A placebo-controlled proof-of-concept study of alirocumab on postprandial lipids and vascular elasticity in insulin-treated patients with type 2 diabetes mellitus

Aim: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) linked to atherogenic dyslipidaemia and postprandial hyperlipidaemia. Alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, improves CVD risk by reducing the concentration of low-density lipoprotein-cholesterol (LDL-C). However, effects of PCK9 inhibitors on other aspects of diabetic dyslipidaemia, particularly in the postprandial situation, are less clear. Material and Methods: Twelve male patients with T2DM on an intensive insulin regimen completed a 6-week randomized, double-blind, placebo-controlled, proof-of-concept study. Participants received three biweekly dosages of subcutaneous alirocumab (150 mg) or placebo. Before and after the intervention, fasting and postprandial triglyceride (TG) plasma levels, apolipoprotein (apo) B48, lipoprotein composition isolated by ultracentrifugation, vascular function and markers of inflammation were evaluated. Results: Alirocumab treatment reduced fasting plasma TG levels (between group median change −24.7%; P = 0.018) and fasting apoB48 serum levels (−35.9%; P = 0.039) compared with placebo. Alirocumab reduced the plasma TG area under the curve (AUC) (−26.4%; P = 0.006) and apoB48 AUC (−55.7%; P = 0.046), as well as plasma TG incremental AUC (−21.4%; P = 0.04) and apoB48 incremental AUC (−26.8%; P = 0.02). In addition, alirocumab reduced fasting and postprandial TG levels in very low-density lipoprotein (VLDL) and LDL. Alirocumab improved fasting pulse wave velocity, but no changes in postprandial markers of inflammation were observed. Conclusions: In addition to the well-known LDL-C-reducing effects, 6 weeks of alirocumab treatment lowered both fasting and postprandial plasma TG levels by reducing the TG levels in VLDL and LDL and the concentration of intestinal remnants

Comparing Problem Formulation for Coupled Sets of Component

In this paper several formulations and comparative test results are presented for problems involving the general paradigm of coupled sets of components. This paradigm is general enough to include systems of systems (SoS) and multidisciplinary design optimization (MDO). It is assumed that these systems involve a (potentially inactive) coordinating component, or "Central Authority" and one or more, potentially interacting, subordinate components. The formulations differ in the amount of control given to the central authority versus the autonomy granted to the subordinate components. Comparative test results are given for several of the formulations on a NASA-generated, public domain, aircraft conceptual design problem

A function of innovation systems approach for analysing the roles of intermediaries in eco-innovation

This article draws from two bodies of literature, innovation intermediaries and technological innovation systems, to develop an approach for analysing the functions of intermediaries in eco-innovation. The link between the functions of innovation intermediaries and the functions of technological innovation systems has seldom been explicitly established in the scientific discourse and thus this article contributes to theoretical development in both literatures. To the technological innovation systems literature, this article addresses the lack of attention to the functions of innovation intermediaries who are a critical part in the formation of networks and also contribute to a number of innovation system functions. To the innovation intermediary literature, the functional approach advocates for a synthesis and consensus building in the literature regarding intermediary functions in view of the several redundancies and ambiguities on the subject matter. Empirical operationalization of the analytical approach including methodological choices from case studies in Region Scania, Sweden and North Rhine Westphalia, Germany are also discussed. The results of our analysis show that the functions of the innovation intermediaries are particularly relevant for the overall goals of an innovation system as compared to the configuration of intermediary actors. Particular challenges with a functional approach in this context include the difficulties of establishing a causal relation between the support functions of intermediaries and eco-innovation outcomes in firms.SHIF

Effects of dapagliflozin on postprandial lipid metabolism in type 2 diabetes mellitus

Objectives: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) modulate lipid metabolism and improve cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The exact cardioprotective mechanism of SGLT2i is unclear. We evaluated the effects of SGLT2i on postprandial lipids, lipoprotein concentrations, glucose and fatty acids. Design: A placebo-controlled randomized, proof-of-concept study. Methods: Fourteen male patients with T2DM on intensive insulin regimen were randomly and double-blind allocated to 12 weeks dapagliflozin (10 mg) or placebo. Postprandial effects were assessed with an 8-h standardized oral fat loading test. Results: Mean glycated A1c did not change by dapagliflozin, but the mean daily insulin dose was significantly reduced. Although dapagliflozin did not affect fasting or postprandial levels of glucose and insulin, it increased the postprandial levels of glucagon. While fasting levels of free fatty acids and beta-hydroxybutyrate (bHBA) were unchanged, dapagliflozin significantly increased the postprandial bHBA response. This was seen in the context of increased postprandial glucagon levels by dapagliflozin, without influencing postprandial insulin or glucose levels. Dapagliflozin did not affect fasting or postprandial plasma cholesterol and triglycerides nor postprandial inflammatory markers. Fasting apolipoprotein B48 was decreased without affecting the postprandial response. Markers of inflammation and vascular function did not change. Conclusion: Treatment with dapagliflozin of patients with T2DM led to a reduction of fasting chylomicron remnants and increased postprandial ketone bodies compared to placebo suggesting enhanced hepatic fatty acid oxidation. The latter may have been caused by decreasing the insulin-glucagon ratio. The beneficial clinical effects seen in the trials using dapagliflozin most likely are not due to effects on postprandial inflammation nor postprandial lipemia.</p

Quality of Life Improves with Alemtuzumab Over 6 Years in Relapsing-Remitting Multiple Sclerosis Patients with or without Autoimmune Thyroid Adverse Events: Post Hoc Analysis of the CARE-MS Studies

Introduction: In clinical trials of alemtuzumab, autoimmune thyroid adverse events (AEs) were frequent. Here, we assess the impact of thyroid AEs on health-related quality of life (HRQL) in alemtuzumab-treated patients with relapsing-remitting multiple sclerosis (RRMS). Methods: In phase 3 CARE-MS I (NCT00530348) and II (NCT00548405) trials, patients with RRMS were administered alemtuzumab 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Patients could participate in an extension study (NCT00930553) through year 6. HRQL was assessed at baseline and annually using the Functional Assessment of Multiple Sclerosis (FAMS), EuroQoL-5 Dimension Visual Analog Scale (EQ-5D VAS), and 36-Item Short-Form Survey (SF-36) questionnaires. Outcomes were analyzed in patients with or without thyroid AEs (nonserious or serious). A subset of patients with thyroid AEs was analyzed to assess HRQL before and during the onset of thyroid AEs. Results: A total of 811 CARE-MS patients were treated with alemtuzumab. Of these, 342 (42%) patients experienced thyroid AEs over 6 years; serious thyroid AEs occurred in 44 (5%) patients. At year 6, HRQL outcomes generally remained slightly improved or similar to core study baseline in alemtuzumab-treated patients with or without thyroid AEs: FAMS (least-squares mean change from baseline without thyroid AEs, 0.7; with nonserious thyroid AEs, 5.1; with serious thyroid AEs, − 5.3), EQ-5D VAS (2.0; 3.0; − 6.8), SF-36 mental component summary (MCS [0.6; 1.6; − 2.8]), SF-36 physical component summary (PCS [0.8; 1.0; 1.1]). Over 6 years, 63–82% of patients in each group had improved/stable SF-36 MCS and PCS scores. Among patients with thyroid AE onset in year 3 (peak incidence), there were minimal differences between HRQL outcomes before onset (year 2) and after onset (year 3). Conclusion: Autoimmune thyroid AEs (serious and nonserious) had minimal impact on HRQL in alemtuzumab-treated patients. These data may aid therapeutic decisions in patients with relapsing MS. © 2020, The Author(s)