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Dipeptidyl Peptidase-IV Inhibitors: Pharmacological Profile and Clinical Use

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Dipeptidyl Peptidase-IV Inhibitors: Pharmacological Profile and Clinical Use F E A T U R E A R TICLE Dipeptidyl Peptidase-IV Inhibitors: Pharmacological Profile and Clinical Use John R. White, Jr., PA, PharmD decade and a half ago, the on insulin biosynthesis and its inhibition creation of molecules that circumvent or choice of an oral antihypergly- of glucagon release.2 reduce the rate degradation by DPP-IV Acemic agent for any particu- Because GLP-1 stimulates insulin while maintaining the agonist effects of lar patient was in some ways a debate secretion only under hyperglycemic GLP-1 has been pursued aggressively. of nuance. Sulfonylureas (SUs) were conditions, there is minimal risk of One GLP-1 analog (exenatide) is avail- the only class available, and provid- hypoglycemia, making this molecule and able in the United States, and another ers were left to sift though pharmacoki- its congeners likely candidates for use as (liraglutide) is in phase III trials. netic, small efficacy, and sometimes sig- antihyperglycemic agents. GLP-1 is also In addition to GLP-1 analogs, mol- nificant side effect differences among associated with increased satiety, possi- ecules that inhibit the activity of DPP-IV the various choices within this class. The bly because it reduces the rate of gastric and thereby prolong the activity of situation today demands a more robust emptying. People with type 2 diabetes endogenous GLP-1 are of great interest. evaluation of multiple categories of med- have reduced circulating levels of GLP-1 Because GLP-1 analogs are proteina- ications with different mechanisms of but retain their ability to respond to this cious in structure, they will most likely action. Providers must consider the pos- hormone. Thus, it is possible to improve all require administration via injection, sible choices of an SU, a biguanide, an glycemic control through administration as exenatide does already. In contrast, DPP-IV inhibitors may be smaller α-glucosidase inhibitor, a meglitinide, of exogenous GLP-1. molecules that can be absorbed intact a thiazolidinedione (TZD), a bile acid Unfortunately, under normal physi- from the gastrointestinal tract, making resin (BAR), or a dipeptidyl peptidase- ological conditions, GLP-1 and GIP are their oral administration possible. One IV (DPP-IV) inhibitor. In addition, sev- rapidly degraded by the enzyme system DPP-IV agent (sitagliptin) is available; eral injectable compounds are available DPP-IV and therefore are not themselves the Food and Drug Administration for the treatment of hyperglycemia. This viable as pharmacological agents. The (FDA) approval of another (vildagliptin) article provides an overview of the func- is probably imminent; and several others tion of the endogenous DPP-IV enzyme I N B R I E F (saxagliptin, alogliptin, and denagliptin) system and the pharmacology and clini- are in development. DPP-IV inhibitors cal use of DPP-IV inhibitors. Sitagliptin is the first agent in a new category of medications, the are an important addition to the list of Incretin Hormones and DPP-IV dipeptidyl peptidase-IV (DPP-IV) pharmacological options for the treat- ment of hyperglycemia. Any discussion of DPP-IV and its inhibitors. It was recently approved in the United States for the manage- inhibitors would be incomplete without Effects of DPP-IV Inhibitors ment of hyperglycemia in patients mention of the endogenous incretin Based on the effects of the DPP-IV with type 2 diabetes; vildagliptin, a hormones glucagon-like peptide-1(GLP enzyme system, inhibition presumably second agent in this class, is likely 1) and glucose-dependent insulinotopic would result in increased serum levels of to join it on the U.S. market soon. hormone (GIP). These hormones are GLP-1, leading to a net antihyperglyce- These compounds accentuate the released from the L and K cells of the activity of endogenously produced mic effect. This effect has been demon- gastrointestinal tract, respectively, when antihyperglyemic incretin hormones strated in both animal and human mod- those cells are stimulated by intraluminal and are generally well tolerated. els. Animal trials evaluating the impact 1 glucose. Both GLP-1 and GIP cause a This article provides an overview of of DPP-IV inhibition have demonstrated glucose-dependent increase in insulin the pharmacology and clinical use improvement in glucose tolerance, secretion. GLP-1 also contributes to of the DPP-IV inhibitors. enhancement of insulin secretion, and glucose homeostasis through its effects even delay in the onset of overt diabetes CLINICAL DIABEtes • Volume 26, Number 2, 2008 53 F E A T U R E A R TICLE in Zucker diabetic fatty rats.3 Further 1 compares the action of endogenous 2 diabetes. One phase III trial demon- animal studies have suggested that GLP-1 with that of DPP-IV inhibitors. strated that sitagliptin administered in inhibition of DPP-IV improves insulin 100-mg and 200-mg daily doses reduced Sitagliptin sensitivity and may reverse glucose tox- hemoglobin A1c (A1C) levels by 0.79 icity.4 It has been suggested that DPP-IV In October 2006, sitagliptin became and 0.94%, respectively, at 24 weeks. inhibition and its resultant preservation the first DPP-IV inhibitor to gain FDA These differences were statistically of endogenous GLP-1 activity may lead approval for the treatment of type 2 significant when compared to placebo to β-cell preservation via augmentation diabetes. Sitagliptin tablets are com- (P < 0.001).6 Patients with A1C levels of GLP-1’s antiapopotic effects. mercially available as 100-mg (beige), > 9.0% showed greater reductions in Although DPP-IV inhibition has 50-mg (light beige), and 25-mg (pink) A1C. Improvements in fasting plasma been associated with an enhancement tablets.5 Sitagliptin is also available in glucose and postprandial glucose levels of β-cell survival and neogenesis in a combination product with metformin were also reported in those treated with streptozotocin-treated diabetic rats,4 this in doses of 50 mg sitagliptin/500 mg sitagliptin. effect has not yet been demonstrated metformin and 50 mg sitagliptin/1,000 In another report, daily doses of in humans. This exciting possibility mg metformin. 100 mg sitagliptin were associated undoubtedly will be evaluated in humans The usual recommended dose of with statistically significant(P < 0.001) as a potential agent or class of agents for sitagliptin is 100 mg per day. However, 0.65% reductions in A1C in patients the prevention of type 2 diabetes. the agent is available in three strengths with an initial mean A1C of 8%.7 DPP-IV inhibitors probably exert to allow for lower dosing in patients with Sitagliptin also has been evaluated most, if not all, of their pharmacological moderate to severe renal impairment. in combination with other antihyper- effects in humans by inhibiting the deg- The sitagliptin-metformin combination glycemic medications. In one trial, 701 radation of GLP-1. Through this func- should be taken twice daily with meals patients with a mean baseline A1C of tion, they cause some of the same effects and titrated slowly to minimize potential 8% (range: 7–10%) who were previously of GLP-1, including stimulation of gastrointestinal side effects associated treated with metformin continued ther- insulin secretion, inhibition of glucagon with metformin. apy with metformin and were random- secretion, and enhancement of β-cell ized to receive either 100 mg sitagliptin Clinical trials mass.1 Conversely, they seem to have or placebo daily for 24 weeks.8 Patients Clinical trials have demonstrated that only a marginal slowing effect on the in the placebo group experienced no sitagliptin is safe and efficacious for the rate of gastric emptying and no obvious changes in A1C, whereas those treated management of hyperglycemia in type effect on satiety or weight loss.1 Table with sitagliptin plus metformin realized a 0.65% reduction in A1C at 24 weeks. Table 1. Effects of Endogenous GLP-I Versus DPP-IV Inhibition In the combination therapy group, 47% of the patients concluded the trial with Feature of Type 2 Diabetes Action of Endogenous Mimicked by DPP-IV GLP-1 Inhibitors? A1C levels < 7%, and 17% reached an A1C of < 6.5%. Only 18% of patients in the placebo group reached an A1C Impaired insulin secretion Glucose-dependent stimula- Yes tion of insulin level < 7%, and only 5% reached an A1C < 6.5%. Similar results have been Hyperglucagonemia Suppression of glucagon Yes published from other clinical trials secretion evaluating the efficacy of combination Reduced pancreatic β-cell Increased synthesis of Yes metformin and sitagliptin therapy.9,10 mass proinsulin One study evauated 353 patients Abnormally high rate of Inhibition of β-cell apop- Probably previously treated with pioglitazone.11 β-cell apoptosis tosis Patients received either 100 mg sita- Gastric emptying ac- Deceleration of gastric Marginally gliptin or placebo daily in addition to 30 celerated, decelerated, or emptying or 45 mg/day pioglitazone for 24 weeks. normal Mean baseline A1C values reported in Hypercaloric energy in- Suppression of appetite/ Not obvious this trial were 8% (range: 7–10%) at take/obesity induction of satiety the completion of a short run-in period Weight loss No pioglitazone. A mean reduction in A1C of 0.7% was reported in patients treated Adapted from Ref. 1 with combination therapy, compared 54 Volume 26, Number 2, 2008 • CliniCAL DIABETES F E A T U R E A R TICLE to no significant change in A1C in the whether sitagliptin is secreted in human Sitagliptin is primarily excreted in an placebo group. breast milk, and the effects on nursing unchanged form in the urine (79%) via In summary, evidence suggests that babies are also unknown. active tubular secretion. The terminal sitagliptin is an efficacious antihypergly- Safety and efficacy in patients < 18 t1/2 of sitagliptin was 12.4 hours after cemic agent when used as monotherapy years of age have not been studied, but a single 100-mg dose in healthy vol- or in combination with metformin nothing thus far suggests that problems unteers.5 A relatively small fraction of or pioglitazone for the treatment of would result from using the agent in sitagliptin undergoes hepatic metabolism type 2 diabetes.
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