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Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here, by using histology, flow cytometry and intravital microscopy, we show that functional loss of sGC in platelets of atherosclerosis-prone Ldlr−/− mice contributes to atherosclerotic plaque formation, particularly via increasing in vivo leukocyte adhesion to atherosclerotic lesions. In vitro experiments revealed that supernatant from activated platelets lacking sGC promotes leukocyte adhesion to endothelial cells (ECs) by activating ECs. Profiling of platelet-released cytokines indicated that reduced platelet angiopoietin-1 release by sGC-depleted platelets, which was validated in isolated human platelets from carriers of GUCY1A1 risk alleles, enhances leukocyte adhesion to ECs. Importantly, pharmacological sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced leukocyte recruitment and atherosclerotic plaque formation in atherosclerosis-prone Ldlr−/− mice. Therefore, pharmacological sGC stimulation might represent a potential therapeutic strategy to prevent and treat CAD.

Introduction Therapeutic inertia refers to the failure to initiate or intensify treatment in a timely manner and is widespread in type 2 diabetes (T2D) despite the well-established importance of maintaining good glycemic control. The aim of this analysis was to quantify the clinical and economic burden associated with poor glycemic control due to therapeutic inertia in patients with T2D in the USA. Methods The IQVIA CORE Diabetes Model was used to simulate life expectancy, costs associated with diabetes-related complications, and lost workplace productivity in US patients. Baseline glycated hemoglobin (HbA1c) levels were 7.0% (53 mmol/mol), 9.0% (75 mmol/mol), 11.0% (97 mmol/mol) 13.0% (119 mmol/mol), or 15.0% (140 mmol/mol), with targets of 6.5% (48 mmol/mol), 7.0% (53 mmol/mol), 8.0% (64 mmol/mol), or 9.0% (75 mmol/mol) depending on baseline HbA1c, across several delayed intensification scenarios (values above target were defined as poor control). The burden associated with intensification delays of 1, 2, 3, 5, and 7 years was estimated over time horizons of 1–30 years. Future costs and clinical benefits were discounted at 3% annually. Results In a population of 13.4 million patients with T2D and baseline HbA1c of 9.0% (75 mmol/mol), delaying intensification of therapy by 1 year was associated with a loss of approximately 13,390 life-years and increased total costs of US dollars (USD) 7.3 billion (1-year time horizon). Longer delays in intensification were associated with a greater economic burden. Delaying intensification by 7 years was projected to cost approximately 3 million life-years and USD 223 billion over a 30-year time horizon. Conclusion Therapeutic inertia is common in routine clinical practice and makes a substantial contribution to the burden associated with type 2 diabetes in the USA. Initiatives and interventions aimed at preventing therapeutic inertia are needed to improve clinical outcomes and avoid excess costs. Electronic Supplementary Material The online version of this article (10.1007/s12325-019-01199-8) contains supplementary material, which is available to authorized users.

Introduction Liraglutide and sitagliptin were compared on glycemic control and all-cause healthcare costs over a 1-year period among older adults with type 2 diabetes (65–89 years) enrolled in a national Medicare Advantage Prescription Drug health plan. Methods This was a retrospective study in which the index date was the first prescription fill for liraglutide or sitagliptin between 25 January 2010 and 31 December 2014. Post-index treatment persistence and glycosylated hemoglobin (HbA1c) at baseline and 1 year (± 90 days) post-index date were required. Patients were excluded if their record included use of insulin during the baseline period. Inverse probability of treatment weighting using stabilized weights was employed with final covariate adjusted regression modeling to estimate the primary outcome (mean change in HbA1c) and secondary outcomes (achieving glycemic goal and costs), each at 1-year post-index date. Results Overall, 3056 patients met the selection criteria, of whom 218 filled prescriptions for liraglutide and 2838 for sitagliptin. Adjusted mean change in HbA1c at 1 year post-index was − 0.42 with liraglutide versus − 0.12 with sitagliptin (P = 0.0012). Adjusted odds of achieving the treatment goals of HbA1c

Introduction This study compared the clinical and economic outcomes of long-term use of liraglutide versus sitagliptin for the treatment of type 2 diabetes (T2DM) in real-world practice in the USA. Methods We identified adult patients (≥ 18 years old) with T2DM who initiated liraglutide or sitagliptin in 2010–2014 using a large claims database. Quarterly glycemic control measures and annual healthcare costs were assessed during the 1st and 2nd years of persistent medication use. Their associations with medication use (liraglutide or sitagliptin) were estimated using multivariable regression models adjusted for patient demographic and clinical characteristics. Results A total of 3113 patients persistently used liraglutide (N = 493) or sitagliptin (N = 2620) for ≥ 1 year [mean age (standard deviation, SD): 53 (8.5) vs. 56 (9.7) years; 48.3% vs. 62.3% males; both p

Introduction The National Health and Nutrition Examination Surveys show that many people with type 2 diabetes (T2D) in the USA fail to achieve recommended treatment targets. In the SUSTAIN 7 randomized controlled trial, once-weekly semaglutide (0.5 and 1.0 mg) was superior to comparative doses of dulaglutide (0.75 and 1.5 mg) in reducing glycated hemoglobin (HbA1c) and body weight in people with T2D. The present study estimated the cost per patient achieving HbA1c treatment targets and weight loss responses with once-weekly semaglutide and dulaglutide in the USA. Methods Numbers needed to treat and annual cost per patient achieving HbA1c targets (including a triple composite endpoint of HbA1c

Quantum chemical investigations at the BP86/def2-SVP, BP86/def2-TZVPP and BP86/TZ2P+ levels of theory have been done for the series of AlH2+ complexes that carry carbodiphosphorane and analogues called tetrylones [X(PPh3)2–AlH2]+ (Al-XPPh) (X = C–Pb) using charge and partitioning methods. The most stable structures of Al-XPPh have been found for carbone CPPh as a mildly side-on style in carbone complex Al-CPPh, while the heavier tetrylone adducts Al-SiPPh−Al-PbPPh have significantly different side-on fashions SiPPh−PbPPh, which exhibit the more acute bending angles in tilted forms linked to AlH2+ fragment. Bond dissociation energies (BDEs), De (kcal/mol), slightly decrease from the strongest bonded carbone, Al-CPPh, to the weaker bonded heavier homologues. The bulky tetrylone ligands XPPh have significantly influenced to the Al-X bond strength in complexes Al-XPPh when calculating BDEs with dispersion interaction. The NBO analysis revealed that the [X(PPh3)2 → AlH2]+ donation comes mainly from the σ- and π-contributions of the ligands. The EDA–NOCV calculations showed that the bond sturdiness of the Al–X bond results from the decrease in [X(PPh3)2 → AlH2]+ donation and electrostatic attraction. The EDA–NOCV data also indicated that AlH2+–tetrylone complexes exhibit not only (PPh3)2X → AlH2+ strong σ-donors and weak π-donors but also (PPh3)2X ← AlH2+ weak π-back donation as π–π electrons shared in complexes.