Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Abstract

SUMMARYDipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucoselowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.

DPP4 inhibitors and cardiovascular outcomes: safety on heart failure

“…The DPP4 is not only available as a circulatory form but is also expressed on endothelial cells, liver, gut, kidney, lungs and T-lymphocytes. [2] Within these tissues, the enzyme acts on multiple substrates of which the most widely studied ones are GLP-1and glucose-dependent insulinotropic polypeptide (GIP). [36] GLP-1 and GIP proteins act by means of a feedback loop that is based on levels of serum glucose.…”

“…It has also been postulated that these drugs act at the level of the hypothalamus to regulate satiety. [2] Given their overall action, it was demonstrated that the DPP4 inhibitors were effective glucose lowering agents and significantly reduced HbA1c values by 0.6% at 24 weeks into treatment. [38] They pose a low risk of hypoglycemia and are weight neutral, which also adds to their safety profile.…”

“…[1] Diabetes accounts for significant morbidity and mortality and is a major risk factor for coronary artery disease, cerebrovascular disease, chronic kidney disease, peripheral vascular disease and microvascular damage in terms of nephropathy, neuropathy and retinopathy. [2] This translates into a discouraging economic burden of about 673 billion US dollars spent in the management of diabetes mellitus. [1]…”

Wound Healing Process, Diabetes and Implications of Dipeptidyl Peptidase IV (DPP IV/CD26)

“…The research was based on known data about GLP-1 peptide as a potent anti-diabetic hormone. Findings of effects that DPP IV/CD26 inhibitors exert in preventing cleavage of GLP-1, hence increasing active GLP-1 in the circulation, led to further studies in the area of DPP IV/CD26 inhibitors development [25,26]. Today, numerous DPP IV/CD26 inhibitors are available and used in clinical practice, most common of them enlisted in Table 2.…”

Effectiveness and Safety of Sitagliptin in Patients with Beta-thalassaemia Major and Diabetes Mellitus: A Case Series

“…For these reasons, the 2015 position statement for type 2 DM recommends considering the use of dipeptidyl peptidase 4 (DPP-4) inhibitors or gliptins as second line agents when the first line agent, metformin, has not achieved optimal glycaemic control 3. The most popular drug in this drug class, sitagliptin, inhibits DPP-4, the key enzyme which inactivates glucagon like peptide 1 (GLP-1),4 leading to increased levels of GLP-1 in the plasma. GLP-1 is a gut hormone which increases insulin secretion and suppresses glucagon secretion in a glucose-dependent manner.…”