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Dipeptidyl Peptidase-4 Inhibitors

Clinical data and clinical implications

From the Department of Clinical Sciences, Division of Medicine, Lund University, Lund, Sweden

Address correspondence and reprint requests to Dr. Bo Ahrén, MD, PhD, Lund University, Division of Medicine, B11 BMC, SE-221 84 Lund, Sweden. E-mail: bo.ahren@med.lu.se

Abbreviations: DPP-4, dipeptidyl peptidase-4 • FDA, Food and Drug Administration • GIP, glucose-dependent insulinotropic polypeptide • GLP-1, glucagon-like peptide-1

The first 300 words of the full text of this article appear below.

The enzyme dipeptidyl peptidase-4 (DPP-4) prevents the inactivation of glucagon-like peptide-1 (GLP-1). Since GLP-1–based therapy is a promising novel treatment of type 2 diabetes, the strategy to inhibit the enzyme has been explored. Several DPP-4 inhibitors are in clinical development; these are orally active and increase levels of active GLP-1, which in turn increases insulin secretion and reduces glucagon secretion and thereby lowers glucose levels. Most experience exists for sitagliptin (Merck) and vildagliptin (Novartis), which both have a long duration of action, allowing once-daily administration. In drug-naïve subjects with type 2 diabetes, both sitagliptin and vildagliptin reduce A1C levels by 1% as monotherapy, as demonstrated in studies up to 52 weeks. Also in combination with metformin and thiazolidinediones, sitagliptin and vildagliptin improve glycemic control with reduction of A1C of 1%. Both sitagliptin and vildagliptin are safe and tolerable with low risk of hypoglycemia. They are both body weight neutral. The studies presented thus far therefore suggest that DPP-4 inhibition is an efficient treatment of type 2 diabetes, both as monotherapy and combination therapy. Because of its efficiency, safety, and tolerability in association with the oral mode of administration, it is expected that DPP-4 inhibition will be a first-line treatment of the early stage of type 2 diabetes, particularly in combination with metformin or thiazolidinediones.

GLP-1 AS AN ANTIDIABETIC HORMONE—

GLP-1 is one of the important incretin hormones; it is released after meal ingestion and stimulates insulin secretion (1). GLP-1 also exhibits strong antidiabetic actions, as initially demonstrated already in the early 1990s (2–4). Thus, infusion of GLP-1 lowers circulating glucose through a combination of stimulation of insulin secretion and inhibition of glucagon secretion. A 6-week study with continuous subcutaneous infusion of GLP-1 showed reduction in fasting and prandial glycemia along with reduction in A1C and improvement both in insulin . . . [Full Text of this Article]

DPP-4 INACTIVATION OF GLP-1—

TWO STRATEGIES FOR GLP-1–BASED THERAPY—

DPP-4 inhibition as a strategy to treat diabetes
Early studies on DPP-4 inhibition
Vildagliptin and sitagliptin
Vildagliptin and sitagliptin as monotherapy
Vildagliptin.
Sitagliptin.
Vildagliptin and sitagliptin in combination therapy
Vildagliptin.
Safety and tolerability of DPP-4 inhibitors
DPP-4 inhibitors and lipid levels
Mechanism of action of DPP-4 inhibition
SUMMARY—

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