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. 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.
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.
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 inactive forms, 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 analogues (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, following administration of alogliptin, GLP-1 levels will increase, ideally resulting in improved glycemic control. As opposed to older agents, such as sulfonylureas, this novel mechanism would theoretically reduce hypoglycemia by reducing fasting and postprandial hyperglycemia.8
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
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, and alogliptin was generally well tolerated when administered daily over 14 days (dose range, 25-400 mg).10 There were no discontinuations due to adverse events, and no serious adverse events or deaths were reported; in the study, adverse events were spontaneously reported or elicited by open-ended questioning. The incidence of hypoglycemia was also 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
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 inadequately controlled using diet or exercise alone. Patients received alogliptin, 6.25 mg to 100 mg daily, or placebo. There were statistically significant reductions in HgbA1C after 12 weeks of treatment when once-daily doses of 12.5 mg to 100 mg were compared with placebo. After 12 weeks statistically significant reductions in fasting plasma glucose were observed in the dosage range 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, doubleblind, 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 and fasting plasma glucose when either dose of alogliptin was added to metformin. No clinically meaningful change in weight was observed between the alogliptin and placebo cohorts.16
Alogliptin in combination with glyburide
In a phase 3, international, multicenter, randomized, doubleblind, 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 with pioglitazone
In a phase 3, international, multicenter, randomized, doubleblind, 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 in HgbA1C and fasting plasma glucose were observed when either dose of alogliptin was added to any of the pioglitazone regimens. With regard to weight, no clinically meaningful difference was observed between the alogliptin and placebo cohorts.18
Alogliptin in combination with insulin
In a phase 3, international, multicenter, randomized, doubleblind, 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.
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 as a surrogate marker for determining efficacy in the treatment of diabetes, and, based on this assessment, alogliptin appears to be a safe and effective treatment for the growing patient population with type 2 diabetes; however, there is concern regarding the current lack of alogliptin trials demonstrating a reduction in macrovascular and microvascular complications in diabetic patients. Scientific and clinical communities have proposed that 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.