Alogliptin: The newest agent to fight the diabetes pandemic
Amy Nicholas, PharmD, CDE1,2, Tracy E. Macaulay, PharmD1,3,4; From the 1Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy; 2PharmacistCARE, 3Department of Pharmacy Services, UKHealthCare; and 4Gill Heart Institute, University of Kentucky, Lexington, KY.
Published on Nov 14, 2008
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According to the American Diabetes Association (ADA), 23.6 million children and adults have diabetes (8% of the US population) and another 5.7 million cases remain undiagnosed.1 Epidemiologists predict that these statistics will double by 2030, further taxing the healthcare system. Medical expenditures are approximately 2.3 times higher for diabetic versus nondiabetic patients, and the annual cost of diabetes is estimated to be $116 billion.2
Traditionally, successful treatment of diabetes has been measured by the ability to achieve strict blood glucose control, which is demonstrated by reductions in fasting blood glucose, random blood glucose, and glycosylated hemoglobin A1C (HgbA1C) levels. This measure of success is supported by evidence showing an increased risk for microvascular and macrovascular diseases, including nephropathy, progressive atherothrombosis, neuropathy, and retinopathy, when hyperglycemia is uncontrolled. Evidence also shows that postprandial hyperglycemia is an independent risk factor for cardiovascular disease;3 however, despite the ability to decrease hyperglycemia, very few diabetes medications have demonstrated reductions in disease complications, while some may actually increase cardiovascular death. This has resulted in a recent push from the medical and scientific communities to develop medications that improve patient outcomes, rather than using glucose control as a surrogate marker of decreased complications. As new drugs are developed, they will likely have to meet higher standards before they are added to an already large armamentarium of pharmacologic agents to treat type 2 diabetes.
The newest class of medication to go before the US Food and Drug Administration (FDA) for approval is the dipeptidyl peptidase-4 inhibitors (DPP-4). With a novel mechanism of action, these agents are being touted as potential monotherapy or add-on therapy for diabetic patients with poor control on standard therapy. We will provide a brief review of alogliptin, which is the newest agent under review by the FDA in this class of medications that may play a key role in the treatment of type 2 diabetes.
Pharmacology Given the large number of patients affected by diabetes, much research has been devoted to understanding the mechanisms of glucose homeostasis. The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which were first identified in 1964, have become 2 important players in this process.4 Incretins are released by enteroendocrine cells (K and L cells) of the gut in response to enteral nutrition. They induce glucose-dependent insulin secretion from pancreatic beta-cells and may help preserve beta-cell function in patients with type 2 diabetes (Figure). Both GLP-1 and GIP are rapidly degraded to inactiveforms, primarily by the enzyme DPP-4. A defect in the level of GLP-1 and a decrease in the pancreatic response to GIP have been shown in patients with type 2 diabetes.7 As a result, DPP-4–resistant GLP-1 analogs (incretin mimetics) and DPP-4–inhibitors, such as alogliptin, are new therapies currently being developed for the treatment of diabetes. There does not appear to be a defect in insulinotropic effects with GLP-1; thus, followingadministration of alogliptin,GLP-1 levels will increase, ideallyresulting in improved glycemiccontrol. As opposed to olderagents, such as sulfonylureas, thisnovel mechanism would theoreticallyreduce hypoglycemia by reducingfasting and postprandialhyperglycemia.8
Pharmacokinetics
The pharmacokinetic profile of alogliptin has been evaluated in phase 1 and 2 clinical trials that included healthy male volunteers and patients with type 2 diabetes.9,10 One study enrolled 36 male subjects, between 18 years and 55 years of age, in 1 of 6 cohorts to evaluate dose and pharmacokinetic parameters of alogliptin.9 The medication was rapidly absorbed (median Tmax, 1-2 hours) with a dose-dependent increase in total drug exposure (mean area under the curve), although exposure to active GLP-1 had no apparent dose response. Alogliptin was slowly eliminated, with a half-life of 12.5 hours and 21.1 hours with the 400-mg dose and 25-mg dose, respectively. The medication was excreted primarily unchanged in the urine (60%-71%). Hepatic metabolism to N-demethylated and N-acetylated metabolites accounted for the remainder of drug elimination. Similar results were demonstrated in patients with type 2 diabetes, irrespective of sex, race, or age, supporting the once-daily dosing regimen.10
Because of the high rate of renal clearance, a pharmacokinetic evaluation in patients with renal impairment was undertaken. Following exposure to a single 50-mg dose of alogliptin, increases in drug levels were observed across all ranges of renal dysfunction: mild (1.7-fold), moderate (2.1-fold), severe (3.2-fold), and end-stage renal impairment (3.8-fold).11 Hepatic dysfunction was not associated with clinically significant changes in pharmacokinetic parameters.12
Safety
Alogliptin seems to be generally well tolerated. In a multiple oral dose study of adult patients with type 2 diabetes, no dose-limiting toxicity was observed, andalogliptin was generally well toleratedwhen administered daily over14 days (dose range, 25-400 mg).10There were no discontinuations dueto adverse events, and no seriousadverse events or deaths were reported;in the study, adverse eventswere spontaneously reported orelicited by open-ended questioning.The incidence of hypoglycemia wasalso low.
Similar results were observed in a single oral dose study of alogliptin in healthy male subjects.9 The drug was generally well tolerated across all doses (dose range, 25-800 mg), and no dose-limiting toxicity was observed.9 All reported adverse events were mild, and no subjects discontinued the study as a result of an adverse drug event.
Several abstracts of trials with study durations of 1 day to 12 weeks were presented at the ADA 68th Annual Scientific Sessions, further demonstrating alogliptin’s tolerability.13,14 No clinically meaningful changes in laboratory values, physical examination findings, or 12-lead electrocardiogram results were noted compared with baseline in several studies.9,10,13,14
Efficacy
Alogliptin monotherapy Fleck and colleagues demonstrated the efficacy of alogliptin monotherapy in a randomized, double-blind, placebo-controlled, dose-ranging study in patients with type 2 diabetes over 12 weeks.13 These patients had newly diagnosed diabetes or were inadequatelycontrolled using diet or exercisealone. Patients received alogliptin,6.25 mg to 100 mg daily, or placebo.There were statistically significant reductions in HgbA1C after12 weeks of treatment when once-dailydoses of 12.5 mg to 100 mgwere compared with placebo. After12 weeks statistically significantreductions in fasting plasma glucosewere observed in the dosagerange of 25 mg to 100 mg.
A phase 3, international, multicenter, randomized, double-blind, placebo-controlled, 3-treatment-arm study in patients with type 2 diabetes over 26 weeks also demonstrated the efficacy and safety of alogliptin monotherapy.15 Patients included in this study were inadequately controlled on diet or exercise alone and received alogliptin 12.5 mg or 25 mg once daily, or placebo. At week 26, there were statistically significant, placebo-corrected reductions in HgbA1C in both groups receiving alogliptin. No significant weight changes were observed.
Alogliptin in combination with metformin In a phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial, the investigators studied the efficacy and safety of alogliptin in combination with metformin (Glucophage) in patients who were inadequately controlled on metformin alone.16 Patients received either alogliptin 12.5 mg or 25 mg once daily, or placebo. At week 26, there were statistically significant, placebo-corrected reductions in HgbA1C andfasting plasma glucose when eitherdose of alogliptin was added tometformin. No clinically meaningfulchange in weight was observedbetween the alogliptin and placebocohorts.16
Alogliptin in combination with glyburide In a phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial, the investigators studied the efficacy and safety of alogliptin in combination with glyburide (Micronase) in patients who were inadequately controlled on glyburide alone.17 Patients received either alogliptin, 12.5 mg or 25 mg once daily, or placebo. At week 26, there were statistically significant, placebo-corrected reductions in HgbA1C when either dose of alogliptin was added to glyburide. No clinically meaningful change in weight or exacerbation of hypoglycemic events was observed when alogliptin was added to glyburide.
Alogliptin in combination withpioglitazone In a phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial, the investigators studied the efficacy and safety of alogliptin in combination with pioglitazone (Actos) in patients who were inadequately controlled on pioglitazone alone or pioglitazone in combination with metformin or a sulfonylurea. Patients received alogliptin 12.5 mg or 25 mg once daily, or placebo. At week 26, statistically significant,placebo-corrected reductions inHgbA1C and fasting plasma glucosewere observed when either dose ofalogliptin was added to any of thepioglitazone regimens. With regardto weight, no clinically meaningfuldifference was observed betweenthe alogliptin and placebocohorts.18
Alogliptin in combination with insulin In a phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial, the investigators studied the efficacy and safety of alogliptin in combination with insulin in patients who were inadequately controlled on insulin alone or insulin with metformin.19 Patients received either alogliptin 12.5 mg or 25 mg once daily, or placebo. There were statistically significant reductions in HgbA1C at week 26 with either dose of alogliptin. Those receiving alogliptin 25 mg daily achieved statistically significant, placebo-corrected reductions in fasting plasma glucose at week 26. With regard to weight, no significant weight gain was observed in any group. The addition of alogliptin did not increase the rate at which hypoglycemia was reported.
Clinical implications Based on the aforementioned clinical studies, alogliptin appears to be efficacious and well tolerated when used alone or in combination with metformin, glyburide, pioglitazone, or insulin. Currently available clinical trials used HgbA1C asa surrogate marker for determiningefficacy in the treatment ofdiabetes, and, based on this assessment,alogliptin appears to be asafe and effective treatment for thegrowing patient population withtype 2 diabetes; however, there isconcern regarding the current lackof alogliptin trials demonstratinga reduction in macrovascular andmicrovascular complications in diabeticpatients. Scientific and clinicalcommunities have proposedthat new entities approved for the treatment of diabetes provide a “proven” benefit. At this point in time, alogliptin will fall short of these expectations. Although trials may be in the pipeline to answer these ultimate efficacy questions,when released, alogliptin will not be the much anticipated panacea that diabetes sufferers await. It also likely will not be a first-line option for these patients,as the cost of alogliptin therapy is expected to be substantially more than generically available first-line treatments.
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9. Christopher R, Covington P, Davenport M, et al. Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects. Clin Ther. 2008;30(3):513-527.
10. Covington P, Christopher R, Davenport M, et al. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. Clin Ther. 2008;30(3):499-512.
11. Karim A, Fleck P, Hetman L, et al. Single-dose pharmacokinetics of the dipeptidyl peptidase-4 inhibitor alogliptin in subjects with renal impairment. Presented at: American Diabetes Association 68th Annual Scientific Sessions;June 6–10, 2008; San Francisco, CA. Abstract 538P.
12. Karim A, Fleck P, Dorsey D, et al. Single-dose pharmacokinetics of alogliptin benzoate (SYR-322), a highly selective dipeptidyl peptidase-4 inhibitor, in subjects with moderate hepatic impairment. Presented at: American Collegeof Clinical Pharmacology 36th Annual Meeting; September 9-11, 2007; San Francisco, CA. Abstract 107.
13. Fleck P, Christopher R, Covington P, et al. Efficacy and safety of alogliptin monotherapy in patients with type 2 diabetes. Presented at: American Diabetes Association 68th Annual Scientific Sessions; June 6–10, 2008; San Francisco, CA. Abstract 479P.
14. Hirayama M, Matsuno K, Fujita T. Pharmacokinetics, pharmacodynamics, and tolerability of single and multipledoses of dipetidyl peptidase-4 inhibitor alogliptin in Japanese Healthy Male Subjects. Presented at: American Diabetes Association 68th Annual Scientific Sessions; June 6–10, 2008; San Francisco, CA. Abstract 521P.
15. DeFronzo R, Fleck P, Wilson C, et al. Alogliptin monotherapy improves control in patients with type 2 diabetes. Presented at: American Diabetes Association 68th Annual Scientific Sessions; June 6–10, 2008; San Francisco, CA. Abstract 466P.
16. Nuack M, Ellis G, Wilson C, et al. Efficacy and safety of alogliptin added to metformin therapy in patients with type 2 diabetes. Presented at: American Diabetes Association 68th Annual Scientific Sessions; June 6–10, 2008; San Francisco, CA. Abstract 477P.
17. Pratley R, Kipnes M, Fleck P. et al. Alogliptin added to sulfonylurea therapy in patients with type 2 diabetes reduces HbA1c without increasing hypoglycemia. Presented at: American Diabetes Association 68th Annual Scientifi c Sessions; June 6–10, 2008; San Francisco, CA. Abstract 445P.
18. Efficacy and safety of alogliptin added to pioglitazone therapy in patients with type 2 diabetes. Presented at: American Diabetes Association 68th Annual Scientific Sessions; June 6–10, 2008; San Francisco, CA. Abstract 478P.
19. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1c without increasing weight gain or hypoglycemia. Presented at: American Diabetes Association 68th Annual Scientific Sessions; June 6–10, 2008; San Francisco, CA. Abstract 444P.
