Christoph F. Ebenbichler

Summary: Background: This real-world study examined clinical characteristics and dyslipidemia management among patients initiating evolocumab across 12 European countries. Austrian data are reported. Methods: Data of consenting adults were collected for ≤ 6 months prior to evolocumab initiation (baseline) and ≤ 30 months post-initiation. Patient characteristics, lipid lowering therapy (LLT, i.e. statin and/or ezetimibe) and lipid values were collected from medical records. Results: In Austria, 363 patients were enrolled. At baseline, 52% of patients initiated evolocumab without background LLT; the median (Q1, Q3) initial low-density lipoprotein cholesterol (LDL-C) level was 142 (111, 187) mg/dL. Within 3 months of evolocumab treatment, median LDL‑C decreased by 59% to 58 (37, 91) mg/dL. This reduction was maintained over time, despite consistently infrequent use of background LLT. LDL-C < 55 mg/dL was attained by 65% of patients (76% with, 55% without background LLT). Evolocumab persistence was ≥ 90% at month 12 and month 30. Conclusion: In Austria, patients were initiated on evolocumab at LDL‑C levels almost 3‑times higher than the guideline-recommended clinical goal (< 55 mg/dL). Persistence with evolocumab was very high. Evolocumab led to a rapid and sustained LDL‑C reduction with 65% attaining the LDL‑C goal. Patients using evolocumab in combination with statins and/or ezetimibe were more likely to attain their LDL‑C goal and thus decrease cardiovascular risk.

Summary: Background: Bariatric surgery is a treatment option for patients with severe obesity and improves parameters of cardiovascular and/or metabolic disease. Carotid intima media thickness (C-IMT) is a surrogate measure of subclinical atherosclerosis. Previous studies showed short to mid-term arrest and even regression of C‑IMT progression following bariatric surgery. We aimed to investigate the long-term effect of weight loss on C‑IMT progression 10 years after bariatric surgery in comparison to a population-based control cohort. Methods: In total, 21 eligible patients were examined preoperatively, at 5 and 10 years after bariatric surgery. Anthropometric parameters, plasma triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), insulin, and glucose were assessed at all three study visits. C‑IMT was measured via B‑mode scans of the common carotid artery. C‑IMT progression was measured in an age-matched and BMI-matched cohort selected from the population-based Bruneck study to compare with changes in C‑IMT progression after bariatric surgery. Results: C‑IMT remained stable over the 10-year observation period after bariatric surgery. The control cohort showed a significant C‑IMT progression over 10 years. The difference in C‑IMT progression over 10 years was significant (p < 0.01) between both cohorts. Conclusion: Weight loss induced by bariatric surgery halts the natural progression of C‑IMT over a 10-year observation period.

Background: Variability in LDL-C control at a population level associates with worse CV outcomes. This could in part be related to variations in patient adherence to self-administration regimens or variability in the response to a given therapy. Potent therapies such as PCSK9 inhibitors (PCSK9i) reduce cardiovascular events but some have questioned whether these therapies, which require dosing every 2 weeks, can offer sustained population level control of LDL-C. Purpose: Using data from the HEYMANS registry, the objective of these analyses was to evaluate, at a population level, various metrics of variability in LDL-C reduction over time with evolocumab treatment. Methods: HEYMANS was a prospective registry including adults initiating evolocumab treatment in clinical practice in 12 European countries between August 2015 to June 2020. Patient data were collected for ≤6 months before evolocumab initiation (baseline) and ≤30 months post initiation. LDL-C measurements were collected per clinical practice. At each 3-month time point in the study, we analysed median (and 95% CI) reductions in LDL-C, and the proportion of patients achieving ≥30% and ≥50% reductions in LDL-C from baseline. Results: Data from 1951 patients were included in this final analysis (62% male, mean age 60 years, median baseline LDL-C 3.98 [Q1–Q3 3.17–5.07]) mmol/L). Most patients (85%) were receiving evolocumab for secondary prevention, with 40% not on oral LLT of whom the majority reported a history of statin intolerance. There was a median of 4 (Q1, Q3: 2, 6) LDL-C measurements per patient during follow-up. Within 3 months of initiating evolocumab treatment, LDL-C levels had reduced by a median of 58% and this reduction was maintained over 30 months (Figure 1). Among patients with an LDL-C value, ∼85% achieved a ≥30% reduction at each follow-up throughout the study, and ∼63% achieved a ≥50% reduction at each visit (Figure 2). Conclusions: In European clinical practice, evolocumab treatment was associated with early and sustained reductions in LDL-C of over 30 months, with limited variability in LDL-C reductions at a population level. Within 3 months of treatment, evolocumab was associated with ∼58% reduction in LDL-C levels that was maintained throughout the study. These data should reassure the clinical community that meaningful, consistent additional reductions in LDL-C can be achieved with use of evolocumab. As greater use of combination therapies is required to achieve lower LDL-C goals, expanding the use of PCSK9i could provide improvements in population level control of LDL-C in European clinical practice. Funding Acknowledgement: Type of funding sources: Private company. Main funding source(s): Amgen (Europe) GmbH

Background: Lipid-lowering treatments (LLTs) require both adherence and persistence to the treatment regimen long-term to maximise treatment benefits. Small molecules require self-medication daily but therapies such as evolocumab are labelled for self-medication every 2 weeks or monthly. Limited data exist concerning the long-term persistence to evolocumab in routine clinical practice. Purpose: Using data from the HEYMANS registry, the objective of this analysis was to evaluate persistence and discontinuation of evolocumab in Europe. Methods: HEYMANS was a prospective registry including adults initiating evolocumab treatment in routine clinical practice in 12 European countries between August 2015 and June 2020. Originally designed to have up to 12 months of follow-up, the protocol was amended (February 2018) to extend follow-up for up to 30 months. Patients yet to complete 12 months follow-up at this date, were followed up for up to 30 months. Therefore, we analysed evolocumab discontinuation separately for the two time periods: 0–12 months (all), 12–30 months (subset). Results: Of the 1951 total patients, 30 patients discontinued participation in the study before 12 months (evolocumab use still ongoing at study discontinuation). Therefore, evolocumab use status was determined for 1921 patients at 12 months. Of these, 1781 (92.7%), remained on evolocumab at 12 months of follow-up (Figure). At 12 months, LDL-C levels were reduced from baseline by a median of 58% (Q1, Q3: 41%, 69%). In total, 1136 patients were eligible for extended follow up after protocol amendment. Of these, 137 patients discontinued study participation before 30 months of follow-up (with evolocumab ongoing). Therefore, evolocumab use status was determined in 999 patients, of whom, 92.2% (921) remained on evolocumab treatment at 30 months of follow-up (Figure). The reductions in LDL-C levels seen at 12 months were sustained throughout the study, with patients continuing to achieve median LDL-C reductions of 58% (Q1, Q3: 42%, 70%) from baseline at 30 months of follow-up. Conclusions: In this real-world study, representative of European practice, of patients who entered the extension phase, the proportion of patients who remained on evolocumab up to 30 months exceeded 90%, and treatment was associated with sustained LDL-C reductions. These data suggest that the self-administration regimen of evolocumab is both feasible and acceptable in general populations, providing long-term sustained, reductions in LDL-C with likely associated health benefits. Funding Acknowledgement: Type of funding sources: Private company. Main funding source(s): Amgen (Europe) GmbH

Cardiovascular disease is the most common cause of death worldwide and is mainly due to atherosclerosis. Elevated levels of low-density lipoprotein cholesterol (LDL-C) are the main risk factor for atherosclerosis. Treatment with existing therapies for dyslipidemia and life-style changes are often sufficient to reach the lipid targets and decrease the cardiovascular risk of patients. However, there are patients who cannot reach their targets. Especially patients with genetically caused dyslipidemias, such as familial hypercholesterolemia, often are not able to reach the targets, leading to an increased cardiovascular risk and higher mortality. Evinacumab is a human monoclonal antibody which binds and inhibits angiopoietin-like protein 3 (ANGPTL3). The inhibition of ANGPTL3 leads to increased activity of the lipoprotein lipase (LPL) and the endothelial lipase (EL). LPL is the main enzyme for hydrolyzation of triglyceride-rich lipoproteins. EL is a phospholipase which preferentially hydrolyzes high-density lipoprotein (HDL) but also decreases circulating LDL-C. The increased LPL and EL activity reduces circulating levels of very-low-density lipoprotein cholesterol, triglycerides, LDL-C and HDL-cholesterol. Evinacumab leads to a significant decrease in circulating lipids and attainment of lipid targets in these patients. Further studies with evinacumab to assess its lipid-decreasing potential and to evaluate its impact on cardiovascular risk and mortality are eagerly awaited.

Introduction Bariatric surgery offers the most effective treatment for obesity, ameliorating or even reverting associated metabolic disorders, such as type 2 diabetes. We sought to determine the effects of bariatric surgery on circulating microRNAs (miRNAs) that have been implicated in the metabolic cross talk between the liver and adipose tissue. Research design and methods We measured 30 miRNAs in 155 morbidly obese patients and 47 controls and defined associations between miRNAs and metabolic parameters. Patients were followed up for 12 months after bariatric surgery. Key findings were replicated in a separate cohort of bariatric surgery patients with up to 18 months of follow-up. Results Higher circulating levels of liver-related miRNAs, such as miR-122, miR-885-5 p or miR-192 were observed in morbidly obese patients. The levels of these miRNAs were positively correlated with body mass index, percentage fat mass, blood glucose levels and liver transaminases. Elevated levels of circulating liver-derived miRNAs were reversed to levels of non-obese controls within 3 months after bariatric surgery. In contrast, putative adipose tissue-derived miRNAs remained unchanged (miR-99b) or increased (miR-221, miR-222) after bariatric surgery, suggesting a minor contribution of white adipose tissue to circulating miRNA levels. Circulating levels of liver-derived miRNAs normalized along with the endocrine and metabolic recovery of bariatric surgery, independent of the fat percentage reduction. Conclusions Since liver miRNAs play a crucial role in the regulation of hepatic biochemical processes, future studies are warranted to assess whether they may serve as determinants or mediators of metabolic risk in morbidly obese patients.

Introduction Prescription patterns of antidiabetic drugs in the period from 2012 to 2018 were investigated based on the Diabetes Registry Tyrol. To validate the findings, we compared the numbers with trends of different national registries conducted in a comparable period of time. Research design and methods Medication data, prescription patterns, age groups, antidiabetic therapies and quality parameters (hemoglobin A1c, body mass index, complications) of 10 875 patients with type 2 diabetes from 2012 to 2018 were retrospectively assessed and descriptively analyzed. The changes were assessed using a time series analysis with linear regression and prescription trends were plotted over time. Results Sodium/glucose cotransporter 2 inhibitors (SGLT-2i) showed a significant increase in prescription from 2012 to 2018 (pConclusions In this long-term, real-world study on prescription changes in the Diabetes Registry Tyrol, we observed significant increase in SGLT-2i, metformin, gliptins and GLP-1a prescriptions. In contrast prescriptions for sulfonylureas declined significantly. Changes were consistent over the years 2012–2018. Changes in prescription patterns occurred even before the publication of international and national guidelines. Thus, physicians change their prescription practice not only based on published guidelines, but even earlier on publication of cardiovascular outcome trials.

Rationale: Hypoxia induces leptin gene expression in human adipocytes via hypoxia-inducible factors (HIF-α/β). Under ambient moderate hypoxia, leptin in adipocytes is elevated for at least 14 days. Leptin is supposedly involved in the reduced food intake, increased utilization of fatty acids for energy production and possible weight loss observed at high altitudes. Literature on adiponectin and visfatin in high altitude is inconsistent with reports of elevated levels and non-elevated levels. Exercise in hypoxia studies in obese subjects have shown a significant weight loss after up to 3 weeks, but it is unclear if this effect holds up for longer time periods. Therefore, we aimed to investigate 32 obese subjects completing 52 exercise and rest sessions within 8 months at either moderate or sham hypoxia and to analyze leptin, adiponectin, and visfatin mRNA-expression at different time points of exposure. Methods: Abdominal subcutaneous fat biopsies were taken from 32 obese subjects before, after 3 months and after 8 months of intervention. Subjects were randomly divided into two groups and exercised at moderate intensity at two different study sites twice a week. The IG was exposed to normobaric hypoxia (FiO₂: 14.0 ± 0.2%,) at exercise and at rest (FiO₂: 12.0 ± 0.2%) and the CG to sham hypoxia. Quantitative real-time polymerase chain reaction (qPCR) was used in order to determine mRNA-levels of leptin, adiponectin, and visfatin. Results: No differences in leptin levels after 3 and 8 months compared to baseline and between groups were found. There was no significant difference regarding adiponectin or visfatin at any time point compared to baseline in the hypoxia group, but an increase after 3 months was seen in the control group at normoxia compared to the hypoxia group (adiponectin: p = 0.029 and visfatin: p = 0.014). Conclusion: In this first several months' duration randomized sham controlled hypoxia exercise and rest study with obese subjects, we found no time extended leptin mRNA-expression in subjects under hypoxia after 3 and 8 months compared to baseline levels. Moderate exercise in normoxia not in hypoxia leads to elevated adiponectin and visfatin levels after 3 months.

We investigated the short‐term effects of dapagliflozin as adjunct to insulin on insulin sensitivity, postprandial glucose excursions and ketone body production in type 1 diabetes mellitus (T1DM). A total of seven male patients completed the randomized, double‐blind, placebo‐controlled cross‐over trial, receiving 10 mg of dapagliflozin daily for 3 days, followed by placebo, or the reverse. At Day 3, hyperinsulinaemic, euglycaemic clamps and oral glucose tolerance test clamps with repeated blood sampling were performed. Required glucose infusion and blood glucose excursions did not differ significantly between dapagliflozin treatment and placebo ( P = 0.491; P = 0.342). Prior to oral glucose, total ketone bodies showed a higher trend following dapagliflozin treatment ( P = 0.051). Following oral glucose, total ketone bodies decreased while concentrations of total GLP‐1 were higher following dapagliflozin ( P = 0.009). Non‐esterified free fatty acids did not differ between dapagliflozin treatment and placebo and ketonuria was absent under both conditions. In T1DM, short‐term addition of dapagliflozin to insulin influenced neither postprandial glucose excursions nor insulin sensitivity. Following oral glucose, total ketone bodies decreased in parallel with an increase in GLP‐1 concentrations, which were higher under dapagliflozin treatment as compared with placebo.