Linagliptin: A thorough Characterization beyond Its Clinical Efficacy

Abstract

Linagliptin, one of the five dipeptidyl peptidase-4 inhibitors available, has recently entered the market both in the US and in most European countries for treatment of type 2 diabetes mellitus. It presents a xanthine-based structure, and is characterized by unique pharmacokinetics, with non-linear profile, long terminal half-life allowing prolonged exposure to the drug. It is eliminated predominately through the intestinal tract and only minimally into urine, so that it can be administered, without any dose adjustment, in conditions of renal impairment. Linagliptin is effective in modifying all parameters of hyperglycemia either in monotherapy, or as add-on therapy, together with metformin or a sulfonylurea. It also exhibits a good tolerability profile with few side effects, absence (when used in monotherapy), or low risk (when in combination with a sulfonylurea) of hypoglycemia. More importantly it has a weight neutral effect. A comprehensive report of the literature on linagliptin is provided, paying attention in particular to preclinical studies, interactions with other drugs, safety and tolerability, and results obtained in animal models that highlight properties of linagliptin suggestive of potential additional uses. Particularly promising appear the data demonstrating a positive effect of linagliptin on metabolic dysfunction and renal and/or cardiovascular damage together with more recently reported effects of linagliptin on tissue repair and neuroprotection.

Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart

“…Linagliptin, a third approved DPP-4 inhibitor for diabetes [12], has previously been shown to reduce infarct size and lipid oxidation after ischemia in an isolated heart preparation [32] as well as inhibit inflammation and immune response in the atherosclerotic state [33]. Phase 3 clinical trials have also provided valuable new insights in the cardiovascular safety profile to show the benefits of linagliptin in patients with type 2 diabetes [34]. In the present study, we found that oral administration of linagliptin on a daily basis inhibits Ang IIinduced cardiac fibrosis without showing any side-effects, suggesting that preservation of endogenous GLP-1 is as effective as an exogenous supply of GLP-1 in attenuating cardiac injury.…”

Milk proteins as a source of tryptophan-containing bioactive peptides

“…In 20 certain instances specific peptide sequences have been linked with DPP-IV inhibition 94,[101][102][103][104][105] . Milk protein-derived DPP-IV inhibitory peptides generally have an IC 50 value in the µM range 28 , which is several orders of magnitude higher than that of gliptins (nM) 106 . To date, four in vivo studies have demonstrated 25 that food protein hydrolysates or peptides with in vitro DPP-IV inhibitory properties were able to induce an increased insulin secretion and a reduction in plasma glucose following an oral glucose tolerance test in rodents.…”

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs

“…Their use is particularly advantageous since they induce low rates of hypoglycemia and are considered weight neutral (DPP4 inhibitors) or can even induce weight loss (GLP1 analogs) [89]. In addition, the large distribution of DPP4 and its pleiotropic effects make this molecule an attractive target for therapeutic intervention beyond the classical use of DPP4 inhibitors as antiglycemic agents [90].…”