial or executive functions. Also, metabolic syndrome was not associated with accelerated cognitive decline, Dr. Samaras reported at the joint meeting of the International Congress of Endocrinology and the Endocrine Society. The analysis controlled for age, sex, education, smoking, the presence of hypertension, diabetes, heart disease, stroke, obesity, and the presence of apolipoprotein E e4 genotype (APOEe4), which increases the risk for Alzheimer's disease. Previous stroke was significantly associated with an even greater memory decline among statin users. Smoking and APOEe4 seemed to be, as well, but the trends were not significant. The subjects were part of the Sydney Memory and Ageing Study, a longitudinal cohort of community-dwelling, well elderly from the affluent part of Sydney. None had dementia. The findings add weight to the Food and Drug Administration's warning about statin use and memory loss in 2012. This has “made me look very closely at who I prescribe statins for. People do report cognitive changes” if asked, said Dr. Samaras, of the Garvan Institute of Medical Research and the University of New South Wales in Sydney. To forestall memory loss, “I wonder if we should have a greater range of appropriate lipid targets for the elderly, just as we have for hemoglobin A,” she said. For now, if an elderly person is “tightly controlled and well under the benchmark we are trying to reach [with statins], then I reduce the dose,” with appropriate follow-up, Dr. Samaras said. Trials of lipid-lowering therapy should include formal cognitive measurements, as well. “As a prescriber, I'd like to know [those] data,” she said. The subjects in the study were about 80 years old on average, and about equally split between men and women. The average body mass index was 27.1 kg/m, and the average fasting glucose level was 100 mg/dL. Sixty percent of statin users and 45.9% of nonusers had metabolic syndrome; 15.2% of statin users and 5.5% of nonusers had diabetes. Dr. Samaras and her colleagues said they had no disclosures. Editor's NoteThis study is in line with what many AMDA members, including me, have observed over the years. Statins can cause significant problems in our elder population (and it's not just with their memory; muscle problems are just one of several other known risks). There are certainly some who tolerate statins well, and some in whom the benefits outweigh the burdens. But it just gives me more ammunition to back me up when I do one of my favorite things: stopping a statin in a nonagenarian with minimal risk factors for vascular disease. It's surprising how often they actually feel noticeably better after this natural, intuitive geriatric intervention: stopping an unnecessary drug.—Karl Steinberg, MD, CMDEditor in Chief This study is in line with what many AMDA members, including me, have observed over the years. Statins can cause significant problems in our elder population (and it's not just with their memory; muscle problems are just one of several other known risks). There are certainly some who tolerate statins well, and some in whom the benefits outweigh the burdens. But it just gives me more ammunition to back me up when I do one of my favorite things: stopping a statin in a nonagenarian with minimal risk factors for vascular disease. It's surprising how often they actually feel noticeably better after this natural, intuitive geriatric intervention: stopping an unnecessary drug. —Karl Steinberg, MD, CMD Editor in Chief

Inclusion of Stroke as an Outcome and Risk Equivalent in Risk Scores for Primary and Secondary Prevention of Vascular Disease

Current guideline statements for primary and secondary prevention of cardiovascular disease (CVD) rely on estimates of absolute risk of coronary events. For example, the American Heart Association guidelines on primary prevention state that persons with ≥10% risk over 10 years of myocardial infarction (MI) or coronary death should be considered for antiplatelet therapy with aspirin.1 Similarly, the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines2 state that target low-density lipoprotein level should be based on projected absolute risk of future coronary events rather than on presence or absence of specific risk factors. These guidelines state that patients at high risk of MI and coronary death, defined as an absolute 10-year risk of ≥20%, should have a target low-density lipoprotein level <100 mg/dL and should receive statin therapy if needed to achieve this goal. Stroke, however, is not included as one of the outcomes contributing to these absolute risk levels. Included in the group of patients with elevated risk, moreover, are those who already have ischemic heart disease, as well as patients deemed to be “coronary heart disease (CHD) risk equivalents,” indicating those at the same elevated risk as patients with ischemic heart disease. CHD risk equivalents include patients with diabetes mellitus, those with multiple risk factors that put them at elevated risk based on calculation of their Framingham Score, and patients with “other forms of symptomatic atherosclerotic disease.” The latter group is further defined to include those with peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), and carotid artery disease. The category of “risk equivalents” in the ATP III guidelines, however, does not include the vast majority (≈80%3) of ischemic stroke patients without carotid artery disease as cause of their stroke. Ischemic stroke is therefore notably excluded from the list of outcomes contributing to …

Lipid-lowering therapy with statins in postmenopausal women: a few answered and many unanswered questions

‘Women have been under-represented in large clinical trials of lipid-lowering therapies and often received less attention than men in trials of CH Dp revention.’ Are lipid disorders as strong a risk factor for cardiovascular disease (CVD) in women as they are in men? Do we have clear evidence that lipidlowering treatments reduce cardiovascular risk in women, more specifically in postmenopausal women? Are therapies as effective and safe in women as they are in men? Coronary heart disease (CHD) is the leading cause of death in men as well as in women in Western societies, and women demonstrate a marked increase in risk in the postmenopausal period [1]. Indeed, half a million women die of CVD in the USA each year. Hence, strategies to reduce the development and progression of atherosclerotic disease in this gender and campaigns directed at increasing awareness are extremely important. Available evidence demonstrates that dyslipidemias play a role in the increase of CHD burden after menopause. Several epidemiological

Cost–effectiveness of HMG-CoA reductase inhibitors in the treatment of dyslipidemia and prevention of CHD

The recent completion of several clinical trials of lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors, or statins, was followed by an update in 2004 concerning the Adult Treatment Panel III guidelines issued by the National Cholesterol Education Program. Within this update, individuals considered at very high risk for coronary heart disease-related events were addressed, wherein the role of an aggressive, intensive lowering of lipid levels to new goals was presented. In achieving target cholesterol levels, the statins collectively represent first-line pharmacotherapeutic strategies, although each of the currently marketed agents differ in relative potency, dose, side effects and cost. As such, research concerning the pharmacoeconomics of lipid-lowering therapy may serve to augment clinical, evidence-based approaches to care. Furthermore, identifying and rectifying suboptimal care within healthcare systems may afford optimal outcomes amongst patients for resources consumed.

The in vitro inhibitory effects of crude extracts of traditional Chinese herbs on 3-hydroxy-3-methylglutaryl-coenzyme A reductase on Vero cells.

Cardiovascular disease is still the leading cause of death in Western countries. Epidemiological studies have shown that hypercholesterolemia is a major risk factor for coronary artery disease. Clinical trials of lipid lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitor have been shown to decrease coronary events and mortality. Flavonoids are polyphenolic natural antioxidants occurring in natural products such as traditional Chinese herbs, fruits and beverages such as tea and wine. The aim of this study was to evaluate the effects of crude extracts from traditional Chinese herbs on HMG Co-A reductase. The methods for analysis of specific inhibitors of mevalonate biosynthesis have been well-established by using Vero cells, a cell line obtained from kidneys of African green monkeys. Crude extracts from different traditional Chinese herbs were dissolved in 1% Dulbecco's modified Eagle's medium and incubated with Vero cells with or without the addition of 1 mM mevalonate or 5 mM sodium acetate for 24 hours in order to observe cell growth. Pravastatin, a specific HMG Co-A reductase inhibitor, was used as a positive control which inhibits Vero cells growth effectively and cell growth inhibition was reversible after 1 mM mevalonate. Among 100 traditional Chinese herbs used for the study, only two herbs: Curcuma zedoaria Roscoe and Poncirus trifoliata Raf. showed significant growth inhibition of Vero cells. This study shows that some crude extracts isolated from traditional medicinal herbs were effective HMG Co-A reductase inhibitors which might be developed into new hypocholesterolemic agents.

The UKPDS: implications for the dyslipidaemic patient.

The UK Prospective Diabetes Study (UKPDS) is the largest intervention trial to date of patients with type 2 diabetes, involving 5102 newly diagnosed diabetic patients. Results showed that 59% of patient deaths were from cardiovascular disease. While intensive treatment of glucose produced a significant 25% reduction in microvascular endpoints compared with diet only (p=0.0099), patients with type 2 diabetes usually have a lipid profile that is highly atherogenic. In the UKPDS, intensive treatment of hyperglycaemia and hypertension did not improve lipid levels. In patients without diabetes, lipid-lowering therapy has been shown to reduce the risk of cardiovascular events in both primary and secondary prevention trials. Currently, a number of large-scale trials of lipid-lowering therapy in patients with diabetes are ongoing. For example, the Lipids in Diabetes Study will determine whether lipid lowering with a statin or fibrate can substantially reduce cardiovascular morbidity and mortality in 5000 patients with type 2 diabetes. The Atorvastatin Study for the Prevention of coronary heart disease ENdpoints (ASPEN) is comparing double-blind treatment with atorvastatin and placebo in 2250 US diabetic patients without coronary heart disease, while a sister trial in the UK, the Collaborative AtoRvastatin Diabetes Study (CARDS), is enrolling 1820 diabetic patients. The results from these trials may provide information that which will help determine the future management of diabetic dyslipidaemia.

Lipid-lowering for lower limb atherosclerosis.

Raised lipid levels, including cholesterol, are important risk factors in the development of lower limb arterial disease (atherosclerosis). The objective of this review was to assess the effects of lipid lowering therapy in patients with lower limb atherosclerosis. The reviewers searched the Cochrane Peripheral Vascular Diseases Group trials register, Embase, reference lists of relevant articles, and contacted trial investigators in Europe and pharmaceutical companies. Randomised trials of lipid-lowering therapy in patients with lower limb atherosclerosis. The main outcomes were mortality, non-fatal events, direct tests of disease progression, indirect measurements of disease, and subjective measures. Two reviewers extracted data and assessed trial quality independently. The reviewers contacted investigators to obtain information needed for the review that could not be found in published reports. There were nine eligible trials, but two were excluded because of poor methodology. The seven remaining trials involved a total of 698 participants from seven different countries. Men and women participated in all but one trial and were generally middle aged to elderly. The follow-up period varied from four months to three years. The overall quality of the included trials was high. The trials were heterogeneous in terms of inclusion criteria, type of drugs used and outcomes measured. Lipid-lowering therapy produced a marked but non-significant reduction in mortality (odds ratio 0.21, 95% confidence interval 0. 03 to 1.17), but little change in non-fatal events (odds ratio 1.21, 95% confidence interval 0.80 to 1.83). In two trials there was a significant overall reduction in disease progression on angiogram (odds ratio 0.47, 95% confidence interval 0.29 to 0.77). The changes in ankle brachial pressure index and walking distance were inconsistent, although trials showed a general improvement in symptoms that could not be combined in a meta-analysis. Side effects were generally mild, with the exceptions of liver toxicity produced by betapyridil and the adverse effect of probucol on lipoprotein profile. Lipid-lowering therapy may be useful in preventing deterioration of underlying disease and alleviating symptoms. These results cannot determine whether one lipid-lowering regimen is better than another.

A Lipid Hypothesis: Prediction, Observation and the Triglyceride/HDL Gap

SummaryLowering serum lipid levels prevents myocardial infarctions. But are we targeting the right lipoproteins in our preventive therapy? Are we getting the maximum benefit? Triglycerides certainly deserve more attention than they have yet received. Most of the trials of lipid-lowering therapy have ignored them and this omission may explain the divergence between the fall in morbidity predicted from the epidemiological evidence and the reductions observed in the clinical trials. The evidence that the statins reduce coronary morbidity and mortality, and that this reduction is associated with a fall in LDL cholesterol, is overwhelming. But the potential value of the statins may be limited by their relative inability to increase the concentration of cardio protective HDL. The fibrates, either alone, or in combination with a statin, retain a central role in the management of patients with mixed hyperlipidaemia who are undoubtedly at high risk of premature coronary artery disease.

Effects of lipid lowering therapy on progression of coronary and carotid artery disease.

Recent data have extended the benefit of lipid lowering therapy to patients with only mildly to moderately elevated LDL-cholesterol, which is typical of patients with coronary artery disease. Meta-analysis of clinical trials of statin therapy with similar sample sizes indicated that the LDL-cholesterol level on treatment was as good a predictor of angiographic benefit as was the percentage reduction in LDL-cholesterol. We review evidence that management of triglyceride-rich lipoproteins, HDL, fibrinogen, lipoprotein particle size, LDL-oxidation, and lipoprotein (a) may also favorably influence atherosclerotic progression. Angiographic and arterial ultrasound trials of lipid lowering therapy have demonstrated benefits on disease progression that are consistent with benefits on myocardial infarction, stroke, and death reported in larger, lengthier trials.

Lipids and atherogenesis in diabetes mellitus

Premature cardiovascular disease is a major burden in diabetes. Increasing cholesterol is associated with increasing vascular risk in diabetes and the absolute excess risk attributable to cholesterol is higher in diabetics than in nondiabetics. Total cholesterol and low density lipoprotein (LDL) cholesterol correlated with arterial endothelial dysfunction as assessed by reduced flow-mediated brachial artery dilatation in insulin-dependent diabetic patients. In noninsulin dependent diabetic patients hypertriglyceridaemia is common and is associated with the accumulation of intermediate density lipoproteins, abnormal postprandial lipid metabolism and small dense LDL. No trials of lipid lowering therapy in the primary or secondary prevention of cardiovascular disease have been targeted specifically to the diabetic population; nevertheless, guidelines have been published for the treatment of dyslipidaemia in diabetic patients recognising the evidence of benefit in non-diabetics and the high intrinsic risk of the diabetic.

Trials of lipid-lowering therapy in secondary prevention of coronary heart disease.

The Scandinavian Simvastatin Survival Study showed that a 35% decrease in LDL-cholesterol was accompanied by a 42% reduction in coronary mortality. Even if the period of time is longer than 1 year for the divergence of survival curves in the simvastatin and placebo groups there are reasons to believe that the beneficial effect of lipid lowering is rapid. The effect may be mediated by stabilization of lipid-rich coronary lesions or by effects on endothelium. Lipid-lowering studies in the acute stage of coronary heart disease are suggested.

Trials of lipid-lowering therapy in primary prevention of coronary heart disease.

The effectiveness of lipid-regulating therapy in the primary prevention of coronary heart disease requires further investigation. The only data available are from trials conducted before the advent of more potent lipid-regulating agents, but several large trials currently in progress are expected to provide valuable evidence about the role of lipid-regulating intervention in primary prevention.

Angiographic trials of lipid-lowering therapy: an update.

The value of specific LDL apheresis in drug-resistant cases of hyperlipidaemia is reviewed, as well as new data on the prevention of new lesion formation, efficacy of therapy based on initial lipid levels, and the consequences of lipid lowering in the angioplasty setting. Studies undertaken in the carotid and femoral bed are included, as is a brief discussion of the use of probucol as an adjunct to lipid-lowering therapy. These studies have emerged on a backdrop of data focused more on reduction of clinical events than on morphologic changes. Studies on the clinical impact of lipid-lowering therapy are included to provide a linkage between the rationale and conclusions of the angiographic trials with the emerging demonstration that cholesterol lowering does indeed reduce both cardiovascular and total mortality without inducing significant noncardiovascular morbidity or mortality.

Fluvastatin and niacin in hypercholesterolemia: A preliminary report on gender differences in efficacy

A total of 74 hypercholesterolemic patients were randomized to receive double-blind treatment for 6 weeks with either 20 mg of fluvastatin daily or placebo. Open-label niacin, to a maximum of 3 g daily, was added to each treatment for a further 9 weeks. Changes in lipid parameters were derived from averaged data, with monotherapy at weeks 3 and 6 and with combination therapy at weeks 12 and 15. The reduction in low-density lipoprotein cholesterol (LDL-C) was significantly greater with fluvastatin (20.8%) compared with placebo (p <0.001) after 3–6 weeks of treatment. At the end of 12–15 weeks, the addition of niacin potentiated the response to 43.7% with the fluvastatin + niacin combination and to 26.5% with the placebo + niacin combination (p <0.001, vs baseline and between treatment groups). Significant gender differences were noted in the LDL-C response to the fluvastatin + niacin combination. Women achieved LDL-C reductions of 54.6% whereas men achieved reductions of 38.2% (p <0.005, between gender groups). Women also tended to have greater LCL-C reductions with the placebo + niacin combination, compared with men (p <0.05). At the end of 12–15 weeks, there were HDL-C increases of 33.1% (p <0.001) whereas triglyceride levels declined by 32.3% (p <0.001). In conclusion, fluvastatin, both as monotherapy and in combination with niacin, proved to be an effective and well-tolerated alternative for the treatment of hypercholesterolemia. The differential response in LDL-C between men and women should be further explored in other trials of lipid-lowering therapy.