linagliptin and Sepsis

Type 2 diabetes (T2D) is a common comorbidity in people living with HIV (PLWH). Anti-hyperglycemic treatment in PLWH is still a challenge, and no randomized controlled studies using new glucose-lowering agents are currently available.. A 55-year-old-women was admitted to our Diabetes Unit because of hyperosmolar hyperglycemic state (HHS) and sepsis. The medical history included HIV infection and insulin-treated diabetes. On clinical examination, the lady appeared dehydrated with dry buccal mucosa, tachycardia, altered mental status, genital infection, and fever. On admission, plasma glucose was 54.5 mmol/L, HbA1c 155 mmol/mol, osmolarity 389.4 mOsm/kg, bicarbonate 24.6 mmol/L with no detectable serum ketones. The patient was treated with i.v. fluid and insulin, and antibiotic therapy commenced. Upon HHS and sepsis resolution, a basal-bolus insulin therapy was implemented that was followed by significant improvement of daily glucose profiles and progressive reduction of insulin requirement until complete discontinuation. A low dose of metformin plus linagliptin was started. Since a severe atherosclerotic disease was diagnosed, a GLP-1 receptor agonist, dulaglutide, was added to metformin upon linagliptin withdrawal with maintenance of good glycemic control, treatment adherence and amelioration of quality of life and no side effects.. This case suggests that GLP-1 receptor agonist therapy may be effective and safe for treatment of T2D with high cardiovascular risk in PLWH, supporting the need of clinical trials directly assessing the safety and the efficacy of GLP-1 receptor agonist in these individuals.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glucose; Glycated Hemoglobin; Heart Disease Risk Factors; HIV Infections; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Linagliptin; Metformin; Middle Aged; Quality of Life; Recombinant Fusion Proteins; Risk Factors; Sepsis

The pathophysiology of sepsis involves inflammation and hypercoagulability, which lead to microvascular thrombosis and compromised organ perfusion. Dipeptidyl peptidase (DPP)-4 inhibitors, e.g., linagliptin, are commonly used anti-diabetic drugs known to exert anti-inflammatory effects. However, whether these drugs confer an anti-thrombotic effect that preserves organ perfusion in sepsis remains to be investigated. In the present study, human umbilical vein endothelial cells (HUVECs) were treated with linagliptin to examine its anti-inflammatory and anti-thrombotic effects under tumor necrosis factor (TNF)-α treatment. To validate findings from in vitro experiments and provide in vivo evidence for the identified mechanism, a mouse model of lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome was used, and pulmonary microcirculatory thrombosis was measured. In TNF-α-treated HUVECs and LPS-injected mice, linagliptin suppressed expressions of interleukin-1β (IL-1β) and intercellular adhesion molecule 1 (ICAM-1) via a nuclear factor-κB (NF-κB)-dependent pathway. Linagliptin attenuated tissue factor expression via the Akt/endothelial nitric oxide synthase pathway. In LPS-injected mice, linagliptin pretreatment significantly reduced thrombosis in the pulmonary microcirculation. These anti-inflammatory and anti-thrombotic effects were independent of blood glucose level. Together the present results suggest that linagliptin exerts protective effects against endothelial inflammation and microvascular thrombosis in a mouse model of sepsis.

Topics: Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Disease Models, Animal; Human Umbilical Vein Endothelial Cells; Humans; Hypoglycemic Agents; Inflammation; Linagliptin; Lipopolysaccharides; Mice; Microcirculation; Sepsis; Thrombosis; Tumor Necrosis Factor-alpha

The mortality rate of patients who develop sepsis-related cardiac dysfunction is high. Many disease conditions (e.g., diabetes) increase the susceptibility to infections and subsequently sepsis. Activation of the NF-κB pathway plays a crucial role in the pathophysiology of sepsis-associated cardiac dysfunction and diabetic cardiomyopathy. The effect of diabetes on outcomes in patients with sepsis is still highly controversial. We here hypothesized that type 2 diabetes (T2DM) augments the cardiac (organ) dysfunction associated with sepsis, and that inhibition of the NF-κB pathway with linagliptin attenuates the cardiac (organ) dysfunction in mice with T2DM/sepsis. To investigate this, 10-week old male C57BL/6 mice were randomized to receive normal chow or high fat diet (HFD), 60% of calories derived from fat). After 12 weeks, mice were subjected to sham surgery or cecal ligation and puncture (CLP) for 24 h. At 1 hour after surgery, mice were treated with linagliptin (10 mg/kg, i.v.), IKK-16 (1 mg/kg, i.v.), or vehicle (2% DMSO, 3 ml/kg, i.v.). Mice also received analgesia, fluids and antibiotics at 6 and 18 h after surgery. Mice that received HFD showed a significant increase in body weight, impairment in glucose tolerance, reduction in ejection fraction (%EF), and increase in alanine aminotransferase (ALT). Mice on HFD subjected to CLP showed further reduction in %EF, increase in ALT, developed acute kidney dysfunction and lung injury. They also showed significant increase in NF-κB pathway, iNOS expression, and serum inflammatory cytokines compared to sham surgery group. Treatment of HFD-CLP mice with linagliptin or IKK-16 resulted in significant reductions in (i) cardiac, liver, kidney, and lung injury associated with CLP-sepsis, (ii) NF-κB activation and iNOS expression in the heart, and (iii) serum inflammatory cytokine levels compared to HFD-CLP mice treated with vehicle. Our data show that pre-existing type 2 diabetes phenotype worsens the organ dysfunction/injury associated with CLP-sepsis in mice. Most notably, inhibition of NF-κB reduces the organ dysfunction/injury associated with sepsis in mice with pre-existing T2DM.

Topics: Animals; Cecum; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Heart Diseases; Humans; Linagliptin; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Piperidines; Pyrrolidines; Sepsis; Signal Transduction

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a novel class of drugs for the treatment of hyperglycaemia. Preliminary evidence suggests that their antioxidant and anti-inflammatory effects may have beneficial effects on the cardiovascular complications of diabetes. In the present study, we investigate in an experimental sepsis model whether linagliptin exerts pleiotropic vascular effects independent of its glucose-lowering properties.. Linagliptin (83 mg/kg chow for 7 days) was administered in a rat model of lipopolysaccharide (LPS) (10 mg/kg, single i.p. dose/24 h)-induced sepsis. Vascular relaxation, reactive oxygen species (ROS) formation, expression of NADPH oxidase subunits and proinflammatory markers, and white blood cell infiltration in the vasculature were determined. Oxidative burst and adhesion of isolated human neutrophils to endothelial cells were measured in the presence of different DPP-4 inhibitors, and their direct vasodilatory effects (isometric tension in isolated aortic rings) were compared. In vivo linagliptin treatment ameliorated LPS-induced endothelial dysfunction and was associated with reduced formation of vascular, cardiac, and blood ROS, aortic expression of inflammatory genes and NADPH oxidase subunits in addition to reduced aortic infiltration with inflammatory cells. Linagliptin was the most potent inhibitor of oxidative burst in isolated activated human neutrophils and it suppressed their adhesion to activated endothelial cells. Of the inhibitors tested, linagliptin and alogliptin had the most pronounced direct vasodilatory potency.. Linagliptin demonstrated pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties independent of its glucose-lowering properties. These pleiotropic properties are generally not shared by other DPP-4 inhibitors and might translate into cardiovascular benefits in diabetic patients.

Topics: Administration, Oral; Animals; Antioxidants; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Humans; Leukocytes; Linagliptin; Lipopolysaccharides; Male; Neutrophils; Oxidative Stress; Purines; Quinazolines; Rats; Rats, Wistar; Respiratory Burst; Sepsis; Vasodilation