Gliptin Therapies for Inhibiting Dipeptidyl Peptidase-4 in Type 2 Diabetes


Wider dissemination of pre-clinical studies with DPP-4 inhibitors, and particularly their adoption into clinical trials, has led to a proliferation in the number of DPP-4 inhibitor compounds under investigation. The outcomes of these trials remain to be seen.53–55


Clinical Use of Gliptins


The dosages and administration schedules used in the treatment of diabetes produces almost total inhibition of DPP-4 activity over 24 hours, increasing the post-prandial circulating concentrations of active GLP-1 and GIP by two- to three-fold. This is associated with increased meal-stimulated or glucose-stimulated insulin secretion and reduced glucagon concentrations.


Three gliptins have become available for clinical use in the UK: sitagliptin (Januvia, 2007), vildagliptin (Galvus, 2008) and saxagliptin (Onglyza, 2009). Their pharmacokinetic features are summarised in Table 1.56–58


Several randomised controlled trials have affirmed the glucose-lowering efficacy of gliptins in type 2 diabetes patients (see Tables 2–4). When used as monotherapy or in combination with other antidiabetic agents,


gliptins have typically reduced glycated haemoglobin (HbA1c) by about 0.5–1%.59–74


usually decreased by about 1–1.5mmol/l, while post-prandial glucose concentrations are lowered by about 3mmol/l.59–74


The effects of gliptins are generally additive to those of other antidiabetic agents, provided there is adequate remaining beta-cell function. Usage has been mainly in combination with agents that improve insulin sensitivity (metformin or a thiazolidinedione). However, gliptins can also be used with a sulphonlyurea or meglitinide to further enhance the insulin response because incretins act on beta-cells via a separate cellular mechanism involving specific G-protein-coupled receptors.


Monotherapy with a gliptin carries a low risk of interprandial hypoglycaemia, although hypoglycaemia is more evident when gliptins are used in combination with other agents, notably sulphonylureas.75–77


This reflects the mode of action via incretins to potentiate nutrient-induced insulin secretion, but not to initiate insulin secretion at low glucose concentrations. Also, the glucagon-lowering effect of GLP-1 is lost at low glucose concentrations, helping to preserve an acute counter-regulatory response.78


The extent to which gliptins raise active GLP-1 concentrations does not appear to be sufficient to significantly reduce the rate of gastric emptying, hence gliptins do not tend to cause the nausea that is sometimes experienced after an injection of GLP-1 agonists. Gliptins are generally regarded as weight-neutral agents and may assist a small amount of weight loss.79,80


They may have a mild satiety effect


by increasing active GLP-1 concentrations in the portal circulation and liver, where GLP-1 triggers vagal afferents, affecting satiety. Gliptins may produce modest improvements in the postprandial lipid profile.81


An exciting future prospect where gliptins could play an important role involves the potential use of pharmacological agents to boost endogenous secretion of incretin hormones. The notion of developing a combinatorial therapy that contains a GLP-1 secretagogue and a gliptin compound is a concept that is gaining momentum. Possible receptor targets on L-cells for increasing GLP-1 exocytosis include GPR119, GPR120 and TG5R.82,83


EUROPEAN ENDOCRINOLOGY


Efficacy is often greater if the baseline HbA1c is >8%. Several studies have shown durable efficacy up to one year. Basal glycaemia is


Table 1: Pharmacokinetic Features of Gliptins Sitagliptin


Launch in UK 2007 Dose


Vildagliptin 2008


100mg OD


Bioavailability ~87% Tmax


Protein bound ~32% Metabolism ~20%


metabolised (mainly liver)


Metabolites Half-life


1–4 hours


50mg BID ~85%


~1.7 hours ~9%


~70%


metabolised (mainly renal)


Very weak activity Mostly inactive ~12 hours


2–3 hours


Saxagliptin 2009


5mg OD 50–75%* 2–4 hours Negligible ~75%


metabolised (mainly liver) Active


2.5–3 hours


Elimination ~80% in urine, ~85% in urine, ~75% in urine, mostly unchanged mostly metabolites mostly metabolites drug


*Bioavailability data from animal studies. BID = twice daily; OD = once daily; Tmax = time to maximum plasma concentration.


Safety and Tolerability of Gliptins The inhibition of DPP-4 could potentially extend the circulating half-lives of many biologically active peptides with an Ala or Pro residue penultimate to the N-terminus, such as bradykinin, encephalins, neuropeptide Y, gastrin-releasing polypeptide, substance P and monocyte chemoattractant protein-1. Thus, gliptins might conceivably affect vasoreactivity, monocyte behaviour, gastrointestinal motility and growth, as well as having an incretin-enhancing effect.78,81


However,


there has been no evidence to date that gliptin therapy has any clinically significant or measurable effects on these physiological functions.


Since DPP-4 doubles as the CD-26 T-cell activating antigen, this has raised suspicion that gliptins could interfere with immune function.84 Gliptins are small molecules that are located deep within the structure of DPP-4, where they interrupt the peptidase activity. They thus leave the outer conformation of the protein intact and the immune function apparently unaffected.


In clinical trials gliptins have been well tolerated. Minor upper respiratory tract infections and urinary tract infections are common adverse events during long-term clinical trials. Despite this, their occurrence during gliptin therapy was not sufficiently raised during the pre-registration trials or during post-marketing surveillance to suggest any specific link to the therapy. Isolated severe hypersensitivity reactions to sitagliptin have been reported during the first three months of therapy. These include anaphylaxis, angioedema, exfoliate skin conditions and, very rarely, emerging signs of Stevens-Johnson syndrome. Monitoring for skin disorders such as rash, blistering and ulceration is recommended for all gliptins, but problems encountered during trials with monkeys have not materialised in humans.57–59


Caution is advised with advancing kidney or liver disease. Dose adjustments can enable sitagliptin and saxagliptin to be used with appropriate caution in severe renal disease, but there is no experience of their use in severe liver disease. Rare reports of raised alanine transaminase levels with vildagliptin have prompted caution in individuals with reduced liver function.85


The three gliptins


currently available do not appear to significantly inhibit or induce the main P450 isoforms, but concomitant medications that inhibit P450 CYP3A4/5 (e.g. ketoconazole) may increase saxagliptin concentrations. Lack of experience with gliptins in patients with


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