Empagliflozin is associated with lower cardiovascular risk compared with dipeptidyl peptidase-4 inhibitors in adults with and without cardiovascular disease: EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study results from Europe and Asia.

BACKGROUND: Studies that have reported lower risk for cardiovascular outcomes in users of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF). METHODS AND RESULTS: Adults initiating empagliflozin and DPP-4i in 2014-2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64-0.86), CVM (HR 0.55; 95% CI 0.38-0.80), HHF or CVM (HR 0.57; 95% CI 0.48-0.67) and stroke (HR 0.79; 95% CI 0.67-0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF. CONCLUSION: These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status.

Young women with familial hypercholesterolemia have higher LDL-cholesterol burden than men: Novel data using repeated measurements during 12-years follow-up.

Background and aims: The concentration and the duration of exposure to low-density lipoprotein cholesterol (LDL-C) (LDL-C burden) is an important determinant of risk for cardiovascular disease and thresholds has recently been estimated. Individuals with familial hypercholesterolemia (FH) have increased risk of premature cardiovascular disease. The overall aim of the present study was to describe differences in LDL-C level and LDL-C burden in females and males with FH visiting an outpatient lipid clinic from a young age, using multiple LDL-C measurements during a follow-up time of 12 years. First, we aimed to study if the LDL-C concentration and the LDL-C burden is different between females and males at ages 0-10, 10-20, 20-30 and >30 years. Second, we aimed to estimate the subject-specific LDL-C burden at age 19 and 30 years, and the proportion of female and male patients that reach suggested LDL-C thresholds indicating high risk of ASCVD. Methods: Data was retrospectively collected from medical records of 438 subjects (207 girls and 231 boys) with FH, referred to the Lipid Clinic, Oslo University Hospital below the age of 19 years. The LDL-C burden was estimated based on repeated LDL-C measurements over time. Results: Subjects were followed over a period of mean 12.0 (SD 7.0) years, with median 10 years (7-17; 25-75 percentiles, minimum 2), with median 6 (4-9; 25-75 percentiles, minimum 2) available LDL-C measurements, starting at mean age 11 (SD 3.9) years. There was a difference in both LDL-C and LDL-C burden between sexes at different ages. On average, males had lower LDL-C over time, although this difference was less pronounced with age and males also had lower estimated LDL-C burden over time, and this difference was further exacerbated with age. Conclusion: Our study shows that young women with FH have a higher LDL-C burden than their male counterparts, potentially explaining the increased excess CVD risk seen among these. It underscores the importance of careful-follow up and early treatment initiation both prior to and after pregnancies in order to limit statin-free periods.

High levels of lipoprotein(a) - assessment and treatment. / Høyt nivå av lipoprotein(a) ­ utredning og behandling.

Approximately 5 % of the population have highly elevated levels of lipoprotein(a) (Lp(a)), which is a genetically determined risk factor for cardiovascular disease. Measuring lipoprotein(a) can improve cardiovascular risk stratification and have consequences for preventive measures. Treatment is targeted at reducing modifiable cardiovascular risk factors, but Lp(a)-lowering drugs are being trialled. This article reviews the management of lipoprotein(a) in clinical practice.

Empagliflozin cardiovascular and renal effectiveness and safety compared to dipeptidyl peptidase-4 inhibitors across 11 countries in Europe and Asia: Results from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study.

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.

Do we need new lipid-lowering agents in the era of PCSK9 inhibitors? Recent advances.

Atherosclerotic disease remains the leading cause of death worldwide. Much of atherosclerotic disease initiation and progression is driven by dyslipidemia. With the advent of statins, ezetimibe, and more recently the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, physicians across all specialties have access to an armamentarium to address this major pathophysiological driver. Nevertheless, there is still a large unmet need in terms of optimizing pharmacotherapeutic lipid lowering strategies. This article will review the evidence pertaining to the major lipid-lowering agents that have been introduced lately, or still are under development, after the advent of statins, ezetimibe and PCSK9 inhibitors. There is cumulating evidence suggesting that there soon will be a broad specter of differential therapies across a variety of mechanistic pathways that will enter clinical medicine. Knowledge about these potential recent advances and various upcoming therapeutic options will make choice easier for physicians, and will lead to more personalized selections of available treatments.

Thirty percent of children and young adults with familial hypercholesterolemia treated with statins have adherence issues.

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<0.001) were significantly higher, whereas LDL-C at the latest visit was lower, (3.1 (0.8) versus 5.3 (1.6) mmol/L; p<0.001) and percentage of patients reaching LDL-C treatment goal was higher, (34.5% versus 2.7%; p<0.001). Gender, BMI, age at first visit and premature cardiovascular disease in first degree relatives were not significantly associated with adherence. CONCLUSION: Thirty percent of young patients with FH had poor adherence to LLT, with lack of motivation as the main reason. Higher age, more visits and more years of follow-up were associated with good adherence.

Long term follow-up of children with familial hypercholesterolemia and relatively normal LDL-cholesterol at diagnosis.

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.

Subjects with familial hypercholesterolemia have lower aortic valve area and higher levels of inflammatory biomarkers.

BACKGROUND: Reduction of the aortic valve area (AVA) may lead to aortic valve stenosis with considerable impact on morbidity and mortality if not identified and treated. Lipoprotein (a) [Lp(a)] and also inflammatory biomarkers, including platelet derived biomarkers, have been considered risk factor for aortic stenosis; however, the association between Lp(a), inflammatory biomarkers and AVA among patients with familial hypercholesterolemia (FH) is not clear. OBJECTIVE: We aimed to investigate the relation between concentration of Lp(a), measurements of the aortic valve including velocities and valve area and circulating inflammatory biomarkers in adult FH subjects and controls. METHODS: In this cross-sectional study aortic valve measures were examined by cardiac ultrasound and inflammatory markers were analyzed in non-fasting blood samples. The study participants were 64 FH subjects with high (n = 29) or low (n = 35) Lp(a), and 14 healthy controls. RESULTS: Aortic valve peak velocity was higher (p = 0.02), and AVA was lower (p = 0.04) in the FH patients compared to controls; however, when performing multivariable linear regression, there were no significant differences. Furthermore, there were no significant differences between the high and low FH Lp(a) groups regarding the aortic valve. FH subjects had higher levels of platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to controls (0.003 ≤ P ≤ 0.03). This result persisted after multiple linear regression. CONCLUSIONS: Middle-aged, intensively treated FH subjects have higher aortic valve velocity, lower AVA, and higher levels of the platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to healthy control subjects. The aortic valve findings were not significant after multiple linear regression, whereas the higher levels of platelet-derived markers were maintained.

Genetic testing is essential for initiating statin therapy in children with familial hypercholesterolemia: Examples from Scandinavia.

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.

Cardiovascular outcomes and LDL-cholesterol levels in EMPA-REG OUTCOME®.

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 <1.8, 1.8-<2.2, 2.2- <2.6, 2.6-3.0, and > 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 <1.8/>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.

Regional Variations in Alirocumab Dosing Patterns in Patients with Heterozygous Familial Hypercholesterolemia During an Open-Label Extension Study.

PURPOSE: During 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). METHODS: Patients (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. RESULTS: Mean 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. CONCLUSIONS: In 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.

Risk of Recurrent Coronary Events in Patients With Familial Hypercholesterolemia; A 10-Years Prospective Study.

Background and Aim: Real world evidence on long term treatment of patients with familial hypercholesterolemia (FH) is important. We studied the effects of intensive lipid lowering medication (LLM) and optimized lifestyle in the study TTTFH-Treat To Target FH. Materials and Methods: Adults with a first known total cholesterol of mean (95% CI) 9.8 mmol/L (9.5, 10.1) were included consecutively in their routine consultation during 2006. Of the patients 86.4% had a pathogenic FH-mutation and the remaining were clinically diagnosed. We included 357 patients and 279 met for follow-up after median 10.0 (min 8.1, max 12.8) years. Results: Mean (95% CI) low density lipoprotein (LDL-C) was reduced from 3.9 (3.8, 4.1) to 3.0 (2.9, 3.2). More men than women used high intensity statin treatment, 85.2 and 60.8%, respectively. Women (n = 129) had higher LDL-C; 3.3 mmol/L (3.0, 3.5), than men; (n = 144) 2.8 mmol/L (2.6, 3.0), p = 0.004. Add-on PCSK9 inhibitors (n = 25) reduced mean LDL-C to 2.0 (1.4, 2.6) mmol/L. At enrollment 57 patients (20.4%) had established atherosclerotic cardiovascular disease (ASCVD), and 46 (80.4%) of them experienced a new event during the study period. Similarly, 222 (79.6%) patients had no detectable ASCVD at enrollment, and 29 of them (13.1%) experienced a first-time event during the study period. Conclusion: A mean LDL-C of 3.0 mmol/L was achievable in FH, treated intensively at a specialized clinic with few users of PCSK9 inhibitors. LDL-C was higher (0.5 mmol/L) in women than in men. In patients with ASCVD at enrollment, most (80.7%) experienced a new ASCVD event in the study period. The FH patients in primary prevention had more moderate CV risk, 13% in ten years.

Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia.

BACKGROUND: Evolocumab and other anti-PCSK9 antibodies reduced adverse cardiovascular outcomes in clinical trials of high-risk patients over <3 years median treatment duration. 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).

Efficacy and Safety of Alirocumab 300 mg Every 4 Weeks in Individuals With Type 2 Diabetes on Maximally Tolerated Statin.

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 <30% from baseline. Efficacy end points included percentage change from baseline to W24 for lipids, and time-averaged LDL-C over W21 to W24. RESULTS: In individuals with T2DM, LDL-C reductions from baseline to W24 and the average of W21 to W24 were significantly greater with alirocumab (-61.6% and -68.8%, respectively) vs placebo. At W24, alirocumab significantly reduced levels of non-high-density lipoprotein cholesterol (HDL-C) and other lipids. At W24, 85.9% and 12.5% of individuals in the alirocumab and placebo groups, respectively, reached both non-HDL-C <100 mg/dL and LDL-C <70 mg/dL. At W12, In total, 18% of alirocumab-treated participants received dose adjustment. The most common treatment-emergent adverse events were upper respiratory tract infection and injection-site reaction. No clinically significant changes in fasting plasma glucose and glycated hemoglobin were observed. CONCLUSION: In individuals with T2DM, alirocumab 300 mg Q4W was generally well tolerated and efficacious in reducing atherogenic lipoproteins.