Concentration-dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice, rats and humans

Fuchs, Holger; Tillement, Jean‐Paul; Urien, Saı̈k; Greischel, Andreas; Roth, Willy

doi:10.1211/jpp.61.01.0008

Cited by 83 publications

(27 citation statements)

References 17 publications

(25 reference statements)

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“…In both animal and in vitro studies, linagliptin demonstrated a greater inhibition of DPP-4 than alogliptin, saxagliptin, sitagliptin or vildagliptin [15]. After absorption, linagliptin binds to plasma proteins in a concentration-dependent manner, giving the drug a nonlinear pharmacokinetic profile [16]. Unlike other DPP-4 inhibitors that are cleared by the kidneys, linagliptin is mainly excreted in the feces [17], [18].…”

Section: Introductionmentioning

confidence: 99%

Linagliptin Improves Insulin Sensitivity and Hepatic Steatosis in Diet-Induced Obesity

Klöting²,

et al. 2012

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Linagliptin (tradjenta™) is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor. DPP-4 inhibition attenuates insulin resistance and improves peripheral glucose utilization in humans. However, the effects of chronic DPP-4 inhibition on insulin sensitivity are not known. The effects of long-term treatment (3–4 weeks) with 3 mg/kg/day or 30 mg/kg/day linagliptin on insulin sensitivity and liver fat content were determined in diet-induced obese C57BL/6 mice. Chow-fed animals served as controls. DPP-4 activity was significantly inhibited (67–89%) by linagliptin (P<0.001). Following an oral glucose tolerance test, blood glucose concentrations (measured as area under the curve) were significantly suppressed after treatment with 3 mg/kg/day (–16.5% to –20.3%; P<0.01) or 30 mg/kg/day (–14.5% to –26.4%; P<0.05) linagliptin (both P<0.01). Liver fat content was significantly reduced by linagliptin in a dose-dependent manner (both doses P<0.001). Diet-induced obese mice treated for 4 weeks with 3 mg/kg/day or 30 mg/kg/day linagliptin had significantly improved glycated hemoglobin compared with vehicle (both P<0.001). Significant dose-dependent improvements in glucose disposal rates were observed during the steady state of the euglycemic–hyperinsulinemic clamp: 27.3 mg/kg/minute and 32.2 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 20.9 mg/kg/minute with vehicle (P<0.001). Hepatic glucose production was significantly suppressed during the clamp: 4.7 mg/kg/minute and 2.1 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 12.5 mg/kg/minute with vehicle (P<0.001). In addition, 30 mg/kg/day linagliptin treatment resulted in a significantly reduced number of macrophages infiltrating adipose tissue (P<0.05). Linagliptin treatment also decreased liver expression of PTP1B, SOCS3, SREBP1c, SCD-1 and FAS (P<0.05). Other tissues like muscle, heart and kidney were not significantly affected by the insulin sensitizing effect of linagliptin. Long-term linagliptin treatment reduced liver fat content in animals with diet-induced hepatic steatosis and insulin resistance, and may account for improved insulin sensitivity.

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Section: Introductionmentioning

confidence: 99%

Linagliptin Improves Insulin Sensitivity and Hepatic Steatosis in Diet-Induced Obesity

Klöting²,

et al. 2012

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“…Therefore, its use in patients with renal insufficiency is safe and does not have any restriction [16]. Therefore, this drug is more advantageous, as compared with other drugs in this category, and is considered to be the treatment of choice in patients with renal insufficiency because kidney dysfunction is quite common in diabetic patients [23–26]. …”

Section: Discussionmentioning

confidence: 99%

Linagliptin versus sitagliptin in patients with type 2 diabetes mellitus: a network meta-analysis of randomized clinical trials

et al. 2017

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BackgroundDiabetes is one of the most common chronic and costly diseases worldwide and type 2 diabetes is the most common type which accounts for about 90% of cases with diabetes. New medication-therapy regimens such as those containing linagliptin alone or in combination with other medications (within the category of DDP-4 inhibitors) must be evaluated in terms of efficacy and compared with other currently used drugs and then enter the medication list of the country. Hence, this study aimed to compare the clinical efficacy of the two drugs, i.e. linagliptin and sitagliptin, in patients with type 2 diabetes.MethodsA systematic review was conducted to identify all clinical trials published by 2015 which compared the two drugs in patients with type 2 diabetes. Using keywords such as “linagliptin”, “type 2 diabetes mellitus”, “sitagliptin” and related combinations, we searched databases including Scopus, PubMed, and Web of Science. The quality of the selected studies was evaluated using the Jadad score. Considering primary and secondary outcomes extracted from the reviewed studies, a network meta-analysis was used to conduct a systematic comparison between the two studied drugs.ResultsThis network meta-analysis included 32 studies (Linagliptin vs PLB: n = 8, Sitagliptin vs PLB: n = 13, Linagliptin + MET vs PLB + MET: n = 4, and Sitagliptin + MET vs PLB + MET: n = 7) and a total of 13,747 patients. The results showed no significant difference between linagliptin and sitagliptin in terms of key efficacy and safety outcomes such as HbA1c changes from baseline, body weight change from baseline, percentage of patients achieving HbA1c <7, and percentage of patients experiencing hypoglycemic events (p > 0.05). The results showed that the efficacy of the two drug regimens was the same.ConclusionsBased on the results, there was no significant difference between the two drugs, i.e. linagliptin and sitagliptin, in terms of efficacy; in other words, the efficacy of the two drugs was the same. Therefore, the use of these two drugs depends on their availability and cost.Graphical abstractGraphical abstract of the network meta-analysis performed to evaluate the alternatives under the study. Electronic supplementary materialThe online version of this article (10.1186/s40199-017-0189-6) contains supplementary material, which is available to authorized users.

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“…In vivo, linagliptin is hardly metabolized and approximately 90% of the compound are excreted in unchanged form by a hepatobiliary route via the feces 15,16. Linagliptin avidly binds to plasma proteins in vivo so that most of the drug is protein bound at therapeutic concentrations in humans 16. It also shows high-affinity binding to the target DPP-4 in different tissues, predominantly in the kidney resulting in a long biological half-life there.…”

Section: Pharmacokinetics and Pharmacodynamics Of Linagliptinmentioning

confidence: 99%

“…Linagliptin is not likely to interfere with drugs metabolized by the CYP 450 enzymatic system because it neither inhibits CYP 450 nor is it metabolized through this system 12,16. Since DPP-4 inhibitors are predominantly used in combination therapy with metformin, the potential interactions of linagliptin and metformin were investigated.…”

Section: Potential Drug-drug Interactionsmentioning

confidence: 99%

Linagliptin–-A Novel Dipeptidyl Peptidase Inhibitor for Type 2 Diabetes Therapy

Gallwitz

2012

Clin Med Insights Endocrinol Diabetes

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Incretin based therapies have been introduced into the treatment options of type 2 diabetes a few years ago. Among them, the orally active DPP-4 inhibitors have established themselves as insulinotropic agents. Their advantage is the glucose-dependent insulinotropic action without an intrinsic risk for causing hypoglycemia. Additionally DPP-4 inhibitors have a glucose dependent glucagonostatic action contributing to improved glucose control. They are weight neutral and show a good safety and tolerability profile with comparable efficacy to sulfonylureas. Linagliptin is a novel DPP-4 inhibitor with a distinct pharmacological profile. In contrast to the other approved DPP-4 inhibitors it is eliminated by a hepatic/biliary route rather than a renal route. Therefore no dose adjustment is recommended in patients with type 2 diabetes and renal impairment. In clinical studies, it has been shown to be non-inferior to sulfonylurea treatment regarding glycemic parameters, but to possess favourable safety advantages regarding hypoglycemia frequency, body weight development and effects on cardioavascular parameters. This article gives an overview on the pharmacology of linagliptin as well as on the clinical data available.

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Concentration-dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice, rats and humans

Abstract: High affinity, but readily saturable binding of BI 1356 to its target DPP-4 accounted primarily for the concentration-dependent plasma protein binding at therapeutic plasma concentrations of BI 1356.

Cited by 83 publications

References 17 publications

Linagliptin Improves Insulin Sensitivity and Hepatic Steatosis in Diet-Induced Obesity

Linagliptin Improves Insulin Sensitivity and Hepatic Steatosis in Diet-Induced Obesity

Linagliptin versus sitagliptin in patients with type 2 diabetes mellitus: a network meta-analysis of randomized clinical trials

Linagliptin–-A Novel Dipeptidyl Peptidase Inhibitor for Type 2 Diabetes Therapy

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