Clinical Trials Of Lipid-lowering Therapy Research Articles

Apolipoprotein B: Bridging the Gap Between Evidence and Clinical Practice.

Despite data suggesting that apolipoprotein B (apoB) measurement outperforms low-density lipoprotein cholesterol level measurement in predicting atherosclerotic cardiovascular disease risk, apoB measurement has not become widely adopted into routine clinical practice. One barrier for use of apoB measurement is lack of consistent guidance for clinicians on how to interpret and apply apoB results in clinical context. Whereas guidelines have often provided clear low-density lipoprotein cholesterol targets or triggers to initiate treatment change, consistent targets for apoB are lacking. In this review, we synthesize existing data regarding the epidemiology of apoB by comparing guideline recommendations regarding use of apoB measurement, describing population percentiles of apoB relative to low-density lipoprotein cholesterol levels, summarizing studies of discordance between low-density lipoprotein cholesterol and apoB levels, and evaluating apoB levels in clinical trials of lipid-lowering therapy to guide potential treatment targets. We propose evidence-guided apoB thresholds for use in cholesterol management and clinical care.

Participation of Women and Older Participants in Randomized Clinical Trials of Lipid-Lowering Therapies

Randomized clinical trials (RCTs) of lipid-lowering therapies form the evidence base for national and international guidelines. However, concerns exist that women and older patients are underrepresented in RCTs. To determine the trends of representation of women and older patients (≥65 years) in RCTs of lipid-lowering therapies from 1990 to 2018. The electronic databases of MEDLINE and ClinicalTrials.gov were searched from January 1990 through December 2018. RCTs of lipid-lowering therapies with sample sizes of at least 1000 patients and follow-up periods of at least 1 year were included. Two independent investigators abstracted the data on a standard data collection form. Patterns of representation of women and older adults were examined overall in lipid-lowering RCTs and according to RCT-level specific characteristics. The participation-to-prevalence ratio (PPR) metric was used to estimate the representation of women compared with their share of disease burden. A total of 60 RCTs with 485 409 participants were included. The median (interquartile range) number of participants per trial was 5264 (1062-27 564). Overall, representation of women was 28.5% (95% CI, 24.4%-32.4%). There was an increase in the enrollment of women from the period 1990 to 1994 (19.5%; 95% CI, 18.4%-20.5%) to the period 2015 to 2018 (33.6%; 95% CI, 33.4%-33.8%) (P for trend = .01). Among common limiting factors were inclusion of only postmenopausal women or surgically sterile women (28.3%; 95% CI, 18.5%-40.7%) or exclusion of pregnant (23.3%; 95% CI, 14.4%-35.4%) and lactating (16.6%; 95% CI, 9.3%-28.1%) women. Women were underrepresented compared with their disease burden in lipid RCTs of diabetes (PPR, 0.74), heart failure (PPR, 0.27), stable coronary heart disease (PPR, 0.48), and acute coronary syndrome (PPR, 0.51). Only 23 RCTs with 263 628 participants reported the proportion of older participants. Overall representation of older participants was 46.7% (95% CI, 46.5%-46.9%), which numerically increased from 31.6% (95% CI, 30.8%-32.3%) in the period 1995 to 1998 to 46.2% (95% CI, 46.0%-46.5%) in the period 2015 to 2018 (P for trend = .43). A total of 53.0% (95% CI, 41.8%-65.3%) and 36.6% (95% CI, 25.6% to 49.3%) trials reported outcomes according to sex and older participants, respectively, which did not improve over time. In this systematic review of RCTs of lipid-lowering therapies, the enrollment of women and older participants increased over time, but women and older participants remained consistently underrepresented. This limits the evidence base for efficacy and safety in these subgroups.

Impact of Lipid-Lowering Therapy on Mortality According to the Baseline Non-HDL Cholesterol Level: A Meta-Analysis.

Previous report showed that more intensive lipid-lowering therapy was associated with less mortality when baseline LDL-C levels were > 100mg/dL. Non-HDL-C is a better predictor of cardiovascular risk than simpler LDL-C. The objective of this meta-analysis was to define the impact of lipid-lowering therapy on the reduction of total and cardiovascular mortality by different baseline levels of non-HDL-C. We performed a meta-analysis including randomized, controlled clinical trials of lipid-lowering therapy, reporting mortality with a minimum of 6months of follow-up, searching in PubMed/Medline, EMBASE and Cochrane Clinical Trials databases. The random-effects model and meta-regression were performed. Twenty nine trials of lipid-lowering drugs, including 233,027 patients, were considered eligible for the analyses. According to the baseline non-HDL-C level, the results on cardiovascular mortality were: (1) ≥ 190mg/dL: OR 0.63 (95% CI 0.53-0.76); (2) 160-189mg/dL: OR 0.82 (95% CI 0.75-0.89); (3) 130-159mg/dL: OR 0.71 (95% CI 0.52-0.98); (4) < 130mg/dL: OR 0.95 (95% CI 0.87-1.05). When evaluating mortality from any cause, the results were the following: (1) ≥ 190mg/dL: OR 0.70 (95% CI 0.61-0.82); (2) 160-189mg/dL: OR 0.91 (95% CI 0.83-0.98); (3) 130-159mg/dL; OR 0.88 (95% CI 0.77-1.00); (4) < 130mg/dL: OR 0.98 (95% CI 0.91-1.06). The meta-regression analysis showed a significant association between baseline non-HDL-C and mortality. In these meta-analyses, lipid-lowering therapy was associated with reduction in the risk of all-cause and cardiovascular mortality when baseline non-HDL-C levels were above than 130mg/dL.

Ideal lipid profile and genes for an extended life span

The world population is aging and a rapid increase is being seen in the very elderly (aged >80 years). Cholesterol levels in general rise with age and high cholesterol has been associated with extreme longevity. The relationship between lipids and cardiovascular events in the extreme elderly is unclear. A number of genetic factors associated with lipid metabolism have also been described as having potential antiaging roles, including the genes encoding lipoprotein-associated factors - apolipoprotein E and cholesterol ester transfer protein; adipose tissue metabolism - adiponectin, leptin, glycaemia; and blood pressure - angiotensinogen. Clinical trials of lipid-lowering therapies have recruited subgroups of moderately elderly patients, but only the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial specifically recruited an elderly population. There is no direct equivalent of the Hypertension in the Very Elderly trial (HYVET) study of antihypertensive patients in the extreme elderly. No heterogeneity has been seen with the effects of statin therapy in the elderly compared with younger age groups on classical cardiovascular endpoints of coronary heart disease and stroke. The optimal cholesterol target, long-term tolerability and the specific effects of statins on other vascular-associated diseases of aging, for example arterial aneurysms, microvascular renal and cerebral disease (dementias), remain to be determined.

Clinical perspective: Have the results of recent clinical trials of lipid-lowering therapies influenced the way we should practice? A Latin American perspective of current issues in clinical lipidology

Traditional tools to evaluate cardiovascular disease risk may underestimate the risk of cardiovascular events. Although reduction of low-density lipoprotein cholesterol (LDL-C) is the mainstay of therapy to mitigate cardiovascular risk from atherosclerosis, noninvasive imaging techniques and biomarkers are now allowing us to identify subclinical atherosclerosis, or high-risk patients, and are providing clinical researchers with new target end points for randomized controlled clinical trials. Current surrogates include carotid intima-media thickness, coronary artery calcification, and high-sensitivity C-reactive protein levels. There is evidence that these biomarkers are useful in clinical practice to improve risk quantification in subjects considered at intermediate risk of coronary events according to clinical risk stratification. Some studies, but not all, have demonstrated achievement of surrogate end points with lipid-lowering therapy in addition to LDL-C reductions. A group of clinical lipidologists from Latin American countries convened to give a perspective on recent clinical trials in clinical lipidology, their designs, and data regarding currently used biomarkers. It was noted that the success of some surrogate end points as possible markers of clinical efficacy has relied heavily on patient selection and trial design. On the basis of current evidence, we believe that correcting elevated LDL-C levels should remain the primary target of therapy for patients with dyslipidemia. The group also agreed that the evidence from recent clinical trials supports the potential role of new biomarkers for the screening and identification of patients at high cardiovascular risk in the absence of overt hyperlipidemia.

Continuation of mortality reduction after the end of randomized therapy in clinical trials of lipid-lowering therapy

Long-term follow-up of clinical trials with lipid-lowering medications has suggested a continuation of event reduction after study completion. To evaluate the persistence of the benefit of lipid-lowering therapy in decreasing mortality after the end of clinical trials, when all patients were advised to take the same open-label lipid-lowering therapy. Through searches of MEDLINE, the Cochrane Library, the Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov until June 2010 we identified randomized clinical trials of lipid-lowering agents with a second report describing results after the end of the trial. Among the 459 trials reviewed, only 8 including 44,255 patients and 8144 deaths qualified for the meta-analysis. All-cause and cardiovascular mortality were lower in the active intervention group during the first phase (0.84, 95% confidence interval [CI] 0.76-0.93; P = .0006 and 0.72, 95% CI 0.63-0.82, P < .0001, respectively) when 71 ± 23% of the patients randomized to receive active therapy actually received it compared with 13 ± 5% of patients who received active therapy although they were randomized to placebo (P = .0001). The lower mortality among those initially randomized to active therapy persisted during the second phase (odds ratio 0.90, 95% CI 0.84-0.97, P = .0035, and 0.82 95% CI 0.73-0.93, P = .0014), when patients in both randomized groups received active therapy in the same proportions (5 ± 2% for both groups). Numerous sensitivity analyses support the conclusions of the paper. The decrease in mortality with lipid-lowering therapy in clinical trials persists after discontinuation of randomized therapy when patients in the treatment and placebo groups receive active therapy.

Clinical Summaries

Clinical Summaries

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.

Status report of lipid-lowering trials in diabetes

The prevention and treatment of coronary heart disease is a major challenge in the overall management of the patient with type 2 diabetes. Diabetic dyslipidaemia is an important risk factor and is open to therapeutic intervention. However, as yet there are no primary or secondary coronary heart disease prevention trials of lipid-lowering therapy reported in diabetic populations. In this review, on-going clinical trials of lipid-lowering therapy in specific diabetic populations will be described.

Mechanical properties of model atherosclerotic lesion lipid pools.

Structural analysis of atherosclerotic coronary arteries has suggested that stress concentrations are associated with plaque rupture and that these stress concentrations are critically dependent on the geometry and mechanical properties of the fibrous cap and lipid pool. Recent clinical trials of lipid-lowering therapy have shown a significant reduction in cardiac events associated with plaque rupture perhaps because of the changing composition of subintimal lipid pools. To test the hypothesis that changes in lipid composition can change the mechanical properties of lipid pools, we measured the dynamic shear moduli of combinations of cholesterol monohydrate crystals, phospholipids, and triglycerides similar to those found in atherosclerotic lesions. Increasing the cholesterol monohydrate concentration from 0% to 50% increased the real component of the dynamic shear modulus (storage modulus or stiffness) by 4.5 times at a frequency of 1 Hz (P < .001). All specimens demonstrated an increase in stiffness with increasing frequencies of stress ranging from 0.1 to 3 Hz. We conclude that the stiffness of model atherosclerotic plaque lipid pools is related to the concentration of cholesterol monohydrate crystals. Because the relative concentration of cholesterol monohydrate increases during early regression of experimental atherosclerosis, the resultant stiffening of the lipid pool may reduce stresses in plaque caps. However, the magnitude of the contribution of changing lipid stiffness to the reduction of cardiac events seen in clinical studies is unclear.