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NEW DRUG DEVELOPMENTS

Sitagliptin: A Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes

Pharmacotherapy Faculty, Florida Hospital Family Practice Residency, Orlando, FL

Erin L St. Onge, PharmD

Campus Director/Clinical Assistant Professor, University of Florida College of Pharmacy, Orlando Campus, Apopka, FL

Reprints: Dr. Miller, Florida Hospital Family Practice Residency, 7975 Lake Underhill Rd., Suite 200, Orlando, FL 32822-8204, fax 407/303-6839, Shannon.miller{at}flhosp.org

	Abstract

Top Abstract Data Sources Pharmacology Pharmacokinetics Clinical Trials Clinical Trial Limitations Adverse Events Drug Interactions Therapeutic Considerations Dosage and Administration Summary References

 
OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor in the management of type 2 diabetes mellitus.

DATA SOURCES: A MEDLINE search (1966-February 2006) was conducted for English-language articles using the terms dipeptidyl peptidase IV inhibitor, incretin, MK-0431, and sitagliptin. Abstracts from the American Diabetes Association annual meetings in 2004 and 2005 were included as sources of data.

STUDY SELECTION AND DATA EXTRACTION: Articles pertaining to the pharmacology of sitagliptin, its pharmacokinetics, safety and efficacy were reviewed.

DATA SYNTHESIS: Sitagliptin is a potent, competitive, reversible inhibitor of the DPP-IV enzyme. It is eliminated renally, with a terminal half-life of 11.8-14.4 hours. In Phase II clinical trials, sitagliptin was found to be superior to placebo for the treatment of type 2 diabetes mellitus. Results of a small trial comparing sitagliptin with glipizide indicate that both treatments are comparable. The efficacy of sitagliptin has also been demonstrated when used as adjunctive therapy with metformin. Few adverse effects have been reported. Weight gain and hypoglycemia have not been seen with sitagliptin therapy.

CONCLUSIONS: Based on its unique mechanism of action, sitagliptin will provide practitioners with an additional tool in the treatment of diabetes. Review of the literature to date implies sitagliptin may be effective as monotherapy in type 2 diabetes. In addition, existing evidence supports the use of sitagliptin as adjunct therapy to sulfonylureas and metformin. Another advantage of sitagliptin use is that it appears to be free from the adverse effects of weight gain and hypoglycemia that are associated with currently available treatments.

Key Words: dipeptidyl peptidase IV inhibitor, incretin, MK-0431, sitagliptin

Published Online, July 25, 2006. www.theannals.com, DOI 10.1345/aph.1G665

THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT
ACPE UNIVERSAL PROGRAM NUMBER: 407-000-06-018-H01

Despite this wide array of treatment options, optimal glycemic control is often unattainable. One of the therapeutic options being designed to target a key area of unexplored pathophysiology includes the incretin mimetic hormones. Incretin hormones are released from cells in the gastrointestinal tract in response to a meal provoking glucose-induced insulin release from the pancreas.²

In recent years glucagon-like peptide (GLP-1), has been the subject of intense research. GLP-1, an incretin hormone, is released from the gut postprandially. The role of GLP-1 in glucose homeostasis is evident through its role in insulin biosynthesis and secretion, as well as inhibition of glucagon release. When the blood glucose level is elevated, GLP-1 stimulates insulin secretion. In addition, GLP-1 reduces appetite, slows gastric emptying, and appears to regulate the growth of insulin producing ß-cells (Figure 1). ³ Intravenous or subcutaneous administration of GLP-1 has been shown to be highly efficacious in the treatment of type 2 diabetes.⁴ However, GLP-1 is rapidly degraded through the action of dipeptidyl peptidase IV (DPP-IV).⁵ Current research is focusing on harnessing the beneficial effects of GLP-1 by inhibiting the DPP-IV enzyme. Theoretically, an inhibitor of DPP-IV should prolong the positive effects of GLP-1 by increasing the amount circulating in the blood. Additionally, because GLP-1 is released in a glucose dependent manner, DPP-IV inhibitors would not be expected to cause hypoglycemia.⁶

View larger version (32K): [in this window] [in a new window]   Figure 1. The role of GLP-1 in glucose homeostasis. DPP-IV = dipeptidyl peptidase IV; GIP = glucose-dependent insulinotropic polypeptide; GLP = glucagon-like peptide; PACAP = pituitary adenylate cyclase-activating polypeptide. Reprinted with permission from Journal of Medicinal Chemistry. Copyright 2004 American Chemical Society.

View larger version (9K): [in this window] [in a new window]   Figure 2. The chemical structure of sitagliptin phospate. Reprinted with permission from Journal of Medicinal Chemistry. Copyright 2005 American Chemical Society.

	Data Sources

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	Pharmacology

Top Abstract Data Sources Pharmacology Pharmacokinetics Clinical Trials Clinical Trial Limitations Adverse Events Drug Interactions Therapeutic Considerations Dosage and Administration Summary References

 
INCRETIN HORMONES
Human
To understand the pharmacology of sitagliptin, it is necessary to review the normal function of incretin hormones. An incretin, as defined by Creutzfeldt⁸ in 1979, is a hormone that meets the following criteria. It is released from the gut in response to nutrients (mainly carbohydrates), stimulates insulin release in a concentration easily achieved after meal ingestion, and causes insulin release in a glucose-dependent manner. One of the gastrointestinal hormones meeting these criteria is GLP-1. Unfortunately, the DPP-IV enzyme blocks the effects of GLP-1. DPP-IV is a cell surface serine protease. The highest concentrations of DPP-IV are found in the kidneys, intestines, and bone marrow, while lower concentrations are present in the liver, pancreas, placenta, thymus, spleen, epithelial cells, vascular endothelium, and lymphoid and myeloid cells.^2,3

Clinical studies have shown that patients with type 2 diabetes have reduced concentrations of intact GLP-1. In a study of 24 patients, 12 subjects had type 2 diabetes and 12 were healthy matched subjects.⁹ After administration of a meal, blood samples were collected at 15, 30, 45, 60, 75, 90, 120, 150, and 180 minutes to determine intact GLP-1 concentrations. The investigators found that intact GLP-1 concentrations were lower in patients with diabetes at 75, 90, and 120 minutes after meal ingestion (p = 0.056, 0.017, and 0.017, respectively). It was also discovered during this period that insulin and C-peptide concentrations were decreased, indicating an abnormal insulin response. Based on these results, the investigators concluded that, in the absence of normal concentrations of intact GLP-1, the insulin response in patients with type 2 diabetes is inadequate. In an effort to overcome this deficiency in patients with type 2 diabetes, DPP-IV inhibitors have been a focus of interest.

Animal
Studies in animals provided the initial evidence that inhibiting DPP-IV increased endogenous GLP-1 concentrations and, therefore, improved glucose tolerance and insulin secretion. Ahren et al.¹⁰ found that, after administering the DPP-IV inhibitor valine-pyrrolidide to mice, the elimination of GLP-1 was prolonged. In addition, DPP-IV inhibitor administration facilitated a rise in GLP-1 levels in response to glucose ingestion resulting in insulin biosynthesis and secretion, thereby reducing glucose concentrations. A study using the DPP-IV inhibitor isoleucine thiazolidide found that circulating DPP-IV concentrations decreased by 65% in obese and lean Zucker rats.¹¹ In response to inhibition of DPP-IV, insulin secretion increased 150% and 27% in the obese and lean rats, respectively. This in turn led to improved glucose tolerance in both samples.

Studies conducted in mice lacking the DPP-IV enzyme further support the hypothesis that inhibition of the DPP-IV enzyme improves glycemic control. Marguet et al.¹² examined the effect of DPP-IV inhibitor valine-pyrrolidide on glucose control in mice missing the DPP-IV enzyme. The investigators found that valine-pyrrolidide did not improve glucose tolerance in mice missing the enzyme. Therefore, they concluded that DPP-IV inhibitors exert all of their glucose-lowering effects through inhibition of the DPP-IV enzyme.

SITAGLIPTIN
Sitagliptin is a potent, competitive, reversible inhibitor of the DPP-IV enzyme. The S-enantiomer is considerably less potent than the R-enantiomer. Sitagliptin is highly selective for the DPP-IV enzyme compared with other similar enzymes.⁶ This selectivity is important as the enzymes DPP 8 and DPP 9 are very similar to DPP-IV; however, inhibition of these enzymes has led to serious toxicities in animals.

To date, 2 studies have been conducted to evaluate the effect of sitagliptin on plasma DPP-IV concentrations in humans. One trial involving the use of sitagliptin in 11 healthy men revealed inhibition of plasma DPP-IV of 80% or higher on day 10 versus placebo.¹³ In addition, it was discovered that sitagliptin at doses of 25 mg/day or higher resulted in a twofold or greater increase in active GLP-1 concentrations compared with placebo (p < 0.001). A follow-up study of 32 middle-aged normoglycemic obese subjects compared sitagliptin 200 mg twice daily with placebo for 28 days.¹⁴ The investigators found that sitagliptin caused 90% inhibition of DPP-IV versus placebo (p < 0.001). In addition, after an oral glucose tolerance test, sitagliptin increased active GLP-1 levels 2.7-fold (p < 0.001) and decreased glucose AUC by 35% (p < 0.05) compared with placebo.

	Pharmacokinetics

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The pharmacokinetics of multiple-dose administration of sitagliptin has been evaluated in 2 studies. Bergman et al.¹³ conducted a double-blind, randomized, placebo-controlled, incremental dose, parallel group study to determine the pharmacokinetic profile of multiple doses of sitagliptin in 11 healthy male subjects. Steady-state plasma concentrations were reached on day 3, as indicated by evaluation of trough plasma concentrations over time. At all doses examined, the plasma AUC on day 10 increased in proportion to the dose administered. Maximum concentrations increased greater than dose proportionately while 24 hour plasma concentrations increased less than dose proportionately. Another randomized, double-blind, placebo-controlled study examined the pharmacokinetics of sitagliptin over a 28 day period in 32 middle-aged (45-63 y), obese (body mass index [BMI] 30-40 kg/m2) subjects.¹⁴ Steady-state was reached by day 2 of dosing, and 90% of sitagliptin was excreted unchanged in urine. Sitagliptin is eliminated renally, with a terminal half-life of 11.8-14.4 hours.

Significant pharmacokinetic changes were not observed in a study of 8 healthy, young (18-45 y), nonobese females; 10 healthy, elderly (65-80 y), nonobese males; 10 healthy, elderly, nonobese females; and 10 healthy, young, obese subjects (BMI 30-40 kg/m²).¹⁵ In each group, 6-8 subjects received sitagliptin 50 mg and 2 received placebo. Plasma and urine samples were collected for 72 hours. AUC and maximum concentration geometric mean ratios with 90% confidence intervals were reported. Urinary pharmacokinetics was similar across all groups (specific data not reported). The investigators concluded that, because modest differences were seen in plasma pharmacokinetics, dose adjustments for gender, age, and obesity might not be necessary.

	Clinical Trials

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Administration of other DPP-IV inhibitors have augmented insulin response to oral glucose and enhanced glucose clearance in animal studies.^2,16 Beyond potentiating insulin response, animal studies with sitagliptin have shown additional benefits. Fischer rats lacking the DPP-IV enzyme are protected against diet-induced obesity, indicating that DPP-IV inhibitors may afford this protection to humans.¹⁷ Studies have also shown improvement in ß-cell functioning, suggesting that this class of drugs may have disease-modifying potential. Data in humans help to clarify these initial studies and further emphasize the efficacy of sitagliptin.

Results from one single-dose, Phase I, randomized, placebo-controlled trial have been reported. That study was followed by 8 Phase II trials, 5 of which were conducted in patients with diabetes. Results from the majority of those trials are available in abstract form only. Phase III trials began in 2004, with expected publication dates of 2006. A summary of published trials and available abstracts is provided in Table 1.

In the Phase I trial, researchers sought to assess the glucose-lowering ability, safety, and tolerability of sitagliptin.¹⁸ Fifty-six patients with type 2 diabetes received single doses of sitagliptin 25 mg, 200 mg, or placebo, each dose separated by a 7 day washout period. Glucose tolerance tests were performed 2 hours after a dose. Patients who received both doses of sitagliptin experienced significant reductions in the area under the glucose curve of 22% (p < 0.001) and 26% (p < 0.001), respectively, in addition to a twofold increase of concentrations of active GLP (p < 0.001). Both doses of sitagliptin also increased plasma insulin (22% and 23%; p < 0.001) and C-peptide (13% and 21%; p < 0.001) while decreasing plasma glucose (8% and 14%; p < 0.001).

Several clinical trials have documented the safety and efficacy of sitagliptin. Preliminary results from Phase II clinical trials were presented at the 2005 annual meeting of the American Diabetes Association. Results from a 12 week, placebo-controlled, parallel-group study in patients with type 2 diabetes showed that use of sitagliptin led to a significant reduction in hemoglobin A1C (A1C).¹⁹ In this dose range-finding study, 552 patients with a baseline A1C of 5.8-10.4% were randomized to 1 of 5 treatment groups: placebo; sitagliptin 25, 50, or 100 mg once daily; or sitagliptin 50 mg twice daily. After 12 weeks, treatment with all doses of sitagliptin reduced A1C, with the largest reduction seen in the 100 mg once-daily group. Observed A1C differences were apparent depending on the A1C at baseline. Patients with a baseline A1C less than 7% had a reduction of 0.4%. Patients with a baseline A1C of 7-8.5% experienced a 0.6% reduction, and those with a baseline A1C of 8.5-10% had a reduction of 0.8%. Treatment was well tolerated, with no significant weight gain reported. One adverse event of hypoglycemia was reported in each of the 4 treatment groups. No adverse events of hypoglycemia were reported in the placebo group.

A limited number of trials have evaluated sitagliptin and standard antihyperglycemic management. One trial compared sitagliptin with glipizide,²⁰ and 2 trials evaluated sitagliptin in combination with metformin.^21,22 In a randomized, double-blind, placebo-controlled trial, 743 patients with type 2 diabetes were randomized to 1 of 6 treatment groups: placebo; sitagliptin 5, 12.5, 25, or 50 mg twice daily; or glipizide 5 mg titrated to 20 mg daily.²⁰ After 12 weeks, sitagliptin significantly reduced A1C from baseline compared with placebo. The largest reduction (0.77%) within the sitagliptin groups was seen in the 50 mg treatment arm. A slightly greater reduction (1%) occurred in the glipizide arm. At week 12, A1C results did not appear to reach a plateau in any treatment group. Similar to previous studies, treatment with sitagliptin was well tolerated, resulting in no significant weight gain. Patients who received glipizide experienced a 1.1 kg weight gain relative to placebo (no p value reported). Hypoglycemia was observed in 4% of patients taking sitagliptin, 17% of those taking glipizide, and 20% of those taking placebo. This ongoing study will further address the efficacy, safety, and ß-cell function improvement associated with sitagliptin.

In a separate trial designed to evaluate efficacy and safety, sitagliptin was added to metformin. Twenty-eight patients with type 2 diabetes and inadequate glycemic control (average baseline A1C 7.7%) with metformin monotherapy were included in a 4 week, 2 period crossover study. Patients were required to be on a stable dose of metformin (>1500 mg/day) for at least 6 weeks prior to initiation of the study and were then randomized to 1 of 2 treatment sequences: adding placebo for 4 weeks followed by adding sitagliptin 50 mg twice daily or vice versa.²¹ At the end of each period, patients were required to remain at the investigational site for 24 hours for frequent blood sampling. After 4 weeks, patients taking metformin and sitagliptin had a 24 hour weighted mean glucose level of 125 mg/dL compared with 157 mg/dL in the metformin and placebo arms. A1C values were not reported at the conclusion of the trial, likely second to its short duration. Patients reported no increase in gastrointestinal adverse events and no hypoglycemia or weight gain.

	Clinical Trial Limitations

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At the time of writing, only one randomized clinical trial had been published evaluating the safety and tolerability of sitagliptin.¹³ The subjects were normoglycemic and in good general health, according to routine medical history and physical exam. The mean age described was 32.7 years. This study represents the first data regarding the use of sitagliptin in humans, but was limited by a small sample size in male patients. Because the population of people that type 2 diabetes affects is diverse, larger scale trials are needed to include elderly patients, as well as women. In addition, patients with comorbid conditions such as obesity, dyslipidemia, hepatic and renal impairment, and hypertension should be evaluated.

Although abstract information is available that further supports efficacy and safety, this information is limited by the inability to fully assess quality and design. Baseline characteristics specific to these studies have not been published and, therefore, it is difficult to ascertain which patient population may benefit from sitagliptin. Given the limited amount of trial information available, future trials of longer duration will be needed to define the use of sitagliptin in patients with diabetes. Endpoints such as fasting and postprandial glucose levels, A1C, insulin, glucagon, and C peptide levels should be further explored. Given the drug's potential to affect the immune system, long-term trials evaluating safety endpoints, such as complete blood cell counts and immunologic markers, such as T-cells, are warranted. Other safety endpoints to assess include blood pressure and platelet counts.

	Adverse Events

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DPP-IV has functions beyond metabolic control. Early trials suggest immunologic effects, thereby implicating it as an integral component of the immune system. It binds adenosinedeaminase, which is important in the normal development and function of the immune system.²³ DPP-IV (also known as T-cell marker CD26) serves as a costimulatory molecule in T-cell activation.¹¹ DPP-IV inhibitors have been shown to inhibit T-cell activity in vitro; however, concentrations required for this activity in vivo are high and, therefore, unlikely to be achieved during clinical use for the treatment of type 2 diabetes. Thus far, no adverse effects related to immune function have been reported with sitagliptin in human subjects.

There are a number of substrates other than GLP-1 that DPP-IV cleaves in vitro, including hormones, neuropeptides, and chemokines.²⁴ In many cases, the cleavage product is inactive. DPP-IV inhibitors prolong the action of hormone YY, neuropeptides such as substance P, and macrophage-derived chemokines. Potential adverse effects resulting from the prolongation of these messengers include inflammation (effect on substance P), increased blood pressure (effect on neuropeptide Y), and allergic reactions (effect on chemokines).

Other theoretical adverse effects associated with this class of drugs may result from the inadvertent inhibition of related enzymes. Enzymes most closely related to DPP-IV include fibroblast-activating protein- (FAP), DPP-II, DPP 8, and DPP 9. DPP 8 is located on activated T-cells, and DPP 9 is located in skeletal muscle, heart, and liver.³ These widely distributed enzymes have been the topic of much research. Their inhibition has been linked to toxic effects in animals, including enlarged spleen, thrombocytopenia, anemia, and other histological pathologies. Available data show that sitagliptin is highly selective for DPP-IV versus other proteases such as DPP 8 and DPP 9.^6,25 This may explain why serious adverse effects have not been reported with sitagliptin. The degree to which other selective DPP-IV inhibitors will inhibit DPP 8 and DPP 9 will likely determine their adverse effect profiles.

Thus far, information from the limited number of clinical trials suggests that sitagliptin does not cause hypoglycemia or weight gain. This is likely due to the drug's mechanism of action. By stimulating insulin secretion in a glucose-dependent manner, it minimizes hypoglycemia and resultant weight gain. The incidence of hypoglycemia was either similar to that with placebo or minimally noted in all trials evaluated. With no significant changes in weight noted in any of the aforementioned trials, sitagliptin may be an attractive alternative or addition to currently available therapy.

	Drug Interactions

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Limited data are available regarding drug interactions associated with the use of sitagliptin. One study in patients with type 2 diabetes was conducted to assess whether coadministration of sitagliptin and metformin would alter the pharmacokinetic profile of either drug. In this randomized trial, patients received sitagliptin 50 mg twice daily plus metformin 1000 mg twice daily, sitagliptin 50 mg twice daily plus placebo, or metformin 1000 mg twice daily plus placebo in three 7 day periods.²² The pharmacokinetics of metformin were not altered when administered with sitagliptin. Similarly, sitagliptin pharmacokinetics were not altered when given in conjunction with metformin. No hypoglycemia was reported, and gastrointestinal adverse events were not significantly different when sitagliptin was added to metformin. Information regarding sitagliptin in combination with other antihyperglycemic agents has not yet been published. Due to sitagliptin's unique mechanism of action, combination therapy, especially with insulin sensitizers, will likely be further explored. In addition, it will be critical to examine any potential interactions with antihypertensives and lipid-lowering therapy as patients with type 2 diabetes are commonly also taking these agents.

	Therapeutic Considerations

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The future of sitagliptin will depend on many factors. The results of the studies reviewed here are promising; however, final approval of the drug will depend on information gathered from the Phase III trials currently underway.

Competition will also affect the use of sitagliptin. Currently, there are several DPP-IV inhibitors undergoing clinical trials at various stages. These include LAF237 (vildagliptin; Novartis), NN 7201 (Novo Nordisk), P93/01 (Probiodrug), P32/98 (Probiodrug), and BMS477118 (Bristol-Myers Squibb). LAF237 or vildagliptin will be the most likely competitor of sitagliptin, as Phase III clinical trials started in late 2005. Studies conducted to date show promise for vildagliptin in type 2 diabetes. In a 4 week clinical trial, the effect of vildagliptin on mean 24 hour glucose and insulin levels and the glucagon response to a meal were examined.²⁶ It was found that vildagliptin significantly reduced mean 24 hour glucose levels (p < 0.001) while insulin levels remained unchanged. In addition, the glucagon response to administration of a meal was significantly reduced (p = 0.005).

Another clinical trial was designed to investigate the efficacy of vildagliptin in metformin-treated patients over 12 and 52 weeks.²⁷ The researchers found that, at 12 weeks, patients taking vildagliptin in combination with metformin experienced a significant (p value not reported) decrease in A1C compared with patients taking metformin plus placebo. In addition, this decrease in A1C was sustained at 52 weeks in the vildagliptin group but A1C increased in the group receiving placebo. Novo Nordisk's NN 7201 and Probiodrug's P32/98 are still in the early stages of research and development. In a study involving rats given P32/98 for 12 weeks, investigators found that P32/98 improved glucose tolerance, insulin sensitivity, hyperinsulinemia, and ß-cell glucose responsiveness.²⁸ P93/01 and BMS-477118 are undergoing Phase II trials and would not be expected to be available for several years.

Finally, clinicians will examine what benefits sitagliptin afford their patients when making therapeutic decisions about its use. Not only does sitagliptin appear to have limited adverse events, but studies also suggest that the drug exhibits disease-modifying potential due to the beneficial effects GLP-1 exerts on the differentiation, proliferation, and survival of ß-cells. In addition, the inhibition of DPP-IV suppresses mediators involved in autoimmune destruction. These combined effects may have further implications for DPP-IV inhibitors in the treatment of type 1 diabetes.²

	Dosage and Administration

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Clinical trials have used both twice- and once-daily dosing of sitagliptin. In one study, 34 healthy male volunteers enrolled in 2 separate study protocols.²⁹ Both protocols were double-blind, randomized, placebo-controlled, alternating-panel studies. Protocol 001 randomized 8 subjects into 2 panels (A and B) for 4 study periods. Six patients in each panel took active drug, while 2 patients received placebo. Subjects in panel A received 1.5, 12.5, 50, and 200 mg during study periods 1, 2, 3, and 4, respectively. Panel B received 5, 25, and 100 mg in periods 1, 2, and 3, respectively. During period 4, subjects received a second dose of 25 mg after a high-fat meal. Protocol 002 consisted of 2 panels (C and D) with 2 study periods each. In each panel, 6 subjects received sitagliptin and 3 received placebo. Subjects in panel C received placebo or 200 and 600 mg of sitagliptin. In panel D, subjects received placebo or sitagliptin 400 and 600 mg. The investigators found that single doses of sitagliptin had a dose-dependent inhibitory effect on DPP-IV activity for up to 24 hours, supporting the use of once-daily dosing.

In another study aimed at evaluating the DPP-IV inhibitor activity of sitagliptin, incremental doses of sitagliptin (25-600 mg daily and 300 mg twice daily) were examined.¹³ Researchers found that plasma DPP-IV enzyme activity was significantly inhibited at all doses. Therefore, they concluded that sitagliptin would be effective with once-daily dosing.

The exact dosage form, strength, and dosing interval to achieve maximum benefits from sitagliptin therapy have not yet been established. Based on the results of currently available studies, we anticipate that an oral dose from 25 to 200 mg once daily would be effective.

	Summary

Top Abstract Data Sources Pharmacology Pharmacokinetics Clinical Trials Clinical Trial Limitations Adverse Events Drug Interactions Therapeutic Considerations Dosage and Administration Summary References

 
Based on its unique mechanism of action, sitagliptin will provide practitioners with an additional weapon in the fight against diabetes. Although it is unknown exactly where it will fit into the treatment of diabetes, several points should be considered. First, clinical studies imply that sitagliptin may be effective as monotherapy in type 2 diabetes. In the study comparing sitagliptin or glipizide with placebo, the A1C reduction reported in both treatment groups did not appear to plateau after 12 weeks of therapy. This suggests that greater reductions in A1C would occur in studies of longer duration. Second, existing evidence supports the use of DPP-IV inhibitors like sitagliptin as adjunct therapy to sulfonylureas and metformin. Finally, sitagliptin appears to be free from the detrimental adverse effects of weight gain and hypoglycemia that plague other available treatments. However, trials of longer duration are necessary to fully evaluate the effects of long-term DPP-IV inhibition.

	Footnotes

 
Dr. Miller owns stock in the Merck Company.

We are grateful to Larry Lopez PharmD, Patricio Bruno DO, Robert Vandervoort PharmD, and Toni Ripley PharmD for insightful ideas and suggestions in preparation of the manuscript. We also thank William Fooshee for expert technical assistance.

	References

Top Abstract Data Sources Pharmacology Pharmacokinetics Clinical Trials Clinical Trial Limitations Adverse Events Drug Interactions Therapeutic Considerations Dosage and Administration Summary References

 

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16. Mitani H, Takimoto M, Hughes TE, Kimura M. Dipeptidyl peptidase IV inhibition improves impaired glucose tolerance in high-fat diet-fed rats: study using a Fischer 344 rat substrain deficient in its enzyme activity.Jpn J Pharmacol 2002;88:442-50.[CrossRef][Medline]
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