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BackgroundContinued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies.MethodsThe EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014–2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary endpoints included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined.FindingsAmong 83,946 matched patient pairs, (0·7 years overall mean follow-up time), initiation of empagliflozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0·70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0·55; 0·48 to 0·63), stroke (0·82; 0·71 to 0·96), and end-stage renal disease (0·43; 0·30 to 0·63) were lower and risk for myocardial infarction, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1·97; 1·28 to 3·03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions.InterpretationResults from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors. Background: Continued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies. Methods: The EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014–2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary endpoints included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined. Findings: Among 83,946 matched patient pairs, (0·7 years overall mean follow-up time), initiation of empagliflozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0·70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0·55; 0·48 to 0·63), stroke (0·82; 0·71 to 0·96), and end-stage renal disease (0·43; 0·30 to 0·63) were lower and risk for myocardial infarction, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1·97; 1·28 to 3·03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions. Interpretation: Results from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors.

Background and aims In familial hypercholesterolemia (FH), statin treatment should be considered from 8 to 10 years of age, but the prevalence of statin use among children is not known. Methods Statin use (2008–2018) among children aged 10–14 and 15–19 years was obtained from the national prescription databases in Norway, Sweden and Denmark. We assumed that all statin users in these age groups had FH, and that the estimated prevalence of FH is 1 in 250 inhabitants. Changes in prevalence rates of statin use between 2008 and 2018 by country, age and sex were estimated using the Joinpoint Regression Program version 4.8.0.1. Differences in prevalence rate ratio each year between countries were analyzed using Poisson regression. Results Among children aged 10–14 years, there was a significant increase in statin use in Norway and Denmark between 2008 and 2018, while in Sweden an increase was only seen after 2014. Among children aged 15–19 years, an increase in statin use was only observed in Norway and Sweden between 2008 and 2018. Statin use was significantly more prevalent in Norway than in Sweden and Denmark each year, and in 2018 the proportion of children using statins was 4–5 times (10–14 years) and 3 times (15–19 years) higher in Norway compared with Sweden and Denmark. In 2018 in Norway, 19% and 35% of children aged 10–14 years and 15–19 years estimated to have FH used statins respectively; corresponding percentages in Sweden were 4.5% and 10%, and in Denmark 3% and 12%. In Norway, the increase in statin use between 2008 and 2018 roughly corresponded to the increase in children with genetically verified FH. Conclusions Between 2008 and 2018, statin use increased in children aged 10–19 years in Norway, Sweden and Denmark, but with large differences between the countries; statin use was 3–5 times more prevalent in Norway than in Sweden and Denmark, which may be due to a more widespread use of genetic testing for FH in Norway.

PurposeDuring the alirocumab open-label extension study ODYSSEY OLE (open-label extension; NCT01954394), physicians could adjust alirocumab dosing for enrolled patients, who were diagnosed with heterozygous familial hypercholesterolemia (HeFH) and who had completed previous phase III clinical trials with alirocumab. This post hoc analysis evaluated the differences in physician–patient dosing decisions between the regions of Western Europe, Eastern Europe, North America, and the rest of the world (ROW).MethodsPatients (n = 909) who received starting dose alirocumab 75 mg every 2 weeks (Q2W) during ODYSSEY OLE (patients from FH I, FH II, and LONG TERM parent studies) were included. Low-density lipoprotein cholesterol (LDL-C) levels were blinded until week 8; subsequently, LDL-C values were communicated to physicians. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible.ResultsMean LDL-C values used for the decision to increase dose from 75 to 150 mg Q2W were higher in Eastern Europe (3.7 mmol/L; 144.0 mg/dL) and ROW (3.8 mmol/L; 145.2 mg/dL) compared with Western Europe (3.1 mmol/L; 118.6 mg/dL) and North America (3.3 mmol/L; 126.6 mg/dL). Irrespective of region, the mean LDL-C at the time of decision to maintain at 75 mg Q2W was approximately 1.8 mmol/L (70 mg/dL). During ODYSSEY OLE (median treatment duration of 131.7 weeks), alirocumab was shown to have no unexpected long-term safety concerns.ConclusionsIn this OLE study, the observed variations in clinical treatment decisions suggest that physicians may perceive the severity of HeFH and/or the treatment of HeFH differently depending on their region.

Background Evolocumab and other anti-PCSK9 antibodies reduced adverse cardiovascular outcomes in clinical trials of high-risk patients over Objectives The OSLER-1 trial (Open Label Study of Long Term Evaluation Against LDL-C Trial) evaluated longer-term effects of evolocumab during open-label hypercholesterolemia treatment for up to 5 years. Methods Patients randomized to standard of care (SOC) or evolocumab 420 mg monthly (evolocumab + SOC) for year 1. After year 1, patients could enter the all-evolocumab period and receive evolocumab + SOC for an additional 4 years. The authors analyzed the persistence of lipid effects and exposure-dependent safety focusing on yearly rates of adverse events (AEs) and anti-drug antibodies over 4.951 patient-years of observation. Results A total of 1,255 patients (safety analysis population) randomized into the year 1 SOC-controlled period and received ≥1 evolocumab dose (mean ± SD age 57 ± 12 years; 53% female). A total of 1,151 patients (efficacy analysis population) progressed to the all-evolocumab period (year 2 and beyond). Evolocumab + SOC persistently lowered mean ± SE low-density lipoprotein cholesterol (LDL-C) by 56% ± 0.6% (n = 1,071), 57% ± 0.8% (n = 1,001), 56% ± 0.8% (n = 943), and 56% ± 0.8% (n = 803) after approximately 2, 3, 4, and 5 years, respectively, from randomization. Mean baseline LDL-C decreased from 140 to 61 mg/dl on treatment. Yearly serious AE rates during evolocumab + SOC ranged from 6.9% to 7.9%, comparable to the 6.8% rate in SOC patients during year 1. Evolocumab discontinuation due to AEs occurred in 5.7% of patients. Two SOC and 2 evolocumab + SOC patients developed new, transient, binding anti-drug antibodies; no neutralizing antibodies were observed. Conclusions The OSLER-1 trial demonstrated consistently excellent LDL-C–lowering efficacy, tolerance, and safety of evolocumab, with no neutralizing antibodies detected, throughout the longest-duration study of a PCSK9 inhibitor reported to date. (Open Label Study of Long Term Evaluation Against LDL-C Trial [OSLER-1]; NCT01439880)

Highlights • 30% of young patients with FH had poor adherence to statins. • Lack of motivation was the main reason. • Higher age, more visits and years of follow-up associated with good adherence. • Closer follow-up and focus on patient engagement is necessary., Objective To assess adherence to lipid lowering therapy (LLT), reasons for poor adherence, and achievement of LDL-C treatment goals in children and young adults with familial hypercholesterolemia (FH). Methods Retrospective review of the medical records of 438 children that started follow-up at the Lipid Clinic, Oslo University hospital, between 1990 and 2010, and followed-up to the end of July 2019. Based on information on adherence to the LLT at the latest visit, patients were assigned to “good adherence” or “poor adherence” groups. Reasons for poor adherence were categorized as: “lack of motivation”, “ran out of drugs”, or “side effects”. Results Three hundred and seventy-one patients were included. Mean (SD) age and follow-up time at the latest visit was 24.0 (7.1) and 12.9 (6.7) years; 260 patients (70%, 95% CI: 65–74%) had “good adherence” and 111 (30%, 95% CI: 25–35%) had “poor adherence”. “Lack of motivation” was the most common reason for poor adherence (n = 85, 23%). In patients with good adherence, compared to patients with poor adherence, age at latest visit (24.6 versus 22.0 years; p = 0.001), years of follow-up (13.5 versus 11.4 years; p = 0.003), and number of visits (8.1 versus 6.5 visits; p, Graphical abstract Image, graphical abstract

Familial hypercholesterolemia (FH) is a genetic disorder with high low-density lipoprotein cholesterol (LDL-C) levels and high risk of cardiovascular disease. The long-term importance of carrying an FH mutation despite having relatively normal LDL-C levels in childhood is not known. We investigated the development of LDL-C levels and need of statin therapy in children with an FH mutation, with pretreatment LDL-C ≤ 4.1 mmol/L (~160 mg/dL), followed-up at lipid clinics in Oslo, Norway and Rotterdam, The Netherlands. Of 742 FH children, 109 (15%) had pretreatment LDL-C ≤ 4.1 mmol/L (~160 mg/dL) [mean (SD) 3.5 (0.5) mmol/L; (~130 (19) mg/dL)] measured at 11.8 (3.9) years of age [mean age (SD)]. After 8.2 (5.2) years [mean (SD)] of follow-up, 71.6% had started statin treatment. Therefore, all children carrying an FH mutation, independent of cholesterol levels, should receive follow-up at specialized lipid clinics for optimal and individualized treatment.

Patients with previous atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) are at high risk of future cardiovascular events. Despite maximally tolerated doses of statins, many patients still have elevated low-density lipoprotein cholesterol (LDL-C) levels. We evaluated the efficacy and safety of alirocumab in patients with ASCVD and/or HeFH on a maximally tolerated dose of statin (rosuvastatin 20 or 40 mg, atorvastatin 40 or 80 mg, or simvastatin 80 mg, or lower doses with an investigator-approved reason) ± other lipid-lowering therapies from 5 placebo-controlled phase 3 trials (52 to 78 weeks). Patients with (n = 2,449) and without (n = 1,050) ASCVD were pooled from the FH I, FH II, HIGH FH, LONG TERM, and COMBO I trials. Patients with HeFH with (n = 575) and without ASCVD (n = 682) were pooled from all trials except COMBO I. High-intensity statins were utilized in 55.7% to 59.0% and in 72.4% to 87.6% of the ASCVD and the HeFH groups, respectively. Efficacy end points included LDL-C percent change from baseline to week 24 stratified by alirocumab dose. Mean baseline demographics and lipid levels were comparable in alirocumab- and placebo-treated patients. LDL-C reductions from baseline at week 24 ranged from 46.6% to 51.3% for alirocumab 75/150 mg and from 54.1% to 61.9% for alirocumab 150 mg in ASCVD and HeFH groups and were sustained for up to 78 weeks. LDL-C reductions with alirocumab were independent of ASCVD and/or HeFH status (interaction p value >0.05). Concordant results were observed for other lipids analyzed. The overall safety in the subgroups analyzed was similar in both treatment arms. Injection-site reactions were observed more frequently with alirocumab versus placebo.

Diabetes and heart failure (HF) are both global epidemics with tremendous costs on society with increased rates of HF hospitalizations and worsened prognosis when co-existing, making it a significant “deadly duo.” The evidence for pharmacological treatment of HF in patients with type 2 diabetes mellitus (T2DM) stems typically from either subgroup analyses of patients that were recruited to randomized controlled trials of HF interventions, usually in patients with reduced ejection fraction (EF), or from subgroup analyses of HF patients recruited to cardiovascular (CV) outcome trials (CVOT) of glucose lowering agents involving patients with T2DM. Studies in patients with HF with preserved EF are sparse. This review summarizes the literature on pathophysiology and interventions aiming to reduce the HF burden in T2DM and includes HF trials of ACEi, digoxin, β-blocker, ARB, If-blocker, MRA, and ARNI involving 38,600 patients, with or without prevalent diabetes, and CV outcome trials in T2DM involving 74,351 patients, with or without prevalent HF. In all HF trials, HF outcomes by prevalent diabetes were reported with an incremental risk of HF and death confessed by prevalent diabetes and a treatment effect similar to those without diabetes. All T2DM CVOTs reported on HF outcomes with heterogeneity between trials with two reporting benefits (empagliflozin and canagliflozin) and two reporting increased risk (saxagliptin, pioglitazone). In vulnerable T2DM patients with concomitant HF, guideline-recommended HF drugs are effective. When choosing glucose-lowering therapy, outcomes from available CVOTs should be considered.

Background Consensus statements recommend that statin treatment in children with heterozygous familial hypercholesterolemia (FH) should be considered from 8 to 10 years of age. Although these recommendations are well known, less is known about actual treatment and treatment goal attainment in children with FH. Objective The objective of the study was to investigate if children with FH were treated according to current recommendations. Methods Retrospective collection of data from medical records of 302 children below 18 years visiting the Lipid Clinic, Oslo University hospital, during 2014 to 2016. Results Ninety-nine percent had a genetically verified FH diagnosis. Mean age (standard deviation) at diagnosis, age at first visit, and time followed at the clinic was 8.5 (3.2), 9.5 (2.9), and 4.4 (2.7) years, respectively. Mean pretreatment low-density lipoprotein cholesterol (LDL-C) was 5.4 (1.4) mmol/L. Mean age at start of lipid-lowering therapy (LLT) was 12.5 (2.0) years, with no significant difference between girls and boys. LLT, mainly statins, was used by 177 (59%) children at their last visit. LDL-C in children treated with LLT was 3.6 (1.2) mmol/L (38% reduction from pretreatment, P Conclusion Mean age at initiation of LLT is above the recommended 10 years of age and many children did not achieve the LDL-C treatment goal, even with follow-up at a dedicated lipid clinic. Earlier diagnosis and more frequent follow-ups are warranted.

Background: Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Children with HeFH exhibit early signs of atherosclerosis manifested by increased carotid intima-media thickness (IMT). In this study, we assessed the effect of 2-year treatment with rosuvastatin on carotid IMT in children with HeFH. Methods: Children with HeFH (age, 6–4.9 mmol/L or >4.1 mmol/L in combination with other risk factors received rosuvastatin for 2 years, starting at 5 mg once daily, with uptitration to 10 mg (age, 6–P values were adjusted for age, sex, carotid artery site, and family relations. Results: At baseline, mean±SD carotid IMT was significantly greater for the 197 children with HeFH compared with the 65 unaffected siblings (0.397±0.049 and 0.377±0.045 mm, respectively; P =0.001). During 2 years of follow-up, the change in carotid IMT was 0.0054 mm/y (95% confidence interval, 0.0030–0.0082) in children with HeFH and 0.0143 mm/y (95% confidence interval, 0.0095–0.0192) in unaffected siblings ( P =0.002). The end-of-study difference in mean carotid IMT between children with HeFH and unaffected siblings after 2 years was no longer significant (0.408±0.043 and 0.402±0.042 mm, respectively; P =0.2). Conclusions: In children with HeFH who were ≥6 years of age, carotid IMT was significantly greater at baseline compared with unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid IMT in children with HeFH than untreated unaffected siblings. As a result, no difference in carotid IMT could be detected between the 2 groups after 2 years of rosuvastatin. These findings support the value of early initiation of statin treatment for low-density lipoprotein cholesterol reduction in children with HeFH. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01078675.

Context In the ODYSSEY CHOICE I trial, alirocumab 300 mg every 4 weeks (Q4W) was assessed in patients with hypercholesterolemia. Alirocumab efficacy and safety were evaluated in a patient subgroup with type 2 diabetes mellitus (T2DM) and who were receiving maximally tolerated statins with or without other lipid-lowering therapies. Methods Participants received either alirocumab 300 mg Q4W (n = 458, including 96 with T2DM) or placebo (n = 230, including 50 with T2DM) for 48 weeks, with alirocumab dose adjustment to 150 mg every 2 weeks at Week (W) 12 if W8 low-density lipoprotein cholesterol (LDL-C) levels were ≥70 mg/dL or ≥ 100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was, Alirocumab 300 mg Q4W was generally well tolerated and efficacious for improving lipid levels (e.g., LDL-C and non–HDL-C) in individuals with T2DM receiving maximally tolerated statin therapy.

Background and aimsIn previous phase III studies, the PCSK9 monoclonal antibody alirocumab was administered at doses of 75 or 150 mg every 2 weeks (Q2W). CHOICE I (NCT01926782) evaluated 300 mg every 4 weeks (Q4W) in patients on either maximally tolerated statin or no statin, both ± other lipid-lowering therapies.MethodsCHOICE I included patients with hypercholesterolemia at moderate-to-very-high cardiovascular risk. Patients were randomized to alirocumab 300 mg Q4W, 75 mg Q2W (calibrator arm), or placebo for 48 weeks, with dose adjustment for either alirocumab arm to 150 mg Q2W at Week (W) 12 if at W8 LDL-C levels were >70/100 mg/dL (1.8/2.6 mmol/L) depending on cardiovascular risk or LDL-C reduction was

Objective: It is well established that higher low-density lipoprotein (LDL)-cholesterol levels are associated with increased cardiovascular risk. We analyzed whether effects of empagliflozin on cardiovascular outcomes varied by different LDL-cholesterol levels at baseline in EMPA-REG OUTCOME. Methods: Participants with type 2 diabetes and high cardiovascular risk received empagliflozin (10/25 mg) or placebo in addition to standard of care. We investigated the time to first 3P-MACE, cardiovascular death, hospitalization for heart failure (HHF) and all-cause mortality for empagliflozin versus placebo between baseline LDL-cholesterol categories 3.0 mmol/L, by a Cox regression including the interaction of baseline LDL-cholesterol category and treatment. Results: Of the 7020 participants randomized and treated, 81.0% received lipid lowering therapy (77.0% statins). Mean ± SD LDL-cholesterol was 2.2 ± 0.9 mmol/L, and 38%/18%, had LDL-cholesterol 3.0 mmol/L. Age, BMI, and HbA1c levels were balanced between the LDL-cholesterol subgroups, but those in the lowest versus highest group, had more coronary artery disease (83.0% vs 59.9%) and statin treatment (88.2% vs 50.9%). Empagliflozin consistently reduced all outcomes across LDL-cholesterol categories (all interaction p-values > 0.05). Conclusion: The beneficial cardiovascular effects of empagliflozin was consistent across higher and lower LDL-cholesterol levels at baseline.

Background - Current treatment goals for familial hypercholesterolemia (FH) recommended by the European Atherosclerosis Society (EAS) are LDL-C ≤2.5 mmol/L (∼100 mg/dL) or ≤1.8 mmol/L (∼70 mg/dL) in very high-risk subjects. Objective - The objective of the present study was to investigate characteristics and treatment status in subjects with genetically verified FH followed at specialized lipid clinics in Norway. Methods - Data from treatment registries of 714 adult (>18 years) subjects with FH. Results - Fifty-seven percent were female. Mean age (SD) at last visit was 44 (16.3) years, and the subjects had been followed at a lipid clinic for 11.1 (7.9) years. Two hundred forty-five (34%) were classified as very-high-risk, and 44% of these had established coronary heart disease. Very-high-risk FH subjects more often received maximal statin dose (54% vs 33%, P < .001), ezetimibe (76% vs 48%, P < .001) or resins (23% vs 9%, P < .001), and achieved LDL-C was lower (3.2 vs 3.5 mmol/L [124 vs 135 mg/dL], P = .003) than normal-risk FH. LDL-C treatment goal was achieved in 25% and 8% of subjects with normal-risk and very-high-risk FH, respectively. Lp(a) levels were available in 599 subjects, and they were divided into 2 groups: ≥90 mg/dL (n = 96) and P < .001). Conclusion - Very few FH subjects achieve their LDL-C treatment goal. New treatment modalities are needed. Independent of LDL-C and other risk factors, high Lp(a) seem to be an important additional risk factor in genetically verified FH.

Background Patients with heterozygous familial hypercholesterolemia (HeFH) who completed the double-blind ODYSSEY LONG TERM parent trial and subsequently enrolled in the open-label extension (OLE) study, ODYSSEY OLE (NCT01954394), provide a unique opportunity to investigate effects of 2 doses of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, within the same patient cohort. Objective The aim of the study was to characterize long-term efficacy and safety of 2 alirocumab dosages and utility of a dose titration strategy in patients with HeFH. Methods After an 8-week washout period, patients with HeFH who completed the LONG TERM study (receiving alirocumab 150 mg every 2 weeks [Q2W]) were eligible to enroll in OLE (n = 214) for up to 40 months' treatment duration. In OLE, patients started on alirocumab 75 mg Q2W. From Week 12, dose adjustment from 75 to 150 mg Q2W or vice versa was possible based on physician's clinical judgment. Results During the LONG TERM trial, alirocumab 150 mg Q2W reduced mean low-density lipoprotein cholesterol (LDL-C) from baseline (162.3 mg/dL) to Week 8 by 63.1%; during OLE, alirocumab 75 mg Q2W reduced mean LDL-C from baseline (166.6 mg/dL) by 47.3% within the same patient cohort. At Week 96, mean LDL-C reduction from OLE baseline was 55.4% vs 46.8% for patients with or without alirocumab dose increase, respectively. Treatment-emergent adverse events leading to permanent treatment discontinuation were observed in 4 patients (1.9%). Conclusions In patients with HeFH, both alirocumab dosages provided consistent LDL-C reductions over a treatment duration of up to 4 years (including 1.5 years of the LONG TERM trial), allowing an individualized approach to LDL-C lowering, depending on baseline LDL-C levels.

Background ODYSSEY OLE (NCT01954394) was an open-label extension (OLE) study for patients with heterozygous familial hypercholesterolemia (HeFH) who had completed previous phase 3 clinical trials with alirocumab. Alirocumab dose could be increased or decreased as per physician judgment. Objective To assess how the alirocumab dosing strategy was used by physicians during OLE. Methods Patients who entered OLE on a starting dose of alirocumab 75 mg every 2 weeks (Q2W) were included in the analysis (those from FH I, FH II, and LONG TERM trials). Those who completed LONG TERM entered an 8-week washout period before receiving alirocumab 75 mg Q2W at the start of OLE. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible, based on the physician's clinical judgment. Results In total, 909 patients with HeFH completed the 3 parent studies and were treated during OLE for a duration of up to 40 months. Most patients (56.7%) were maintained on 75 mg Q2W throughout OLE, whereas 43.3% of patients had their dose increased to 150 mg Q2W. The dose was subsequently decreased in 7.4% of the patients in whom alirocumab was initially uptitrated. Overall, treatment-emergent adverse events were similar between those who had received placebo or alirocumab in the parent studies. Conclusions In the opinion of physicians, alirocumab 75 mg Q2W enabled over half of patients with HeFH to achieve sufficient low-density lipoprotein cholesterol lowering.

Background and aims ODYSSEY OLE (open-label extension; NCT01954394) included patients diagnosed with heterozygous familial hypercholesterolemia (HeFH), receiving maximally tolerated statins, who had completed one of four Phase 3 double-blind parent studies (all 18 months' duration), with the aim to assess longer-term safety and efficacy of alirocumab. Methods Patients received starting dose alirocumab 75 mg every 2 weeks (Q2W; patients from FH I, FH II, and LONG TERM) or alirocumab 150 mg Q2W (patients from HIGH FH). Low-density lipoprotein cholesterol (LDL-C) levels were blinded to the patient and physician until Week 8; from Week 8, LDL-C levels were communicated to physicians. From Week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible per physician's clinical judgment according to patient's LDL-C levels. Results Patients who had received alirocumab (n = 655) compared with placebo (n = 330) in the parent studies exhibited similar rates of treatment-emergent adverse events (TEAEs; 87.3% vs. 83.9%) during OLE (2.5 years median alirocumab exposure). Overall, 33 patients (3.4%) experienced TEAEs leading to permanent treatment discontinuation. At Week 8, alirocumab reduced mean LDL-C by 44.2% (reduction from 151.9 mg/dL at parent study baseline to 84.9 mg/dL); reduction in LDL-C was consistent to Week 96 of OLE. Reductions in lipid parameters were similar regardless of treatment allocation in the parent study. Conclusions In patients with HeFH, no unexpected long-term safety concerns were observed with alirocumab compared with previously published data; durability of LDL-C-lowering over 3 years (including 1.5 years of parent trials) was demonstrated.

There are little long-term data on patients with familial hypercholesterolemia (FH) who initiated lipid-lowering therapy during childhood.To study long-term outcomes in young adults with FH who participated in clinical trials on lipid-lowering therapy during childhood.Participants in at least 1 of 6 clinical trials that took place between 1999 and 2008 were interviewed in 2011 or 2013. Frequency of medical consultations, use of lipid-lowering therapy, lipid levels, side effects, diet, tobacco use, and emotional issues were investigated using information from interviews, blood samples and medical records.Of the 118 individuals who participated in the trials, 67 (57%) were included. Median age was 25 years, and median time before follow-up was 10 years. Forty-eight (72%) participants were using statins at follow-up, 8 (12%) were also using ezetimibe, and 19 (28%) were not using any lipid-lowering therapy. Mean LDL-cholesterol (LDL-C) was 3.68 mmol/L in statin users and 6.08 mmol/L in non-users (P.001). Only 6 (9%) participants reached treatment goal, ie, an LDL-C ≤2.5 mmol/L. Participants who attended a consultation ≤2 years before follow-up had a significantly lower LDL-C compared with those who had a consultation2 years before follow-up (4.10 and 5.17 mmol/L, respectively; P = .02). Statin users had their last consultation more recently than non-users (median 1.4 and 2.2 years, respectively; P = .02).Statins are underused in this population, and most patients have not reached treatment goal. Those with recent consultations had lower LDL-C levels and were more often statin users. Therefore, yearly consultations for young adults with FH seem warranted.

We appreciate the comments of Dr Koh regarding our recent publication in Circulation .1 We comment here on the issues raised. Undoubtedly, patients with heterozygous familial hypercholesterolemia (HeFH) should be treated with lipid-lowering medication from a young age to prevent premature cardiovascular disease. However, from what age exactly and to what extent low-density lipoprotein (LDL) cholesterol (LDL-C) should be lowered remain difficult questions, and the answers are probably different for each individual because many factors contribute to cardiovascular risk. From the baseline data of the CHARON trial (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label), the difference in carotid intima-media thickness (c-IMT) between subjects with HeFH and unaffected siblings was shown to be significant before the age of 8 years.2 This finding may suggest that statins should be started possibly from a younger age than is currently recommended because treatment should preferably be started before the process of atherosclerosis is detectable. Another study …

Background Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is safe and effective in reducing low-density lipoprotein cholesterol in adults with familial hypercholesterolemia. A dedicated study, HAUSER-RCT, is being conducted to examine the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia (HeFH). Objective To present the rationale and design of the HAUSER-RCT study. Methods The HAUSER-RCT study is a double-blind, randomized, multicenter, placebo-controlled study designed to characterize the efficacy, safety, and tolerability of evolocumab treatment as an add-on to diet and lipid-lowering therapy, including a stable, optimized dose of statin, in pediatric patients aged 10 to 17 years with HeFH. Approximately, 150 patients will be randomized in a 2:1 ratio to receive 24 weeks of monthly evolocumab or placebo. The study will include approximately 51 sites located in North America, South America, Europe, South Africa, Australia, and New Zealand. The primary efficacy endpoint is the percent change in low-density lipoprotein cholesterol from baseline to week 24. A key secondary efficacy endpoint is the percent change in other lipid parameters from baseline to week 24. Other assessments include Tanner staging, carotid intima-media thickness, and cognitive tests. At the end of the study, consenting patients can participate in an 18-month open-label extension study (HAUSER-OLE). Results The study is ongoing and the results will be communicated at the end of the study. Conclusions The HAUSER-RCT study, the largest randomized, placebo-controlled study with proprotein convertase subtilisin/kexin type 9 inhibitors being conducted in the pediatric HeFH population, aims to provide efficacy, safety, and tolerability data of evolocumab as an add-on therapy in these patients.

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P

Background Mutations in the genes for the low-density lipoprotein receptor ( LDLR ), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). Objective The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. Methods Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR , apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 ( LDLRAP1 ), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. Results Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39–114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10–165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. Conclusion Clinically meaningful LDL-C–lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH.

Objectives Familial hypercholesterolemia (FH) is a hereditary and usually asymptomatic condition characterized by elevated blood cholesterol and increased risk of premature cardiovascular disease. It is treated with dietary modifications and lipid lowering drugs. The objective was to learn about young FH patients’ perceptions and choices regarding treatment. Methods Data were collected through in-depth interviews with 24 patients (ages 16–35), and analysed according to Grounded Theory. Results The findings are presented as theoretical concepts describing the participants’ way of handling their condition. The core category was identified as “Thoughts of consequences vs. Postponing thoughts of consequences”, which could be described through the following subcategories: 1. Normalising the condition, 2. Belittling of treatment vs. Committed to treatment and 3. Trust in advice vs. Avoid unnecessary interference. The participants’ position regarding these categories was described to affect motivation and challenges with treatment. Conclusions Participants who postpone the thoughts of consequences, belittle the treatment and avoid unnecessary interference represent a challenge to health care practitioners. Practical implications Practitioners should explore aspects such as thoughts of consequences, view of treatment and the feeling of interference to be able to better understand illness behaviour, adjust their communication and hopefully improve adherence.

The Open-Label Study of Long-term Evaluation Against LDL-C (OSLER-1) evaluated the durability of long-term efficacy and safety during long-term therapy with evolocumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9).To determine whether LDL-C level reductions with evolocumab persist across different populations. Secondary objectives included assessment of adverse events, antidrug antibodies, and factors contributing to treatment discontinuation.This ongoing, randomized open-label extension trial (OSLER-1) was conducted at 192 sites in 18 countries. A total of 1324 of 1666 patients randomized into 1 of 5 12-week double-blind phase 2 parent studies completed a parent study and chose to participate in OSLER-1; 1255 received 1 or more evolocumab doses. As of August 2016, 812 of 1324 (61%) had 208 weeks of follow-up. This current study was conducted from October 2011 to August 2016, with a data cutoff of August 26, 2016.During year 1, patients were randomized to evolocumab, 420 mg, plus standard of care (SOC) or SOC alone. After year 1, all patients continuing the study received evolocumab, 420 mg, plus SOC.Lipids, safety, and tolerability every 12 weeks. A multivariate model identified factors associated with discontinuation of evolocumab.At parent study baseline, the mean (SD) age of the population was 57.1 (11.6) years, with 52.9% being women. The median LDL-C level was 133 mg/dL (to convert to millimoles per liter, multiply by 0.0259). After 52 weeks, evolocumab plus SOC was associated with a significant reduction in LDL-C level by 61% (95% CI, -63% to -60%) vs 2% (95% CI, -5% to -0.2%) with SOC alone (P .001). At approximately 2, 3, and 4 years of study follow-up, the median LDL-C level was reduced by 59% (95% CI, -60% to -57%), 59% (95% CI, -61% to -58%), and 57% (95% CI, -59% to -55%), respectively, from parent study baseline. For patients receiving statin therapy unchanged from baseline, at week 208, the median LDL-C level reduction was 58%. No neutralizing antibodies to evolocumab were detected. The annualized incidence of new-onset diabetes was 4% in the SOC alone group and, adjusting for duration of evolocumab exposure, 2.8% in the evolocumab plus SOC group. Neurocognitive event rates were 0% (SOC alone) and 0.4% (evolocumab plus SOC). A total of 79% of patients persisted with evolocumab treatment, with a mean exposure duration of 44 months.In the longest clinical trial exposure to a PCSK9 inhibitor to date, evolocumab produced sustained reductions in LDL-C levels. The annual frequency of adverse events did not occur more frequently with cumulative exposure during open-label observation.clinicaltrials.gov Identifier: NCT01439880.

OBJECTIVE To assess the efficacy/safety of canagliflozin, a sodium–glucose cotransporter 2 inhibitor, compared with glimepiride over 104 weeks in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS In this randomized, double-blind study, patients (N = 1,450) received canagliflozin 100 or 300 mg or glimepiride (titrated up to 6 or 8 mg/day) during a 52-week core period followed by a 52-week extension. RESULTS At week 104, reductions from baseline in A1C were −0.65%, −0.74%, and −0.55% (−7.1, −8.1, and −6.0 mmol/mol) with canagliflozin 100 and 300 mg and glimepiride, respectively. Durability analyses showed sustained A1C lowering with both canagliflozin doses versus glimepiride. Reductions in body weight (−4.1%, −4.2%, and 0.9%, respectively) and systolic blood pressure (−2.0, −3.1, and 1.7 mmHg, respectively) were seen with canagliflozin 100 and 300 mg compared with glimepiride at week 104. The overall adverse event (AE) incidence was 73.3%, 77.9%, and 78.4% with canagliflozin 100 and 300 mg and glimepiride; the incidence of AE-related discontinuations was low across groups (6.2%, 9.5%, and 7.3%, respectively). Incidences of genital mycotic infections, urinary tract infections, and osmotic diuresis–related AEs were higher with canagliflozin than glimepiride; these were generally mild to moderate in intensity and led to few discontinuations. Fewer patients had hypoglycemia episodes with canagliflozin 100 and 300 mg than glimepiride (6.8%, 8.2%, and 40.9%). Mild decreases in estimated glomerular filtration rate occurred initially with canagliflozin; these attenuated over 104 weeks. CONCLUSIONS Canagliflozin provided durable glycemic improvements compared with glimepiride and was generally well tolerated in patients with type 2 diabetes receiving background treatment with metformin over 104 weeks.

Objective The atherosclerotic process is driven by elevated Low-density lipoprotein (LDL)-cholesterol in combination with enhanced inflammatory responses. Several mediators participate in this complex inflammatory network including members of the tumour necrosis factor (receptor) superfamily. Familial hypercholesterolemia (FH) is associated with increased risk of developing premature atherosclerosis. Statin treatment may normalize LDL-cholesterol levels, but it is not known if the inflammatory responses are normalized in statin-treated FH patients. Methods In long-term statin-treated FH subjects ( n = 33) and healthy controls ( n = 10) the expression of tumour necrosis factor (receptor) superfamily related genes in peripheral blood mononuclear cells (PBMC) were analyzed by real-time quantitative RT-PCR. TNFα release was measured in PBMC from patients and controls by immunoassay. Results In FH patients with normal LDL-cholesterol, after a median of 17 years of statin treatment, our major findings were: (i) Gene expression of CD137, LIGHT (lymphotoxins inducible expression, competes with HSV glycoprotein D for HVEM, a receptor expressed on T-lymphocytes), HVEM (Herpesvirus entry mediator), the two TNFα Receptors (TNFR1 and TNFR2), TNF related apoptosis inducing ligand (TRAIL) and CD40 were increased in PBMC from FH patients compared to controls. (ii) The release of TNFα in PBMC from FH patients, in response to LPS was increased compared to controls. (iii) PBMC from FH patients had enhanced spontaneous release of TNFα when incubated in the presence of control serum and in particular in the presence of FH serum. Conclusion Despite long-term statin therapy, an increased expression of several TNF related genes in PBMC isolated from FH patients was observed. Our findings may implicate a pathogenic role for inflammation and TNF related molecules in FH, and these findings suggest the possibility that novel treatment modalities beyond that of statins and lipid lowering drugs may be useful in FH subjects.

Objectives The purpose of this study was assess the effect of evolocumab (AMG 145) on lipoprotein (Lp)(a) from a pooled analysis of 4 phase II trials. Background Lp(a), a low-density lipoprotein (LDL) particle linked to the plasminogen-like glycoprotein apolipoprotein(a), shows a consistent and independent positive association with cardiovascular disease risk in epidemiological studies. Current therapeutic options to reduce Lp(a) are limited. Methods A pooled analysis of data from 1,359 patients in 4 phase II trials assessed the effects of evolocumab, a fully human monoclonal antibody to PCSK9, on Lp(a), the relationship between Lp(a) and lowering of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B, and the influence of background statin therapy. Lp(a) was measured using a standardized isoform-independent method. Results Evolocumab treatment for 12 weeks resulted in significant (p Conclusions Inhibition of PCSK9 with evolocumab resulted in significant dose-related reductions in Lp(a). While the mean percentage of reduction was significantly greater in those patients with baseline Lp(a) of ≤125 nmol/l, the absolute reduction was substantially larger in those with levels >125 nmol/l.

Familial hypercholesterolemia is an autosomal dominant disorder. Heterozygous familial hypercholesterolemia (FH) has an estimated incidence of 1 per 300-500 births and is characterized by increased serum total- and low-density lipoprotein-cholesterol levels and an increased risk of coronary heart disease. Early diagnosis and cholesterol-lowering treatment are essential to prevent premature coronary heart disease. Effective screening strategies are therefore of great importance. Screening can be done as selective or general population screening. There is no generally accepted screening program for FH in children and adolescents. In The Netherlands a systematic genetic family cascade screening program has been going on since 1994. In most countries there is no systematic screening for the disease, but clinical and genetic family cascade screening has been applied. Selective screening programs have failed to identify a large number of FH cases. Recommendations for general pediatric population screening have therefore emerged. Controversy exists as to which approach should be adopted. Family cascade screening has been estimated to be the most cost-effective screening method. No general pediatric screening program has been tested on a larger scale, validated or subjected to cost-benefit analyses.

Background Homozygous familial hypercholesterolemia (HoFH), which affects 1 in a million individuals, leads to extremely elevated levels of cholesterol and early-onset cardiovascular disease. Objective The aim of this study was to assess all 7 HoFH patients treated with low-density lipoprotein (LDL) apheresis in Norway with respect to quality of life, clinical and laboratory assessments, and cardiovascular status. Methods Apheresis treatment and assessment of cardiovascular status was performed at local hospitals but coordinated by the Lipid Clinic that has followed all patients since diagnosis. Quality of life was evaluated by a validated questionnaire. Results Results are shown as median (min-max). LDL cholesterol at diagnosis (untreated) was 704 (592–1268) mg/dL (18.2 [15.3–32.8] mmol/L). Medication was initiated at age 9 (2–35) years, and apheresis treatment at age 10 (6–44) years. Regular once-weekly apheresis combined with the maximum-tolerable doses of a statin and ezetimibe reduced LDL cholesterol to 197 (170–282) mg/dL (5.1 [4.5–7.3] mmol/L) pre-apheresis and 85 (50–108) mg/dL (2.2 [1.3–2.8] mmol/L) post-apheresis. Calculated interval mean LDL cholesterol was 162 (135–220) mg/dL (4.2 [3.5–5.7] mmol/L). Duration of apheresis treatment was 11 (1–24) years. Cardiovascular manifestations progressed in most patients despite the apheresis treatment. The subjects' quality of life was comparable with that of a healthy population, with the exception of two patients, who were significantly affected by coronary disease. Conclusions Well-tolerated, once-weekly LDL apheresis achieves lower interval mean LDL cholesterol levels between apheresis treatments than previously reported for apheresis every second week. However, progressions of cardiovascular manifestations still occurred, which highlights the importance of earlier and even more aggressive treatment and follow-up in HoFH.