Search

Aim: To compare the associations between concomitant liraglutide use versus no liraglutide use and the risk of major adverse cardiovascular events (MACE) and all‐cause mortality among patients receiving basal insulin (either insulin degludec [degludec] or insulin glargine 100 units/mL [glargine U100]) in the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE). Materials and Methods: Patients with type 2 diabetes and high cardiovascular risk were randomized 1:1 to degludec or glargine U100. Hazard ratios for MACE/mortality were calculated using a Cox regression model adjusted for treatment and time‐varying liraglutide use at any time during the trial, without interaction. Sensitivity analyses were adjusted for baseline covariates including, but not limited to, age, sex, smoking and prior cardiovascular disease. Results: At baseline, 436/7637 (5.7%) patients were treated with liraglutide; after baseline, 187/7637 (2.4%) started and 210/7637 (2.7%) stopped liraglutide. Mean liraglutide exposure from randomization was 530.2 days. Liraglutide use versus no liraglutide use was associated with significantly lower hazard rates for MACE [0.62 (0.41; 0.92)95%CI] and all‐cause mortality [0.50 (0.29; 0.88)95%CI]. There was no significant difference in the rate of severe hypoglycaemia with versus without liraglutide use. Multiple sensitivity analyses yielded similar results. Conclusions: Use of liraglutide was associated with significantly lower risk of MACE and death in patients with type 2 diabetes and high cardiovascular risk using basal insulin. [ABSTRACT FROM AUTHOR]

The tone of vascular smooth muscle cells is a primary determinant of the total peripheral vascular resistance and hence the arterial blood pressure. Most forms of hypertension ultimately result from an increased vascular tone that leads to an elevated total peripheral resistance. Regulation of vascular resistance under normotensive and hypertensive conditions involves multiple mediators, many of which act through G protein–coupled receptors on vascular smooth muscle cells. Receptors that mediate vasoconstriction couple with the G-proteins Gq-G11 and G12-G13 to stimulate phosphorylation of myosin light chain (MLC) via the Ca2+/MLC kinase– and Rho/Rho kinase–mediated signaling pathways, respectively. Using genetically altered mouse models that allow for the acute abrogation of both signaling pathways by inducible Cre/loxP-mediated mutagenesis in smooth muscle cells, we show that Gq-G11–mediated signaling in smooth muscle cells is required for maintenance of basal blood pressure and for the development of salt-induced hypertension. In contrast, lack of G12-G13, as well as of their major effector, the leukemia-associated Rho guanine nucleotide exchange factor (LARG), did not alter normal blood pressure regulation but did block the development of salt-induced hypertension. This identifies the G12-G13–LARG–mediated signaling pathway as a new target for antihypertensive therapies that would be expected to leave normal blood pressure regulation unaffected. [ABSTRACT FROM AUTHOR]

Patients (pts) (n=1012) with T2D (A1C 7-11%) on oral antidiabetic drugs (OADs) were randomized 1:1 to open label IDegLira or IGlar U100 in a 104 week trial to assess treatment durability. The primary endpoint was time from randomization to treatment intensification (A1C ≥7.0% at 2 consecutive visits including week 26); pts who met the primary endpoint discontinued study drug. Baseline characteristics were similar. Over 104 weeks, fewer pts with IDegLira required intensification vs. IGlar U100 (37.4% vs. 66.2%). Pts treated with IDegLira had a significantly longer time to intensification (median: >2 years/~1 year for IDegLira/IGlar U100; Figure). There was greater effect with IDegLira vs. IGlar U100 after 104 weeks, had intensification not been needed, in terms of: pts achieving A1C <7% (55.7 vs. 28.5%), and A1C <7% with no weight gain (20.9 vs. 6.3%), lower estimated mean insulin dose (36 vs. 51 U; estimated treatment difference -14.9 U), and 56% lower rate of severe or blood glucose confirmed symptomatic hypoglycemia (0.38 vs. 0.86 events/patient-year of exposure, (p<0.0001 for all). Safety results were similar. Improved long-term glycemic control, evidenced by significantly longer time to treatment intensification, was achieved with IDegLira vs. IGlar U100 in pts previously uncontrolled on OADs. Disclosure: V.R. Aroda: Consultant; Self; ADOCIA, AstraZeneca, Becton, Dickinson and Company, Novo Nordisk Inc., Sanofi, Zafgen, Inc. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; AstraZeneca, Calibra Medical, Eisai Inc., Janssen Research & Development, Novo Nordisk Inc., Sanofi, Theracos, Inc. G. Gonzalez-Galvez: Advisory Panel; Self; Amgen Inc., AstraZeneca, Janssen Pharmaceuticals, Inc., Metabolic Solutions Development Company, Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. Consultant; Self; Amgen Inc., AstraZeneca, Janssen Pharmaceuticals, Inc., Metabolic Solutions Development Company, Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Metabolic Solutions Development Company, Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. M. Haluzik: Advisory Panel; Self; AstraZeneca, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Johnson & Johnson, Lilly Diabetes. Speaker's Bureau; Self; Novartis AG. R.J. Silver: Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S. R. Grøn: Employee; Self; Novo Nordisk A/S. N. Halladin: Employee; Self; Novo Nordisk A/S. P. Örsy: Employee; Self; Novo Nordisk A/S. G. Sesti: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, GlaxoSmithKline plc., Novo Nordisk A/S, Servier. Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, GlaxoSmithKline plc., Novo Nordisk A/S, Servier. Funding: Novo Nordisk A/S [ABSTRACT FROM AUTHOR]