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Dipeptidyl Peptidase-4 Inhibitors Clinical Data and Clinical Implications

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Dipeptidyl Peptidase-4 Inhibitors Clinical Data and Clinical Implications Bench to Clinic Symposia EDITORIAL REVIEW Dipeptidyl Peptidase-4 Inhibitors Clinical data and clinical implications BO AHREN´ , MD, PHD TWO STRATEGIES FOR GLP-1– BASED THERAPY — To harness the antidiabetic action of GLP-1 and at the he enzyme dipeptidyl peptidase-4 tion and stimulates insulin secretion (1). same time overcome the problem of the (DPP-4) prevents the inactivation of GLP-1 also exhibits strong antidiabetic rapid inactivation of the native hor- T glucagon-like peptide-1 (GLP-1). actions, as initially demonstrated already mone, two strategies have been ex- Since GLP-1–based therapy is a promis- in the early 1990s (2–4). Thus, infusion plored. Both these strategies have been ing novel treatment of type 2 diabetes, the of GLP-1 lowers circulating glucose shown to be successful. One approach strategy to inhibit the enzyme has been through a combination of stimulation of is to use GLP-1 receptor agonists explored. Several DPP-4 inhibitors are in insulin secretion and inhibition of gluca- (GLP-1 mimetics), which are not de- clinical development; these are orally ac- gon secretion. A 6-week study with con- graded by DPP-4. A representative of tive and increase levels of active GLP-1, tinuous subcutaneous infusion of GLP-1 this approach is exenatide (Byetta; Lilly) which in turn increases insulin secretion showed reduction in fasting and prandial (8), which is now approved for use in and reduces glucagon secretion and glycemia along with reduction in A1C the treatment of diabetes both in the U.S. and Europe. Liraglutide (Novo thereby lowers glucose levels. Most expe- and improvement both in insulin secre- Nordisk) is another example of this rience exists for sitagliptin (Merck) and tion and insulin action and reduction in strategy. The other approach for GLP- vildagliptin (Novartis), which both have a body weight, which illustrates the po- 1–based therapy is to inhibit the en- long duration of action, allowing once- tency of GLP-1–based therapy (5). daily administration. In drug-naı¨ve sub- zyme activity of DPP-4 (1,9–13). jects with type 2 diabetes, both sitagliptin and vildagliptin reduce A1C levels by DPP-4 INACTIVATION OF ϳ1% as monotherapy, as demonstrated DPP-4 inhibition as a strategy to GLP-1 — It was early understood that treat diabetes in studies up to 52 weeks. Also in combi- GLP-1 is unattractive as chronic therapy nation with metformin and thiazo- The rationale for the strategy of inhibiting of diabetes because the hormone is rap- DPP-4 in the treatment of type 2 diabetes lidinediones, sitagliptin and vildagliptin idly inactivated by the action of the en- improve glycemic control with reduction is to prevent the inactivation of GLP-1 and ϳ zyme DPP-4 (6). This enzyme is widely therefore to enhance and prolong the ac- of A1C of 1%. Both sitagliptin and expressed in several organs and circulates vildagliptin are safe and tolerable with tion of the endogenously released incretin in a soluble form (7). It acts by cleavage of hormone. This strategy was first summa- low risk of hypoglycemia. They are both the two NH -terminal amino acids of bio- body weight neutral. The studies pre- 2 rized by Holst and Deacon (14), who active peptides, provided that the second showed that DPP-4 inhibition increases sented thus far therefore suggest that amino acid is alanine or proline. Since the DPP-4 inhibition is an efficient treatment circulating levels of GLP-1 in experimen- second NH2-terminal amino acid in tal animals and that the insulinotropic ac- of type 2 diabetes, both as monotherapy GLP-1 is alanine, GLP-1 is cleaved to a and combination therapy. Because of its tion of exogenously administered GLP-1 truncated form [sometimes called GLP-1 efficiency, safety, and tolerability in associ- is augmented by DPP-4 inhibition. Later (9-36)amide] (6). This truncated form of ation with the oral mode of administration, studies demonstrated that the prevention GLP-1 is largely inactive; therefore, the it is expected that DPP-4 inhibition will be a of inactivation of GLP-1 by DPP-4 inhibi- cleavage of GLP-1 by DPP-4 is an inacti- first-line treatment of the early stage of type tion markedly increases the active GLP-1 vation process. The cleavage is rapid, 2 diabetes, particularly in combination with in the circulation. For example, as shown metformin or thiazolidinediones. which is the reason why native GLP-1 has in dogs, the active GLP-1 under fasting a short half-life (Ͻ2 min). Therefore, it is conditions accounts for only ϳ10% of to- GLP-1 AS AN necessary to use multiple daily injections tal GLP-1, whereas after DPP-4 inhibition ANTIDIABETIC HORMONE — of continuous subcutaneous infusion of 99% of GLP-1 is in the active form (15). GLP-1 is one of the important incretin GLP-1 for maintenance of glycemic con- The increase in concentrations of active hormones; it is released after meal inges- trol when using the native GLP-1. GLP-1 following administration of DPP-4 inhibitors has subsequently been con- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● firmed in clinical studies (Fig. 1). It has From the Department of Clinical Sciences, Division of Medicine, Lund University, Lund, Sweden. also been demonstrated that DPP-4 inhi- Address correspondence and reprint requests to Dr. Bo Ahre´n, MD, PhD, Lund University, Division of bition increases not only prandial but also Medicine, B11 BMC, SE-221 84 Lund, Sweden. E-mail: [email protected]. Received for publication 4 February 2007 and accepted in revised form 11 February 2007. fasting levels of active GLP-1 (16). In fact, Published ahead of print at http://care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc07-0233. DPP-4 inhibition results in an overall in- B.A. has been a consultant for Novartis and Merck. crease in GLP-1 levels with preserved cir- Abbreviations: DPP-4, dipeptidyl peptidase-4; FDA, Food and Drug Administration; GIP, glucose- cadian rhythm throughout the day (Fig. dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion 2). Since DPP-4 is also the inactivation factors for many substances. enzyme for the other incretin hormone, © 2007 by the American Diabetes Association. glucose-dependent insulinotropic 1344 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Ahre´n It was found that following a 4-week treatment period, fasting, prandial, and mean glucose levels were reduced by Ͼ1 mmol/l, and even though the study was only 4 weeks in duration, A1C was low- ered by 0.5%. The treatment was also highly tolerable and safe, suggesting the feasibility of this approach for the treat- ment of type 2 diabetes. Vildagliptin and sitagliptin Following these initial animal studies and the successful proof-of-concept study in humans, several DPP-4 inhibitors have been developed, which are in different stages in clinical development (Table 1). Vildagliptin (LAF237, Galvus; Novartis) and sitagliptin (MK-0431, Januvia; Merck) have been explored in detail (23– 25). They are orally active and rapidly ab- sorbed, and both efficiently inhibit plasma DPP-4 activity—plasma DPP-4 activity is inhibited by almost 100% al- ready at 15–30 min after oral administra- tion, and Ͼ80% inhibition lasts for Ͼ16 h (26). They are therefore both possible to administer once daily; sitagliptin has been approved by the Food and Drug Admin- istration (FDA) (October 2006), whereas vildagliptin has been applied for ap- proval. Both compounds are planned to be used in a dose of 100 mg once daily. Whereas hepatic insufficiency does not seem to alter pharmacokinetics of the Figure 1—Plasma levels of active GLP-1, glucose, insulin, and glucagon before and after intake compounds, renal insufficiency increases of a standardized breakfast (at time 0) after 4 weeks of treatment with vildagliptin (100 mg daily; circulating sitagliptin (28). Therefore, in n ϭ 18) or placebo (n ϭ 19) in subjects with type 2 diabetes (reproduced with permission from the patients with moderate (creatinine clear- Endocrine Society, ref. 26). ance Ͻ50 ml/min) or severe (creatinine clearance Ͻ30 ml/min) renal insuffi- polypeptide (GIP) (5), the concentrations mean A1C 7.4%, and mean fasting glu- ciency, the dose of sitagliptin should be of active GIP are also increased through- cose 9.0 mmol/l) were treated with the reduced to 50 and 25 mg, respectively, out the 24-h period after DPP-4 inhibition DPP-4 inhibitor NVP-DPP728 (Novartis). and the FDA recommends that renal func- (16). This is, however, probably of less importance for the antidiabetic action of DPP-4 inhibition, since GIP seems to have lost much of its insulinotropic action in diabetes and, furthermore, since GIP stimulates rather than inhibits glucagon secretion (17). Early studies on DPP-4 inhibition The strategy to inhibit DPP-4 as a treat- ment of diabetes was initially verified in animal studies, which demonstrate that genetic deletion of DPP-4 (18) or pharma- cological inhibition of DPP-4 improves glucose tolerance and insulin secretion in a variety of experimental models (12,19– 21). The final proof-of-concept study in Figure 2—Plasma levels of intact GLP-1 during 13.5-h sampling comprising three standardized humans was published in 2002 (22). Pa- meals the day before and after 28 days’ treatment with vildagliptin (100 mg twice daily) in nine tients with drug-naı¨ve type 2 diabetes drug-naı¨ve patients with type 2 diabetes (reproduced with permission from the Endocrine Society, (mean age 65 years, mean BMI 27 kg/m2, ref. 16). DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1345 DPP-4 inhibitors Table 1—DPP-4 inhibitors in various stages of clinical development according to various pared with treatment with metformin at databases in the public domain 1 g twice daily (n ϭ 254) in subjects with type 2 diabetes (33).
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