Severe familial hypercholesterolaemia: Current and future management

SummaryFamilial hypercholesterolaemia is an inherited disorder, leading to accumulation of low-density lipoprotein (LDL) particles in plasma and premature cardiovascular disease. Although the phenotype of the rare homozygous form is always severe, the phenotypic expression of the common heterozygous familial hypercholesterolaemia can vary considerably. Beyond the magnitude of the LDL-cholesterol elevation and the type of mutation, additional genetic, metabolic and environmental cardiovascular risk factors lead to the substantial variations in the clinical manifestations and severity of atherosclerotic disease. Heterozygous familial hypercholesterolaemia is often under-diagnosed and under-treated, and there is an unmet need in terms of management of severe heterozygous forms. Homozygous and severe heterozygous familial hypercholesterolaemia should receive more intensive treatment and alternative therapeutic approaches are needed for these high-risk patients. In this article, we review the recommendations for diagnosis and treatment of severe familial hypercholesterolaemia and the agents currently available or under development

Atherogenic markers in predicting cardiovascular risk and targeting residual cardiovascular risk

Abstract Low-density lipoprotein (LDL) cholesterol (LDL-C) is the primary target in cardiovascular (CV) disease prevention and is commonly used in estimating CV risk; however, alternative markers may be needed when LDL-C is not an appropriate marker (e.g. in the presence of low LDL-C levels or elevated triglyceride [TG] levels). Non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (apoB) are markers of atherogenic lipoproteins with evidenced associations with CV risk and are, therefore, recommended as secondary targets, appropriate for use in the presence of elevated TG levels. The reported strength of the associations of non-HDL-C and apoB in comparison to LDL-C is conflicting between studies, potentially due to discordance of the markers which can alter their predictive pattern. Although LDL-C levels are commonly managed with statin treatment, a residual risk of CV events still remains, and an abnormal lipid profile can persist. Combination therapy to further reduce LDL-C levels can be beneficial; a statin therapy combined with other LDL-C-lowering therapy further reduced the number of CV events. In addition, targeting other markers, including non-HDL-C, apoB, total cholesterol and TGs may also be beneficial, specifically in patients with low HDL-C and elevated TG levels. More clinical evidence is required before definitive recommendations can be made; however, a statin–fenofibrate combination demonstrated favourable reductions in major CV events in these specific patients

Pharmaceutical strategies for reducing LDL-C and risk of cardiovascular disease

Abstract A key strategy in preventing cardiovascular (CV) disease is the reduction of low-density lipoprotein cholesterol (LDL-C). Statins are a crucial therapy for achieving LDL-C reductions, with the highest tolerated dose often prescribed, especially for patients who are at the greatest risk of CV disease. However, statin intolerance, heterogeneous responses to statins and non-adherence make alternative therapies necessary in some cases. Statins can be combined with a multitude of therapies with synergistic mechanisms of action to effectively manage lipid profiles, while improving safety and tolerability profiles. Addition of a cholesterol absorption inhibitor, bile acid sequestrant or fibrate to statin therapy leads to greater numbers of patients achieving and maintaining LDL-C goals. Furthermore, combination therapies can alter the plasma profiles of other molecules involved in hypercholesterolaemia, including triglycerides and high-density lipoprotein cholesterol. An additional strategy is proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition therapy, for use in patients who are statin intolerant, patients with heterozygous or homozygous familial hypercholesterolaemia, and patients at very high CV risk, as a potential means for achieving large LDL-C reductions and maintaining LDL-C goals. Clinical trials have demonstrated that PCSK9 inhibition therapy is not only effective but can also be combined with statin therapy to ensure greater reductions in LDL-C. Current, ongoing studies are investigating the efficacy of novel therapies, including selective peroxisome proliferator-activated receptor (PPAR) alpha modulators, PCSK9-specific ribonucleic acid (RNA) interference and anti-inflammatory therapies

294 Implementation time of a lipid lowering therapy in patients with dyslipidemia: results of Prysme study

Despite the availability of specific guidelines, the management of dyslipidemia in practice is not optimal.Objective and methodologyPRYSME, a non-interventional multicentre study carried out with 1226 general practitioners, aimed to describe the implementation time of a lipid lowering treatment according to cardiovascular risk level (primary objective) and to identify its determinants. Were eligible patients treated for a dyslipidemia diagnosed less than 2 years ago. Demographic and clinical characteristics and circumstances of diagnosis and treatment initiation were collected.Results3268 patients were included (mean age: 57 years old, males: 64%). 26% were obese and 45% overweight. Only 12% had no cardiovascular risk factors (CRF) at the time of dyslipidemia diagnosis. The most frequent CRF were arterial hypertension (50%), smoking (43%), family history of premature coronary heart disease (28%), HDL-c <0.4g/l (20%) whereas 15% of the patients had a personal history of cardiovascular disease. Dietary programs were initially implemented for 98% of the patients. More than 90% were treated with a statin. The implementation time of the treatment (evaluated according to the biological confirmation of dyslipidemia), according to the initial number of CRF, was as following:0 CRF1 CRF2 CRF≥ 3 CRFSecondary preventionTotal[-3;0] months34.3%28.6%27.1%29.3%49.1%33.1%]0;3] months23.1%26.2%26.4%24.0%21.9%23.9%> 3 months42.6%45.3%46.5%46.8%29.0%43.0%Chi-2 test : P<0.001The main determinant of an early implementation of a lipid lowering therapy (≤ 3 months) was secondary prevention (OR=1.8). The number of CRF had no significant impact.ConclusionThis study underlines the lack of awareness towards cardiovascular risk factors in the management of dyslipidemia, particularly while considering the implementation time of a lipid lowering therapy

Effects of a multifaceted intervention on cardiovascular risk factors in high-risk hypertensive patients: the ESCAPE trial, a pragmatic cluster randomized trial in general practice

BACKGROUND: Several observational studies on hypertensive patients have shown a gap between therapeutic targets recommended in guidelines and those achieved in daily practice. The ESCAPE trial aimed to determine whether a multifaceted intervention focused on general practitioners (GPs), could increase significantly the proportion of hypertensive patients at high risk in primary prevention who achieved all their recommended therapeutic targets. METHODS: A pragmatic, cluster randomized trial involving 257 GPs randomized by region. The GPs in the intervention group had a one-day training session and were given an electronic blood pressure measurement device and a short recommendation leaflet. Along with usual follow-up, they focused one consultation on hypertension and other cardiovascular risk factors every six months for two years. They also received feedback at baseline and at one year on their patients’ clinical and biological parameters. Main outcome measures were change in the proportion of patients achieving all their therapeutic targets and each individual therapeutic target at two years, and quality of life. RESULTS: 1,832 high-risk hypertensive patients were included. After two years, the proportion of patients achieving all their therapeutic targets increased significantly in both groups, but significantly more in the intervention group: OR (odds-ratio) 1.89, (95% confidence interval (CI) 1.09 to 3.27, P = 0.02). Significantly more patients achieved their blood pressure targets in the intervention group than in the usual care group: OR 2.03 (95% CI 1.44 to 2.88, P < 0.0001). Systolic and diastolic blood pressures decreased significantly more in the intervention group than in the usual care group, by 4.8 mmHg and 1.9 mmHg, respectively (P < 0.0001 for both). There were no significant difference changes in physical and mental quality of life between groups. CONCLUSION: An easy-to-perform, multifaceted intervention targeting only GPs increased significantly the proportion of high-risk hypertensive patients in primary prevention achieving their recommended therapeutic targets. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov, number NCT0034885

253: The effect of statins on the risk of first non-fatal myocardial infarction: A population-based observational study using the PGRx information system

BackgroundDespite demonstrated positive effects in a number of clinical trials, the evidence is lacking as to the impact of statins on the risk of first myocardial infarction (MI) in real life settings.ObjectivesTo assess the impact of real life statin utilization on the risk of first non-fatal MIMethodsCase-control methodology using the pharmacoepidemiological information system PGRx. Data on comorbidities, risk factors and medications were obtained from medical records and patient telephone interviews. General practices (n=371) and cardiology centres (n=60) across France were employed in the study. Cases were patients with the first MI ≤ 1 month before the date of recruitment (n=2238). Controls were patients seen by a general practitioner (GP) with no restriction as to the reasons of consultation (n=2238), matched to MI cases on gender, age, frequency of visits to a doctor, date of recruitment and personal history of non-cardiovascular chronic disease. Statin exposure was defined as any utilisation in the two-year prior to date of MI in cases or recruitment date in controls. Adjusted odds ratios (OR) of the risk of first MI was estimated by multiple conditional logistic regression models. Comparative effectiveness and propensity to use of individual statin molecules were assessed.ResultsThe use of statins was associated with a lower MI risk (adjusted OR 0.67 [95% CI 0.56 - 0.79] for current use (within 2 months before the index date) and 0.73 [0.62 0.86] for any use within 24 months). Among individual statins, rosuvastatin was associated with the lowest MI risk (adjusted OR 0.49 [0.35 - 0.68] for any use in 24 months preceding the index date) followed by simvastatin (0.62 [0.46 - 0.84]).ConclusionsIn this first major population-based observational study we reproduced the results observed in recent meta-analyses accounting for real life compliance and population variability. The results could be of interest and applicable to other industrialised countries as the observed risk reduction was constant across MI risk levels

Echocardiographic Evidence for Valvular Toxicity of Benfluorex: A Double-Blind Randomised Trial in Patients with Type 2 Diabetes Mellitus

OBJECTIVES: REGULATE trial was designed to compare the efficacy and safety of benfluorex versus pioglitazone in type 2 diabetes mellitus (DM) patients. METHODS: Double-blind, parallel-group, international, randomised, non-inferiority trial. More than half of the 196 participating centres were primary care centres. Patients eligible had type 2 DM uncontrolled on sulfonylurea. 846 were randomised. They received study treatment for 1 year. 423 patients were allocated to benfluorex (150 to 450 mg/day) and 423 were allocated to pioglitazone (30 to 45 mg/day). Primary efficacy criterion was HbA(1c). Safety assessment included blinded echocardiographic evaluation of cardiac and valvular status. RESULTS: At baseline, patients were 59.1 ± 10.5 years old with HbA1c 8.3 ± 0.8%, and DM duration 7.1 ± 6.0 years. During the study, mean HbA1c significantly decreased in both groups (benfluorex: from 8.30 ± 0.80 to 7.77 ± 1.31 versus pioglitazone: from 8.30 ± 0.80 to 7.45 ± 1.30%). The last HbA1c value was significantly lower with pioglitazone than with benfluorex (p<0.001) and non-inferiority of benfluorex was not confirmed (p = 0.19). Among the 615 patients with assessable paired echocardiography (310 benfluorex, 305 pioglitazone), 314 (51%) had at least one morphological valvular abnormality and 515 (84%) at least one functional valvular abnormality at baseline. Emergent morphological abnormalities occurred in 8 patients with benfluorex versus 4 with pioglitazone (OR 1.99), 95% CI (0.59 to 6.69). Emergent regurgitation (new or increased by one grade or more) occurred more frequently with benfluorex (82 patients, 27%) than with pioglitazone (33 patients, 11%) (OR 2.97), 95% CI (1.91 to 4.63) and were mainly rated grade 1; grade 2 (mild) was detected in 2 patients with benfluorex and 3 with pioglitazone. There was no moderate or severe regurgitation. CONCLUSION: After 1 year of exposure, our results show a 2.97 fold increase in the incidence of valvular regurgitation with benfluorex and provide evidence for the valvular toxicity of this drug

Plant sterols and cardiovascular disease: a systematic review and meta-analysis†

The impact of increased serum concentrations of plant sterols on cardiovascular risk is unclear. We conducted a systematic review and meta-analysis aimed to investigate whether there is an association between serum concentrations of two common plant sterols (sitosterol, campesterol) and cardiovascular disease (CVD). We systematically searched the databases MEDLINE, EMBASE, and COCHRANE for studies published between January 1950 and April 2010 that reported either risk ratios (RR) of CVD in relation to serum sterol concentrations (either absolute or expressed as ratios relative to total cholesterol) or serum sterol concentrations in CVD cases and controls separately. We conducted two meta-analyses, one based on RR of CVD contrasting the upper vs. the lower third of the sterol distribution, and another based on standardized mean differences between CVD cases and controls. Summary estimates were derived by fixed and random effects meta-analysis techniques. We identified 17 studies using different designs (four case–control, five nested case–control, three cohort, five cross-sectional) involving 11 182 participants. Eight studies reported RR of CVD and 15 studies reported serum concentrations in CVD cases and controls. Funnel plots showed evidence for publication bias indicating small unpublished studies with non-significant findings. Neither of our meta-analyses suggested any relationship between serum concentrations of sitosterol and campesterol (both absolute concentrations and ratios to cholesterol) and risk of CVD. Our systematic review and meta-analysis did not reveal any evidence of an association between serum concentrations of plant sterols and risk of CVD