Ezetimibe therapy: mechanism of action and clinical update.

The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve targets with statin therapy alone or have partial or complete intolerance to them. For such patients, the use of adjuvant therapy capable of providing incremental LDL-C reduction is advised. One such agent is ezetimibe, a cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border. Its primary target of action is the cholesterol transport protein Nieman Pick C1 like 1 protein. Ezetimibe is an effective LDL-C lowering agent and is safe and well tolerated. In response to significant controversy surrounding the use and therapeutic effectiveness of this drug, we provide an update on the biochemical mechanism of action for ezetimibe, its safety and efficacy, as well as the results of recent randomized studies that support its use in a variety of clinical scenarios

Evidence review : liraglutide for the treatment of type 2 diabetes

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of liraglutide in the treatment of type 2 diabetes mellitus, based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The manufacturer proposed the use of liraglutide as a second or third drug in patients with type 2 diabetes whose glycaemic control was unsatisfactory with metformin, with or without a second oral glucose-lowering drug. The submission included six manufacturer-sponsored trials that compared the efficacy of liraglutide against other glucose-lowering agents. Not all of the trials were relevant to the decision problem. The most relevant were Liraglutide Effects and Actions in Diabetes 5 (LEAD-5) (liraglutide used as part of triple therapy and compared against insulin glargine) and LEAD-6 [liraglutide in triple therapy compared against another glucagon-like peptide-1 agonist, exenatide]. Five of the six trials were published in full and one was then unpublished. Two doses of liraglutide, 1.2 and 1.8 mg, were used in some trials, but in the two comparisons in triple therapy, against glargine and exenatide, only the 1.8-mg dose was used. Liraglutide in both doses was found to be clinically effective in lowering blood glucose concentration [glycated haemoglobin (HbA1c)], reducing weight (unlike other glucose-lowering agents, such as sulphonylureas, glitazones and insulins, which cause weight gain) and also reducing systolic blood pressure (SBP). Hypoglycaemia was uncommon. The ERG carried out meta-analyses comparing the 1.2- and 1.8-mg doses of liraglutide, which suggested that there was no difference in control of diabetes, and only a slight difference in weight loss, insufficient to justify the extra cost. The cost-effectiveness analysis was carried out using the Center for Outcomes Research model. The health benefit was reported as quality-adjusted life-years (QALYs). The manufacturer estimated the cost-effectiveness to be £15,130 per QALY for liraglutide 1.8 mg compared with glargine, £10,054 per QALY for liraglutide 1.8 mg compared with exenatide, £10,465 per QALY for liraglutide 1.8 mg compared with sitagliptin, and £9851 per QALY for liraglutide 1.2 mg compared with sitagliptin. The ERG conducted additional sensitivity analyses and concluded that the factors that carried most weight were: in the comparison with glargine, the direct utility effects of body mass index (BMI) changes and SBP, with some additional contribution from HbA1c in the comparison with exenatide, HbA1c, with some additional effects from cholesterol and triglycerides in the comparison with sitagliptin, HbA1c and direct utility effects of BMI changes. The European Medicines Agency has approved liraglutide in dual therapy with other oral glucose-lowering agents. NICE guidance recommends the use of liraglutide 1.2 mg in triple therapy when glycaemic control remains or becomes inadequate with a combination of two oral glucose-lowering drugs. The use of liraglutide 1.2 mg in a dual therapy is indicated only in patients who are intolerant of, or have contraindications to, three oral glucose-lowering drugs. The use of liraglutide 1.8 mg was not approved by NICE. The ERG recommends research into the (currently unlicensed) use of liraglutide in combination with long-acting insulin

Olmesartan-based monotherapy vs combination therapy in hypertension: A meta-analysis based on age and chronic kidney disease status.

Antihypertensive monotherapy is often insufficient to control blood pressure (BP). Several recent guidelines advocate for initial combination drug therapy in many patients. This meta-analysis of seven randomized, double-blind studies (N = 5888) evaluated 8 weeks of olmesartan medoxomil (OM)-based single-pill dual-combination therapy (OM+amlodipine/azelnidipine or hydrochlorothiazide) vs OM monotherapy in adults with hypertension. BP-lowering efficacy, goal achievement, and adverse events were assessed in the full cohort and subgroups (elderly/nonelderly and patients with and without chronic kidney disease). In the full cohort at week 8, for dual therapy vs monotherapy, seated BP was lower (137.5/86.1 mm Hg vs 144.4/89.9 mm Hg), and the mean change from baseline in BP and BP goal achievement (<140/90 mm Hg) were greater (-22.7/-15.0 mm Hg vs -16.0/-11.3 mm Hg and 51.2% vs 34.7%, respectively). Adverse events were similar between groups. BP-lowering efficacy among subgroups mirrored the findings in the full cohort whereby changes were significantly greater following OM dual-combination therapy vs OM monotherapy

Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing:a population-based study

Background<p></p> Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.<p></p> Methods<p></p> We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.<p></p> Results<p></p> Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.<p></p> Conclusions<p></p> We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis

Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase

Background Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. Objectives This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Methods Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Results Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03). Conclusions Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms

Do Acute Coronary Events Affect Lipid Management and Cholesterol Goal Attainment in Germany?

Objective To document utilization of lipid-lowering therapy, attainment of low-density lipoprotein cholesterol target values, and cardiovascular outcomes in patients hospitalized for acute coronary syndrome in Germany. Methods The Dyslipidemia International Study II was a multicenter, observational study of the prevalence of dyslipidemia and lipid target value attainment in patients surviving any acute coronary syndrome event. Among patients on lipid-lowering therapy for ≥3 months, use of lipid-lowering therapy and lipid profiles were assessed at admission and again at 120 ± 15 days after admission (the follow-up time point). Multivariate logistic regression was used to identify variables predictive of low-density lipoprotein cholesterol target value attainment in patients using lipid-lowering therapy. Results A total of 461 patients hospitalized for acute coronary syndrome were identified, 270 (58.6%) of whom were on lipid-lowering therapy at admission. Among patients on lipid-lowering therapy, 90.7% and 85.9% were receiving statin monotherapy at admission and follow-up, respectively. Mean (SD) lowdensity lipoprotein cholesterol levels in patients on lipid-lowering therapy were 101 (40) mg/dl and 95 (30) mg/dl at admission and follow-up, respectively. In patients with data at both admission and followup (n= 61), low-density lipoprotein cholesterol target value attainment rates were the same (19.7%) at both time points. Smoking was associated with a 77% lower likelihood of attaining the low-density lipoprotein cholesterol target value. Conclusion Hospitalization for an acute event does not greatly alter lipid management in acute coronary syndrome patients in Germany. Both lipid-lowering therapy doses and rates of low-density lipoprotein cholesterol target value attainment remained essentially the same several months after the event

Persistent hypertriglyceridemia in statin-treated patients with type 2 diabetes mellitus

Purpose: This paper reports the results of an audit that assessed the prevalence of residual hypertriglyceridemia and the potential need for intensified management among patients with statin-treated type 2 diabetes mellitus (T2DM) in primary care in the UK. Patients and methods: A cross-sectional, observational, systematic audit of patients with diagnosed diabetes from 40 primary care practices was undertaken. The audit collected basic demographic information and data on prescriptions issued during the preceding 4 months. T2DM patients were stratified according to the proportion that attained European Society of Cardiology treatment targets. Results: The audit collected data from 14,652 patients with diagnosed diabetes: 89.5% (n = 13,108) of the total cohort had T2DM. Of the people with T2DM, 22.2% (2916) were not currently receiving lipid-lowering therapy. Up to approximately 80% of these people showed evidence of dyslipidemia. Among the group that received lipid-lowering therapy, 94.7% (9647) were on statin monotherapy, which was usually simvastatin (69.5% of patients receiving statin monotherapy; 6707). The currently available statins were prescribed, with the most common dose being 40 mg simvastatin (44.2%; 4267). Irrespective of the statin used, around half of the patients receiving statin monotherapy did not attain the European Society of Cardiology treatment targets for triglycerides, low-density lipoprotein, high-density lipoprotein, and total cholesterol. Conclusion: T2DM patients managed in UK primary care commonly show persistent lipid abnormalities. Clinicians need to optimize compliance with lipid-lowering and other medications. Clinicians also need to consider intensifying statin regimens, prescribing additional lipid-modifying therapies, and specific treatments aimed at triglyceride lowering to improve dyslipidemia control in statin-treated patients with T2DM

Measurement of low‐density lipoprotein cholesterol levels in primary and secondary prevention patients: Insights from the PALM registry

Background The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommended testing low-density lipoprotein cholesterol ( LDL -C) to identify untreated patients with LDL -C ≥190 mg/dL, assess lipid-lowering therapy adherence, and consider nonstatin therapy. We sought to determine whether clinician lipid testing practices were consistent with these guidelines. Methods and Results The PALM (Patient and Provider Assessment of Lipid Management) registry enrolled primary and secondary prevention patients from 140 US cardiology, endocrinology, and primary care offices in 2015 and captured demographic data, lipid treatment history, and the highest LDL -C level in the past 2 years. Core laboratory lipid levels were drawn at enrollment. Among 7627 patients, 2787 (36.5%) had no LDL -C levels measured in the 2 years before enrollment. Patients without chart-documented LDL -C levels were more often women, nonwhite, uninsured, and non-college graduates (all P\u3c0.01). Patients without prior lipid testing were less likely to receive statin treatment (72.6% versus 76.0%; P=0.0034), a high-intensity statin (21.5% versus 24.3%; P=0.016), nonstatin lipid-lowering therapy (24.8% versus 27.3%; P=0.037), and had higher core laboratory LDL -C levels at enrollment (median 97 versus 92 mg/dL; P\u3c0.0001) than patients with prior LDL -C testing. Of 166 individuals with core laboratory LDL -C levels ≥190 mg/dL, 36.1% had no LDL -C measurement in the prior 2 years, and 57.2% were not on a statin at the time of enrollment. Conclusions In routine clinical practice, LDL -C testing is associated with higher-intensity lipid-lowering treatment and lower achieved LDL -C level

Liraglutide for the treatment of type 2 diabetes : a single technology appraisal

This paper presents a summary of the Evidence Review Group (ERG) report into the clinical effectiveness and cost-effectiveness of liraglutide in the treatment of type 2 diabetes mellitus, based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer proposed the use of liraglutide as a second or third drug in patients with type 2 diabetes whose glycaemic control was unsatisfactory with metformin, with or without a second oral glucoselowering drug. The submission included six manufacturer-sponsored trials that compared the efficacy of liraglutide against other glucose-lowering agents. Not all of the trials were relevant to the decision problem. The most relevant were Liraglutide Effects and Actions in Diabetes 5 (LEAD-5) (liraglutide used as part of triple therapy and compared against insulin glargine) and LEAD-6 [liraglutide in triple therapy compared against another glucagon like peptide-1 (GLP-1) agonist, exenatide]. Five of the six trials were published in full and one was then unpublished. Two doses of liraglutide, 1.2 and 1.8 mg, were used in some trials but in the two comparisons in triple therapy, against glargine and exenatide, only the 1.8-mg dose was used. Liraglutide in both doses was found to be clinically effective in lowering blood glucose concentration [glycated haemoglobin (HbA1c)], reducing weight (unlike other glucose-lowering agents, such as sulphonylureas, glitazones and insulins, which cause weight gain) and also reducing systolic blood pressure (SBP). Hypoglycaemia was uncommon. The ERG carried out meta-analyses comparing the 1.2- and 1.8-mg doses of liraglutide, which suggested that there was no difference in control of diabetes, and only a slight difference in weight loss, insufficient to justify the extra cost

Persistence with statin therapy in Hungary

Introduction: Persistence with lipid-lowering drug therapy by cardiovascular patients in Hungary has not been studied previously. This study was designed to determine the rate with which Hungarian patients with hyperlipidemia persist in taking lipid-lowering agents, and to compare this with rates reported from other countries. Material and methods: This was a retrospective study that utilized data from the Institutional Database of the National Health Insurance Fund to analyze persistence rates with statins and ezetimibe. The study included data for patients who started lipid-lowering therapy between January 1, 2007, and March 31, 2009. Variables included type of lipid-lowering therapy, year of therapy start, and patient age. Main outcome measures were medians of persistence in months, percentages of patients persisting in therapy for 6 and 12 months, and Kaplan-Meier persistence plots. Results: The percentage of patients who persisted with overall statin therapy was 46% after 1 month, 40.3% after 2 months, 27% after 6 months, and 20.1% after 12 months. Persistence was slightly greater for statin therapy started during 2008 than during 2007. Older patients were more persistent with therapy than younger patients. Persistence with the combination of ezetimibe-statin therapy was greater than with statin or ezetimibe monotherapy. Conclusions: Persistence with statin therapy by patients in Hungary was low compared with other countries. Low persistence may have negated potential clinical benefits of long-term statin therapy