Dipeptidyl Peptidase-4 Inhibitor Linagliptin Research Articles

DPP-4 inhibition by linagliptin ameliorates age-related mild cognitive impairment by regulating microglia polarization in mice

Extensive preclinical evidence demonstrates a causative link between insulin signaling dysfunction and the pathogenesis of Alzheimer's disease (AD), and diabetic drugs may represent a promising approach to fighting AD. However, it remains to be determined which antidiabetic drugs are more effective in preventing cognitive impairment. Thus, the present study investigated the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on cognitive impairment in middle-aged mice by comparing it with the effect of metformin. We found that DPP-4 activity increased in the hippocampus of middle-aged mice, and DPP-4 was mainly expressed by microglia rather than astrocytes and oligodendrocytes. DPP-4 directly regulated M1/M2 microglia polarization following LPS or IL-4 stimulation, while DPP-4 inhibitor, linagliptin, suppressed M1-polarized activation and induced M2-polarized activation. Both linagliptin and metformin enhanced cognitive ability, increased hippocampal synaptic plasticity and neurogenesis, and decreased age-related oxidative stress and inflammation by regulating microglia polarization in the hippocampus of middle-aged mice. The combination of linagliptin and metformin showed a maximum protective effect compared to the individual drugs alone. Loss of macrophage inflammatory protein-1α (MIP-1α), a DPP-4 substrate, abrogated the cognitive protection and anti-inflammation effects of linagliptin. Therefore, the current investigation exhibits a potential utility for DPP-4 inhibition in attenuating microglia-mediated inflammation and preventing mild cognitive impairment (MCI) in middle-aged mice, and the effect was partly mediated by MIP-1α.

Comparison of gliclazide vs linagliptin on hypoglycemia and cardiovascular events in type 2 diabetes mellitus: A systematic review.

Cardiovascular outcome trials have demonstrated cardiovascular safety of glimepiride (a sulfonylureas) against dipeptidyl peptidase-4 inhibitor linagliptin. Gliclazide (another newer sulfonylureas) has shown similar glycemic efficacy and 50% decreased risk of hypoglycemia compared to glimepiride. Considering the absence of cardiovascular outcome trials for gliclazide, we decided to conduct a systematic review of the literature to assess the car-diovascular (CV) safety by assessing the risk for major adverse CV events and hypoglycemia risk of gliclazide vs linagliptin in patients with type 2 diabetes (T2D). This systematic review followed the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to analyze all the clinical studies published from 2008 that compared the two drugs in patients with T2D with no risk of CV disease (CVD). We included only evidence designated high quality by the Oxford Center for Evidence-based Medicine-Levels of Evidence. Eight clinical studies were included in the narrative descriptive analysis (gliclazide: 5 and linagliptin: 3). The CV safety of gliclazide in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial and of linagliptin in the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA) and CARdiovascular Outcome study of LINAgliptin vs glimepiride in patients with T2D (CAROLINA) trials were excluded from the comparative analysis as these trials demonstrated CV and hypoglycemia benefits in patients at high risk of CVD. However, since these are landmark trials, they were discussed in brief to show the CV benefits and low hypoglycemia risk of gliclazide and linagliptin. We did not find any study comparing gliclazide with linagliptin. Hence, direct comparison of their major adverse CV events and hypoglycemia risk could not be carried out. However, the literature meeting the inclusion criteria showed that both drugs were effective in achieving the desired glycemic control and had low major adverse CV events and hypoglycemia risk in adult patients with no history of CVD. Gliclazide can be considered an effective and safe glucose-lowering drug in T2D patients with no established CVD but at high risk of CVD due to their T2D status. Future randomized controlled trials comparing gliclazide with linagliptin or dipeptidyl peptidase-4 inhibitors can confirm these findings.

DPP-4 Inhibitor and Sulfonylurea Differentially Reverse Type 2 Diabetes-Induced Blood-Brain Barrier Leakage and Normalize Capillary Pericyte Coverage.

Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). Although accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. Here, we investigated whether two clinically used antidiabetics, the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride, which restore T2D-induced brain vascular pathology. Microvascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months before sacrifice. We demonstrate that T2D caused leakage of the blood-brain barrier (BBB), induced angiogenesis, and reduced pericyte coverage of microvessels. However, linagliptin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalized T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial activation, increased microglial-vascular interaction, and increased collagen IV density. This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage, which may contribute to antidiabetic neurorestorative effects.

Dual inhibition of SGLT2 and DPP-4 promotes natriuresis and improves glomerular hemodynamic abnormalities in KK/Ta-Ins2Akita mice with progressive diabetic kidney disease

Natriuresis is closely linked to glomerular hemodynamics in diabetic kidney disease (DKD), and is known to be influenced by inhibition of sodium-glucose cotransporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4). In the present study, we investigated whether dual inhibition of SGLT2 and DPP-4 exerts an additive effect on promoting natriuresis and how it ameliorates glomerular hemodynamic abnormalities via the natriuretic effect in DKD. Eight-week-old male KK/Ta-Ins2Akita (KK/Ta-Akita) mice which develop progressive DKD were orally once-daily given either SGLT2 inhibitor empagliflozin (30 mg/kg) alone, DPP-4 inhibitor linagliptin (5 mg/kg) alone or a combination of empagliflozin (30 mg/kg) plus linagliptin (5 mg/kg) for 6 weeks. In vehicle-treated control KK/Ta-Akita mouse group, markedly enhanced glomerular albumin filtration and glomerular filtration rate (GFR) were observed. These renal alterations were dramatically attenuated in KK/Ta-Akita mouse group treated with a combination of empagliflozin plus linagliptin. Notably, the combination therapy provided greater reduction in glomerular albumin filtration and GFR along with higher urinary excretion of sodium and a potential afferent arteriolar vasoconstrictor adenosine than the empagliflozin monotherapy. Significant reduction in urinary excretion levels of a potential afferent arteriolar vasodilator prostaglandin E2 (PGE2) relative to the baseline values was observed after the combination therapy but not the monotherapy. These results suggest that dual inhibition of SGLT2 and DPP-4 highly promotes a distal tubular sodium delivery and thereby contributes to the appropriate modulation of preglomerular arteriolar tone and intraglomerular pressure via an increase in adenosine release and a reduction in PGE2 secretion from macula densa in DKD.

The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates LPS-induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the Epac1/AKT pathway

Pulmonary microvascular endothelial cells (PMVECs) barrier dysfunction is a main pathophysiological feature of sepsis-related acute lung injury (ALI). This study aimed to investigate whether the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin could protect against LPS-induced PMVECs barrier disruption and its underlying molecular mechanisms. A classical ALI animal model and LPS-treated PMVECs were applied and all were treated with or without linagliptin. Cellular experiments demonstrated that linagliptin could mitigate LPS-induced PMVECs hyperpermeability and intercellular junction (VE-cadherin, β-catenin, and ZO-1) disruption in a dose-dependent manner. Correspondingly, it was observed that linagliptin pretreatment distinctly relieved LPS-induced lung injury, oxidative stress, and pulmonary edema in vivo. Furthermore, we found that the inhibition of oxidative stress by linagliptin may be achieved by reversing impaired mitochondrial function. Mechanistically, linagliptin administration promoted the activation of the Epac1 pathway and its downstream AKT pathway, while inhibition of the Epac1/Akt signaling pathway significantly alleviated the above-mentioned protective effect of linagliptin on the PMVECs barrier. Taken together, these data suggest that linagliptin can effectively reserve PMVECs barrier dysfunction and inhibit oxidative stress to protect against ALI via activating the Epac1/AKT signaling pathway, and thus may become a potential clinical therapeutic strategy for ALI.

Safety and effectiveness of empagliflozin and linagliptin fixed-dose combination therapy in Japanese patients with type 2 diabetes: final results of a one-year post-marketing surveillance study

ABSTRACT Background Fixed-dose combination (FDC) of the sodium-glucose co-transporter 2 inhibitor empagliflozin and the dipeptidyl peptidase-4 inhibitor linagliptin was approved for type 2 diabetes (T2D) treatment in Japan in 2018. We conducted a post-marketing surveillance study of empagliflozin/linagliptin FDC in routine clinical practice in Japan. Research design and methods This one-year, prospective, multicenter, observational study investigated the safety and effectiveness of empagliflozin/linagliptin FDC in Japanese patients with T2D. The primary outcome was incidence of adverse drug reactions (ADRs). Results Among 1146 patients, mean (SD) age was 63.8 (12.8) years and 22.08% were aged ≥75 years. Mean (SD) glycated hemoglobin (HbA1c) was 7.66% (1.21); fasting plasma glucose (FPG) was 142.90 mg/dl (43.75). ADRs were experienced by 32 (2.79%) patients (1 serious ADR); ADRs of important identified risk included urinary tract infection (7 patients [0.61%]), hypoglycemia (2 [0.17%]), ketoacidosis (0), genital infection (1 [0.09%]), and volume depletion (1 [0.09%]). Overall mean (SD) change from baseline in body weight, HbA1c, and FPG were −1.08 kg (3.21), −0.39% (1.11), and −7.90 mg/dl (39.12), respectively. Conclusions Empagliflozin/linagliptin FDC was effective and generally well tolerated in Japanese patients with T2D; no new safety concerns were identified. Trial Registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03761797)

Repositioning Linagliptin for the Mitigation of Cadmium-Induced Testicular Dysfunction in Rats: Targeting HMGB1/TLR4/NLRP3 Axis and Autophagy.

Cadmium, a ubiquitous environmental toxicant, disrupts testicular function and fertility. The dipeptidyl peptidase-4 inhibitor linagliptin has shown pronounced anti-inflammatory and anti-apoptotic features; however, its effects against cadmium-evoked testicular impairment have not been examined. Herein, the present study investigated targeting inflammation, apoptosis, and autophagy by linagliptin for potential modulation of cadmium-induced testicular dysfunction in rats. After 60 days of cadmium chloride administration (5 mg/kg/day, by gavage), testes, epididymis, and blood were collected for analysis. The present findings revealed that linagliptin improved the histopathological lesions, including spermatogenesis impairment and germ cell loss. Moreover, it improved sperm count/motility and serum testosterone. The favorable effects of linagliptin were mediated by curbing testicular inflammation seen by dampening of HMGB1/TLR4 pathway and associated lowering of nuclear NF-κBp65. In tandem, linagliptin suppressed the activation of NLRP3 inflammasome/caspase 1 axis with consequent lowering of the pro-inflammatory IL-1β and IL-18. Jointly, linagliptin attenuated testicular apoptotic responses seen by Bax downregulation, Bcl-2 upregulation, and suppressed caspase 3 activity. With respect to autophagy, linagliptin enhanced the testicular autophagy flux seen by lowered accumulation of p62 SQSTM1 alongside upregulation of Beclin 1. The observed autophagy stimulation was associated with elevated AMPK (Ser487) phosphorylation and lowered mTOR (Ser2448) phosphorylation, indicating AMPK/mTOR pathway activation. In conclusion, inhibition of testicular HMGB1/TLR4/NLRP3 pro-inflammatory axis and apoptosis alongside stimulation of autophagy were implicated in the favorable actions of linagliptin against cadmium-triggered testicular impairment.

Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice.

BACKGROUNDObesity and comorbidities onset encompass gut dysbiosis, altered intestinal permeability, and endotoxemia. Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease (NAFLD) management. Peroxisome proliferator-activated receptor (PPAR)-alpha activation and dipeptidyl-peptidase-4 (DPP-4) inhibition alleviate NAFLD, but the mechanism may involve gut microbiota modulation and merits further investigation. AIMTo address the effects of PPAR-alpha activation and DPP-4 inhibition (isolated or combined) upon the gut-liver axis, emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice. METHODSMale C57BL/6J mice were fed a control diet (C, 10% of energy as lipids) or a high-fat diet (HFD, 50% of energy as lipids) for 12 wk, when treatments started, forming the groups: C, HF, HFA (HFD + PPAR-alpha agonist WY14643, 2.5 mg/kg body mass), HFL (HFD + DPP-4 inhibitor linagliptin, 15 mg/kg body mass), and HFC (HFD + the combination of WY14643 and linagliptin). RESULTSThe HFD was obesogenic compared to the C diet. All treatments elicited significant body mass loss, and the HFC group showed similar body mass to the C group. All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations. These metabolic benefits restored Bacteroidetes/Firmicutes ratio, resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups. At the gene level, treated groups showed higher intestinal Mucin 2, Occludin, and Zo-1 expression than the HFD group. The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals. These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol, reassuring the role of the proposed treatments on NAFLD mitigation.CONCLUSIONPPAR alpha activation and DPP-4 inhibition (isolated or combined) tackled NAFLD in diet-induced obese mice by restoration of gut-liver axis. The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through anti-inflammatory signals. These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.

Abelmoschus esculentus subfractions ameliorate hepatic lipogenesis and lipid uptake via regulating dipeptidyl peptidase-4-With improving insulin resistance.

Nonalcoholic fatty liver disease (NAFLD) is recognized as the liver component of metabolic syndrome. The regulation of hepatic lipid should be emphasized to prevent accompanying illness. As AMP-activated protein kinase (AMPK) and sterol regulatory element binding protein (SREBP) regulate lipid metabolism, CD36 and fatty acid synthase (FAS) promote lipid uptake and lipogenesis respectively, while acetyl-CoA carboxylase (ACC) is an indicator of negative feedback. The increase of IRS-1 phosphorylation at the residue ser307 (p-ser307-IRS-1) and decrease of p-ser473-Akt (p-Akt) are viewed as the insulin resistance markers, and our previous reports suggested dipeptidyl peptidase-4 (DPP-4) mediates insulin resistance, the crucial factor of metabolic syndrome. Abelmoschus esculentus (AE) fruit is well-known for its antidiabetic utility. We had isolated several AE subfractions by successive steps, and found that F1 and F2 were especially valid in suppressing DPP-4 signaling. Since little is known if AE works on NAFLD, now we first attempt to investigate whether AE is useful to attenuate hepatic lipogenesis and lipid uptake in liver cells, along with improving the metabolic targets. We demonstrated that AE subfractions attenuated the hepatic lipid accumulation induced by free fatty acids. Treatment of AE alleviated FAS and returned the level of p-ser79-ACC (p-ACC). Although F1 was more effective on AMPK, F2 seemed more stable to attenuate SREBP-1. Moreover, as fatty acids stimulated the expression of CD36, F2 showed a superior effect to down-regulate the lipid uptake. Both AE subfractions reduced the generation of ROS, decreased the level of p-ser307-IRS-1, and restored the expression of p-Akt. Moreover, treatment of DPP-4 inhibitor linagliptin revealed that, AE could prevent the hepatic lipogenesis, oxidative burden, and the related insulin resistance via downregulating DPP-4. In conclusion, the present investigation revealed that AE, especially F2, is potential to be developed as adjuvant to prevent NAFLD.

Safety and tolerability of linagliptin in Asians with type 2 diabetes: a pooled analysis of 4457 patients from 21 randomized, double-blind, placebo-controlled clinical trials

ABSTRACT Background Safety and tolerability of glucose-lowering drugs is a key consideration for use in type 2 diabetes (T2D). We evaluated the safety and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin in Asian patients with T2D. Research design and methods This was a post-hoc, descriptive pooled analysis of 21 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2D patients lasting ≤52 weeks. We evaluated adverse events (AEs) and laboratory parameters in Asian participants living in Asia, both overall and in the East Asian subgroup. Results This analysis included 4457 Asian patients overall (2712 receiving linagliptin; 1745 receiving placebo) and 3057 (68.6%) East Asians. AEs were reported in 1510 (55.7%) Asian patients receiving linagliptin and 1032 (59.1%) receiving placebo but were considered drug-related in only 13.0% of each group. Serious AEs occurred in 109 (4.0%) linagliptin patients and 90 (5.2%) placebo patients. The most common AEs were nasopharyngitis (6.4% linagliptin, 7.3% placebo), upper respiratory tract infection (5.7% linagliptin, 6.5% placebo), and hypoglycemia (7.3% linagliptin, 6.3% placebo). One linagliptin patient had pancreatitis; none had bullous pemphigoid. No clinically relevant mean changes in laboratory parameters occurred. These findings were consistent in East Asians. Conclusions Linagliptin is well tolerated in Asian T2D patients, including East Asians, with low risk for AEs.

Linagliptin ameliorated interleukin-29-induced reduction of extracellular matrix genes through the nuclear factor erythroid 2-related factor 2 (Nrf2)/sry-type high-mobility-group box (SOX)-9 axis in an in vitro study on C-28/I2 chondrocytes

ABSTRACT Osteoarthritis (OA) is a severe orthopedic disease commonly observed in the elderly population and is closely related to the degradation of extracellular matrix (ECM) in cartilage tissues. Interleukin-29 (IL-29) is a cytokine that has been recently linked with the progression of OA. However, the physiological roles of IL-29 in ECM genes and function are unknown. Linagliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor recently reported to exert significant anti-inflammatory properties. In this study, we used IL-29 to stimulate C-28/I2 chondrocytes to build an inflammatory injury model. We aimed to investigate the protective effect of Linagliptin on IL-29-induced degradation of ECM. We found that IL-29 stimulation reduced the expressions of Col2a1 and Acan in C-28/I2 chondrocytes, and this effect was mediated by SRY-related high-mobility group box gene-9 (SOX-9), as we showed that overexpression of SOX-9 could rescue the reduction of Col2a1 and Acan. Interestingly, we found that IL-29 stimulation pronouncedly promoted the expression of DPP-4. Treatment with 100 nM of the DPP-4 inhibitor Linagliptin ameliorated IL-29-induced expressions of SOX-9, Col2a1, and Acan. Lastly, the nuclear level of nuclear factor erythroid 2-related factor 2 (Nrf2) was dramatically declined in IL-29-challenged chondrocytes and the protective effects of Linagliptin on the expressions of SOX-9, Col2a1, and Acan were abolished by the knockdown of Nrf2. Taken together, our data reveal that Linagliptin ameliorated IL-29-induced reduction of ECM genes partially through the Nrf2/SOX-9 axis in C-28/I2 chondrocytes. Further in vivo and clinical studies will be done to clarify the protective benefits of Linagliptin in OA.

Plasma Nitrate Levels Are Related to Metabolic Syndrome and Are Not Altered by Treatment with DPP-4 Inhibitor Linagliptin: A Randomised, Placebo-Controlled Trial in Patients with Early Type 2 Diabetes Mellitus.

The depletion of nitrate and nitrite, stable nitric oxide (NO) end-products, promotes adipose tissue dysfunction and insulin resistance (IR). Dipeptidyl peptidase-4 (DPP-4) inhibitors have the potentially beneficial side effect of increasing NO availability. In this study, nitrate and nitrite levels and the effects of DPP-4 inhibitor linagliptin were investigated in relation to metabolic syndrome (MetS) markers. Treatment-naive patients with early type 2 diabetes mellitus (T2DM) (n = 40, median age 63 IQR (55–67) years, 63% male, mean HbA1c 45 ± 4.4 mmol/mol) were randomized (1:1) to linagliptin (5 mg/day) or placebo. MetS-related markers (body mass index (BMI), triglycerides, HOMA-IR, gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and adiponectin), plasma levels of nitrate, nitrite, total free thiols (TFT) and vegetable intake were estimated at baseline and after 4 and 26 weeks of treatment. Plasma nitrate, but not nitrite, correlated positively with vegetable intake (r = 0.38, p = 0.018) and was inversely associated with HOMA-IR (r = −0.44, p = 0.006), BMI (r = −0.35, p = 0.028), GGT (r = −0.37, p = 0.019) and CRP (r = −0.34, p = 0.034). The relationship between nitrate and HOMA-IR remained significant after adjusting for BMI, CRP, vegetable intake and GGT. With stable vegetable intake, nitrate and nitrite, TFT, adipokines and CRP did not change after 26 weeks of linagliptin treatment. While plasma nitrate is inversely associated with MetS, linagliptin treatment does not significantly influence nitrate and nitrite concentrations, oxidative stress, adipose tissue function and systemic inflammation.

Linagliptin prevents left ventricular stiffening by reducing titin cleavage and hypophosphorylation.

The metabolic syndrome (MetS) is an escalating problem worldwide, causing left ventricular stiffening, an early characteristic of diastolic dysfunction for which no treatment exists. As diastolic dysfunction and stiffening in MetS patients are associated with increased circulating dipeptidyl peptidase‐4 (DPP‐4) levels, we investigated whether the clinically approved DPP‐4 inhibitor linagliptin reduces left ventricular stiffness in MetS‐induced cardiac disease. Sixteen‐week‐old obese ZSF1 rats, displaying the MetS and left ventricular stiffness, received linagliptin‐supplemented or placebo diet for four weeks. Linagliptin significantly reduced obesity, hyperlipidaemia, and hyperglycaemia and improved left ventricular relaxation. This improved relaxation was related to decreased cardiac fibrosis and cardiomyocyte passive stiffness (F passive). The reduced F passive was the result of titin isoform switching from the stiff N2B to the more flexible N2BA and increased phosphorylation of total titin and specifically its N2Bus region (S4080 and S3391). Importantly, DPP‐4 directly cleaved titin in vitro, resulting in an increased F passive, which was prevented by simultaneous administration of linagliptin. In conclusion, linagliptin improves left ventricular stiffness in obese ZSF1 rats by preventing direct DPP4‐mediated titin cleavage, as well as by modulating both titin isoform levels and phosphorylation. Reducing left ventricular stiffness by administering linagliptin might prevent MetS‐induced early diastolic dysfunction in human.

Adverse event profiles of dipeptidyl peptidase-4 inhibitors: data mining of the public version of the FDA adverse event reporting system

BackgroundTo describe and analyze the patterns of adverse events associated with dipeptidyl peptidase-4 inhibitors (DPP-4is) (sitagliptin, saxagliptin, linagliptin, vildagliptin, and alogliptin) from the FDA Adverse Event Reporting System (FAERS) and to highlight areas of safety concerns.MethodsAdverse events spontaneously submitted to the FAERS between 2004 Q1 to 2019 Q2 were included. The online tool OpenVigil 2.1 was used to query the database. The research relied on definitions of preferred terms (PTs) specified by the Medical Dictionary for Regulatory Activities (MedDRA) and the standardized MedDRA Queries (SMQ). The reporting odds ratio (ROR), with 95% confidence intervals (CIs) was calculated for disproportionality analysis.ResultsOver 16 years, a total of 9706 adverse event reports were identified. Alogliptin was excluded from further analysis due to insufficient sample size. Compared with the non-insulin antidiabetic drugs, the four DPP-4is were all disproportionately associated with four SMQs: “gastrointestinal nonspecific inflammation and dysfunctional conditions,” “hypersensitivity,” “severe cutaneous adverse reactions,” and “noninfectious diarrhoea”. As for PT level analyses, DPP-4is are associated with higher reporting of the gastrointestinal tract, pancreas, malignancies, infection, musculoskeletal disorders, general disorders, hypersensitivity, and skin AEs.ConclusionsData mining of the FAERS is useful for examining DPP-4 inhibitors-associated adverse events. The findings of the present study are compatible with clinical experience, and it provides valuable information to decision-makers and healthcare providers in clinical practice.

Effect of the dipeptidyl peptidase-4 inhibitor linagliptin on atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits: iMap-IVUS and pathological analysis.

Dipeptidyl peptidase-4 (DPP-4) inhibitors have potential as a treatment for atherosclerosis. However, it is unclear whether DPP-4 inhibitors stabilize atherosclerotic plaque or alter the composition of complex plaque. Sixteen Watanabe heritable hyperlipidemic rabbits aged 10-12weeks with atherosclerotic plaque in the brachiocephalic artery detected by iMap™ intravascular ultrasound (IVUS) were divided into a DPP-4 inhibitor group and a control group. Linagliptin was administered to the DPP-4 inhibitor group via nasogastric tube at a dose of 10mg/kg/day for 16weeks, and control rabbits received the same volume of 0.5% hydroxyethylcellulose. After evaluation by IVUS at 16weeks, the brachiocephalic arteries were harvested for pathological examination. IVUS revealed that linagliptin significantly reduced the plaque volume and vessel volume (control group vs. DPP-4 inhibitor group: ∆plaque volume, 1.02 ± 0.96mm3 vs. - 3.59 ± 0.92 mm3, P = 0.004; ∆vessel volume, - 1.22 ± 2.36mm3 vs. - 8.66 ± 2.33 mm3, P = 0.04; %change in plaque volume, 6.90 ± 5.62% vs. - 15.06 ± 3.29%, P = 0.005). With regard to plaque composition, linagliptin significantly reduced the volume of fibrotic, lipidic, and necrotic plaque (control group vs. DPP-4 inhibitor group: ∆fibrotic volume, 0.56 ± 1.27mm3 vs. - 5.57 ± 1.46mm3, P = 0.04; ∆lipidic volume, 0.24 ± 0.24mm3 vs. - 0.42 ± 0.16mm3 P = 0.04; ∆necrotic volume, 0.76 ± 0.54mm3 vs. - 0.84 ± 0.25mm3, P = 0.02). Pathological examination did not show any significant differences in the %smooth muscle cell area or %fibrotic area, but infiltration of macrophages into plaque was reduced by linagliptin treatment (%macrophage area: 12.03% ± 1.51% vs. 7.21 ± 1.65%, P < 0.05). These findings indicate that linagliptin inhibited plaque growth and stabilized plaque in Watanabe heritable hyperlipidemic rabbits.

DPP-4 Inhibitor Linagliptin Ameliorates Oxidized LDL-Induced THP-1 Macrophage Foam Cell Formation and Inflammation.

IntroductionAtherosclerosis is one of the major causes of cardiovascular diseases. Lipid uptake and accumulation in macrophages play a major role in atherosclerotic plaque formation from its initiation to advanced atheroma formation. The dipeptidyl peptidase-4 (DPP-4) inhibitor Linagliptin is commonly used to lower blood glucose in type 2 diabetes patients. Recent studies report that Linagliptin has cardiovascular protective and anti-inflammatory effects.MethodsTHP-1 macrophage cells were treated with 100 nM PMA for 72 hour to induce foam cell formation. The differentiated cells were exposed to 100 μg/mL ox-LDL in the presence or absence of the DPP-4 inhibitor Linagliptin. The expression levels of DPP-4 and inflammatory cytokines were detected by RT-PCR, ELISA, and Western blot experiments. The cellular ROS level was measured by staining the cells with the fluorescent probe DCFH-DA. The separation of lipoprotein fractions was achieved by high-performance liquid chromatography (HPLC). The cells were labeled with fluorescent-labeled cholesterol to measure cholesterol efflux, and lipid droplets were revealed by Nile red staining.ResultsThe presence of Linagliptin significantly reduced ox-LDL-induced cytokine production (IL-1β and IL-6) and ROS production. Linagliptin ameliorated ox-LDL-induced lipid accumulation and impaired cholesterol efflux in macrophages. Mechanistically, this study showed that Linagliptin mitigated ox-LDL-induced expression of the scavenger receptors CD36 and LOX-1, but not SRA. Furthermore, Linagliptin increased the expression of the cholesterol transporter ABCG1, but not ABCA1.ConclusionLinagliptin possesses a potent inhibitory effect on THP-1 macrophage-derived foam cell formation in response to ox-LDL. This effect could be mediated through a decrease in the expression of CD36 and LOX-1 on macrophages and an increase in the expression of the cholesterol transporter ABCG1. This study indicates that the DPP-4 inhibitor Linagliptin plays a critical role in preventing foam cell formation in vitro. However, future research using an atherosclerotic animal model is necessary to determine its effectiveness and to prove its potential implication in the prevention and treatment of atherosclerosis.

The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans.

Despite a similar mechanism of action underlying their glucose-lowering effects in type 2 diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitors have diverse molecular structures, raising the prospect of agent-specific, glucose-independent actions. To explore the issue of possible DPP-4 inhibitor cardiac heterogeneity, we perfused different DPP-4 inhibitors to beating mouse hearts ex vivo, at concentrations equivalent to peak plasma levels achieved in humans with standard dosing. We studied male and female mice, young non-diabetic mice, and aged diabetic high fat diet-fed mice and observed that linagliptin enhanced recovery after ischemia-reperfusion, whereas sitagliptin, alogliptin, and saxagliptin did not. DPP-4 transcripts were not detected in adult mouse cardiomyocytes by RNA sequencing and the addition of linagliptin caused ≤0.2% of cardiomyocyte genes to be differentially expressed. In contrast, incubation of C166 endothelial cells with linagliptin induced cell signaling characterized by phosphorylation of Akt and endothelial nitric oxide synthase, whereas the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine increased serine 16 phosphorylation of the calcium regulatory protein, phospholamban in cardiomyocytes. Furthermore, linagliptin increased cardiomyocyte cGMP when cells were co-cultured with C166 endothelial cells, but not when cardiomyocytes were cultured alone. Thus, at a concentration comparable to that achieved in patients, linagliptin has direct effects on mouse hearts. The effects of linagliptin on cardiomyocytes are likely to be either off-target or indirect, mediated through NO generation by the adjacent cardiac endothelium.

Effects of dipeptidyl peptidase-4 inhibitor linagliptin versus sulphonylurea glimepiride on systemic haemodynamics in overweight patients with type 2 diabetes: A secondary analysis of an 8-week, randomized, controlled, double-blind trial.

AimTo determine the glucose‐independent effect of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin versus the sulphonylurea glimepiride on systemic haemodynamics in the fasting and postprandial state in patients with type 2 diabetes (T2D).Materials and MethodsIn this prespecified secondary analysis of a phase IV, double‐blind trial, 46 metformin‐treated, overweight patients with T2D were included and randomly assigned (1:1) to once‐daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. In a sub‐study involving 26 patients, systemic haemodynamics were also assessed following a standardized liquid meal (Nutridrink Yoghurt style). Systemic haemodynamics (oscillometric device and finger photoplethysmography), arterial stiffness (applanation tonometry) and cardiac sympathovagal balance (heart rate variability [HRV]) were measured in the fasting state and repetitively following the meal. Ewing tests were performed in the fasting state.ResultsFrom baseline to week 8, linagliptin compared with glimepiride did not affect systemic haemodynamics, arterial stiffness or HRV in the fasting state. Linagliptin increased parasympathetic nervous activity, as measured by the Valsalva manoeuvre (P = .021) and deep breathing test (P = .027) compared with glimepiride. Postprandially, systolic blood pressure (SBP) dropped an average of 7.6 ± 1.6 mmHg. Linagliptin reduced this decrease to 0.7 ± 2.3 mmHg, which was significant to glimepiride (P = .010).ConclusionsWhen compared with glimepiride, linagliptin does not affect fasting blood pressure. However, linagliptin blunted the postprandial drop in SBP, which could benefit patients with postprandial hypotension.

923-P: Improved Glycemic Variability and Control without Increased Risk of Hypoglycemia when Linagliptin Is Added to Glimepiride Therapy in Patients with HNF1A-Diabetes

Sulfonylurea (SU) is first-line treatment of hepatocyte nuclear factor 1-alpha (HNF1A)-diabetes but has limitations due to the risk of hypoglycemia. We hypothesized that SU in combination with the dipeptidyl peptidase-4 inhibitor linagliptin would provide an efficacious treatment with less glycemic variability and hypoglycemia in patients with HNF1A-diabetes compared with SU monotherapy. In a randomized, double-blinded, crossover trial, patients with HNF1A-diabetes (n = 19, [mean ± SD]; age: 43 ± 14 years; BMI 24 ± 3 kg/m2; HbA1c 7.4 ± 0.2% [57 ± 7 mmol/mol]) were randomly assigned to treatment with glimepiride + linagliptin (16 weeks), wash-out (4 weeks) and treatment with glimepiride + placebo (16 weeks) (or vice versa). Treatments were evaluated by continuous glucose monitoring (CGM), HbA1c and a meal test. Compared with glimepiride + placebo, glimepiride + linagliptin showed significant improvements in glycemic variability (assessed as coefficient of variation (CV) and SD on CGM), HbA1c and body weight (Figure 1). Incidence of hypoglycemia (assessed by patient-reported episodes and CGM) was similar between treatments. In conclusion, linagliptin as add-on treatment to SU in patients with HNF1A-diabetes improved glycemic variability, glycemic control and body weight without increasing the risk of hypoglycemia. Disclosure A.S. Christensen: None. S. Haedersdal: None. J. Støy: None. H. Storgaard: None. U. Kampmann: Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. M. Seghieri: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Hansen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Norgine B.V., Novo Nordisk A/S. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp &amp; Dohme Corp., Sanofi.

Early Combination Therapy with Linagliptin and Metformin in People with Type 2 Diabetes Improves Glycemic Control to HbA1c ≤ 6.5% without Increasing Hypoglycemia: Pooled Analysis of Two Randomized Clinical Trials.

IntroductionClinical guidelines suggest a glycated hemoglobin A1c (HbA1c) target of ≤ 6.5% for type 2 diabetes patients with short duration of disease, few comorbidities and/or long life expectancy—provided this goal can be achieved safely. We explored whether initial combination treatment with the dipeptidyl peptidase-4 inhibitor linagliptin and metformin could provide better glycemic control (HbA1c ≤ 6.5%) than metformin alone without increasing hypoglycemia.MethodsWe pooled and analyzed individual patient data from two randomized clinical trials of early combination therapy with linagliptin and metformin versus metformin monotherapy. The primary outcome in both trials was the change in HbA1c from baseline to week 24. We evaluated the percentage of patients who achieved HbA1c ≤ 6.5% at week 24 and the incidence of adverse events.ResultsMost (> 70%) of the 1160 patients analyzed were treatment naive, and more than half had had diabetes for ≤ 1 year; mean baseline HbA1c was approximately 8.7%. Combination therapy with linagliptin and metformin resulted in more patients achieving HbA1c ≤ 6.5% than metformin alone, both for a metformin dose of 500 mg (40.1 vs. 22.9%, respectively, odds ratio [OR] 2.84, 95% confidence interval [CI] 1.87–4.32) and 1000 mg (49.5 vs. 35.4%, respectively, OR 2.28, 95% CI 1.54–3.40). Hypoglycemia occurred in < 3% of patients, with a comparable incidence between treatment groups. Other adverse events were also balanced between groups.ConclusionEarly combination treatment with linagliptin and metformin can improve the chances of achieving tight glycemic control (HbA1c ≤ 6.5%) without increasing the risk of hypoglycemia or other adverse events.Trial RegistrationClinicalTrials.gov, NCT00798161 and NCT01708902.