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P T. 2011;36(12): 807-812, 842
Drug Forecast

Efficacy and Safety of Linagliptin (Tradjenta) in Adults With Type-2 Diabetes Mellitus

Maisha Kelly Freeman PharmD, MS, BCPS

INTRODUCTION

Current estimates indicate that diabetes affects approximately 26 million people in the U.S. (8.3% of the population). Almost 19 million people have diabetes, and the disease remains undiagnosed in an estimated 7 million people. Diabetes is associated with significant morbidity, including kidney failure, non-traumatic lower-limb amputations, neuropathies, hypertension, periodontal disease, and blindness. In addition, diabetes is a major risk factor for heart disease and stroke and is the seventh leading cause of death in the U.S.1

Diabetes also incurs a substantial financial burden. In 2007, the estimated total cost (direct costs plus indirect costs) associated with diabetes was $174 billion in the U.S. Direct medical costs totaled $116 billion, and indirect costs accounted for $58 billion.1

The burden of uncontrolled diabetes, in terms of hospitalizations, is also substantial, according to the National Hospital Discharge Survey (NHDS). Based on NHDS data, the total number of hospitalizations in the U.S. was estimated to be 38.8 million in 2004. Approximately 5.2 million admissions had at least one diagnostic code indicating diabetes, and approximately 609,000 admissions were primarily the result of diabetes. Of the latter, approximately 191,181 (31.4%) admissions were due to uncontrolled diabetes. Most of the hospitalizations were categorized as emergencies or urgent. The rates of preventable hospitalizations among Caucasians and African-Americans were 8 and 18 per 100,000 individuals with a diagnosis of diabetes, respectively.2

First-line treatment recommendations for patients with type-2 diabetes often involve lifestyle changes, including exercise, meal planning, and weight loss. Pharmacological interventions are effective and should be combined with lifestyle changes for individuals who are unable to achieve goals for glycemic control despite diet and exercise.

Metformin (Glucophage, Bristol-Myers Squibb), a biguanide, is considered the agent of choice for the treatment of type-2 diabetes and should be included in therapeutic interventions for these patients (unless contraindicated), based on the drug’s proven ability to reduce the risk of diabetes-related or cardiovascular death.3,4

Multiple therapeutic agents are typically required for the optimal management of type-2 diabetes. If metformin is contraindicated or is therapeutically insufficient, the most commonly used second-line oral agents include sulfonylureas, such as glimepiride (Amaryl, sanofi-aventis); meglitinides (glinides), such as repaglinide (Prandin, Novo Nor-disk); and alpha-glucosidase inhibitors, such as acarbose (Precose, Bayer). Insulin therapy may be initiated, but the use of insulin depends on several factors, including blood glucose levels, the duration of the disease, and the medication profile and overall health of the patient. Most antidiabetic agents lower glycosylated hemoglobin (HbA1c) by approximately 0.7% to 2.0%.3

Linagliptin (Tradjenta, Boehringer Ingelheim) is a new dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of type-2 diabetes. The drug received FDA approval in May 2011.5 This article reviews the indication, pharmacology, efficacy, safety, usage, and cost of linagliptin.

INDICATION

Linagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes. This drug should not be used in patients with type-1 diabetes or in those with diabetic ketoacidosis. Linagliptin has not been studied in combination with insulin.6

PHARMACOLOGY

Mechanism of Action

Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This activity, in turn, increases the plasma concentrations of active incretin hormones, thereby stimulating the release of insulin in a glucose-dependent manner and decreasing circulating levels of glucagon. GLP-1 and GIP are involved in the physiological regulation of glucose homeostasis. Both hormones increase the biosynthesis of insulin and its secretion from pancreatic beta cells in the presence of normal or elevated levels of blood glucose. In addition, GLP-1 reduces glucagon secretion from pancreatic alpha-cells, resulting in a reduction in glucose output in the liver.6

The other DPP-4 inhibitors currently available in the U.S.—saxagliptin (Onglyza, Bristol-Myers Squibb) and sitagliptin (Januvia, Merck)—also act by slowing the inactivation of incretin hormones.7,8

Chemical Structure

Although the three FDA-approved DPP-4 inhibitors share a common mechanism of action, each has unique chemical features.9 Linagliptin, for example, has a xanthine-based structure (Figure 1), which may be a key factor in the drug’s long terminal elimination half-life (more than 100 hours).6 The long half-life of linagliptin may be more beneficial for patients who occasionally miss their doses of medication, compared with the substantially shorter half-lives of saxagliptin and sitagliptin (2.5 and 12.4 hours, respectively).7,8

Enzyme Binding

Linagliptin binds tightly, but not irreversibly, to the DPP-4 enzyme. Tightly bound inhibitors are important; once they are attached to the target enzyme, the enzyme’s function remains inhibited even after the free drug has been eliminated from the systemic circulation or removed from the specific site of action. This pharmacological feature may explain linagliptin’s 24-hour inhibition profile.9 In a study of multiple oral doses of linagliptin in men with type-2 diabetes, the 5- and 10-mg doses provided DPP-4 inhibition of more than 80% at 24 hours after dosing.10

Pharmacodynamics

Thomas and colleagues evaluated the in vitro potency and selectivity of linagliptin and compared it with the other DPP-4 inhibitors.11 The relative in vitro potencies of DPP-4 inhibition among the three FDA-approved compounds, expressed as half the minimal inhibitory concentration (IC50), were 1 nM for linagliptin, 19 nM for sitagliptin, and 50 nM for saxagliptin. In addition, linagliptin is 40,000-fold more selective for DPP-4 than for DPP-8 or DPP-9, whereas the corresponding selectivity for sitagliptin and saxagliptin is more than 2,500-fold and less than 100-fold, respectively.9,11,12 Thus, linagliptin selectively inhibits DPP-4 activity, but not DPP-8 or DPP-9 activity, in vitro at concentrations that approximate therapeutic exposures.6

Pharmacokinetics

Several studies have described the pharmacokinetic profile of linagliptin in both healthy subjects and patients with type-2 diabetes.10,1317

After the administration of increasing intravenous (IV) doses of linagliptin in healthy men, the absolute bioavailability of linagliptin 10 mg was found to be approximately 30%.13 Linagliptin showed nonlinear pharmacokinetics after IV infusions of 0.5 to 10 mg. The steady-state volume of distribution increased with dose, from 380 to 1,540 L.

In a study of men with type-2 diabetes who received oral linagliptin (1 mg, 2.5 mg, 5 mg, or 10 mg) once daily for 12 days, the drug’s terminal half-life ranged from 113 to 131 hours for all dosing groups.10 Similar half-lives were reported in the healthy men receiving increasing IV doses of linagliptin (126–139 hours).13

Healthy Japanese men showed elimination half-lives ranging from 96.9 to 175.0 hours after receiving single escalating oral doses of linagliptin (1 mg, 2.5 mg, 5 mg, and 10 mg) once daily for 12 days.17 The labeling for linagliptin states that the drug’s half-life is more than 100 hours.6

The metabolism and disposition of linagliptin were evaluated in healthy subjects who were given the radiolabeled drug orally as 5 mg or intravenously as 10 mg.14 The apparent total clearance of linagliptin was 374 mL/minute, and the mean terminal half-life was 155 hours. The major metabolite of linagliptin (the S-3-hydroxypiperidinyl derivative) accounted for at least 10% of the systemic exposure of the parent compound after oral administration. The half-life of the metabolite was 10.8 hours. Most of the linagliptin dose was eliminated unchanged after both oral and IV administration. Oral linagliptin was eliminated primarily via the fecal route (84.7%). The cytochrome P450 (CYP) 3A4 enzyme was responsible for the metabolism of linagliptin.

Table 1 presents a comparison of the pharmacokinetic characteristics of the three available DPP-4 inhibitors.68,18

KEY CLINICAL STUDIES

Linagliptin has been studied as monotherapy and as combined with metformin, pioglitazone (Actos, Takeda), and a sulfonylurea (e.g., glimepiride). It has not been studied in combination with insulin.6

Monotherapy

A randomized, placebo-controlled phase 3 study evaluated the effect of linagliptin monotherapy on glycemic control and on markers of beta-cell function in patients with inadequately controlled type-2 diabetes.19 A total of 503 patients were randomly assigned to linagliptin 5 mg (n = 336) or placebo (n = 167) once daily. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment.

At 24 weeks, linagliptin significantly reduced HbA1c from baseline compared with placebo (adjusted mean, a decrease of 0.69%; P < 0.0001). In a subgroup of patients with a baseline glycosylated hemoglobin (HbA1c) of 9.0% or higher, the adjusted mean change with linagliptin was 1.01% (P < 0.0001). A reduction in HbA1c of 0.5% or more at 24 weeks occurred more often in the linagliptin group than in the placebo group (47.1% vs. 19.0%, respectively; odds ratio = 4.2; P < 0.0001). Fasting plasma glucose was significantly improved with linagliptin, compared with placebo (–1.3 mmol/L; P < 0.0001). Linagliptin also significantly reduced 2-hour postprandial glucose by 3.2 mmol/L (P < 0.0001).19

Hyperglycemia was the most common adverse event (AE), occurring in 8.6% of the linagliptin group and in 22.8% of the placebo group. The most frequently reported AEs that were more common with linagliptin than with placebo included headache, hypertension, and back pain.19

In another double-blind monotherapy trial, 220 patients with type-2 diabetes were randomly assigned to treatment with linagliptin 5 mg (n = 147) or placebo (n = 73) for 18 weeks.6 Only patients who were ineligible for metformin were recruited for this study.

The mean change from baseline in HbA1c was −0.4% with linagliptin and −0.1% with placebo. Fasting plasma glucose was also reduced with linagliptin compared with placebo (by 0.5 mg/dL). Rescue therapy was required by 12% of the linagliptin group and by 18% of the placebo group.6

Combination Therapy

Add-on Combination Therapy With Metformin

A double-blind, randomized study was conducted to evaluate the efficacy and safety of add-on therapy with linagliptin in patients with type-2 diabetes that was inadequately controlled with metformin (1,500 mg/day or more).20 A total of 701 patients were assigned to receive linagliptin 5 mg once daily (n = 524) or placebo (n = 177), in addition to metformin, for 24 weeks.

Significant reductions in HbA1c (a treatment difference of 64%) and fasting plasma glucose were observed between treatment groups (P < 0.0001). The AE profiles of both treatment groups were similar. No elevations in liver transaminases or creatinine levels were observed. Hypoglycemia was rare (linagliptin, 0.6%; placebo, 2.8%).20

In another study, Forst et al. added linagliptin to ongoing metformin therapy in patients with type-2 diabetes that was inadequately controlled with metformin alone.21 A total of 333 patients were randomly assigned to receive double-blind linagliptin (1 mg, 5 mg, or 10 mg once daily) or placebo, or open-label glimepiride (1–3 mg once daily). The primary endpoint was the change from baseline in HbA1c at week 12 in patients receiving combination therapy compared with those receiving metformin.

Linagliptin doses of 1 mg, 5 mg, and 10 mg provided mean, placebo-corrected reductions in HbA1c of 0.40% (P = 0.01 vs. placebo), 0.73% (P < 0.0001), and 0.67% (P < 0.0001), respectively. Placebo-corrected mean changes in fasting plasma glucose for the three linagliptin doses were −1.1 mmol/L (P = 0.002), −1.9 mmol/L (P < 0.0001), and −1.6 mmol/L (P = 0.0001), respectively.21

The incidence of AEs was similar for all treatment groups. None of the patients in the linagliptin and placebo groups experienced hypoglycemia, whereas hypoglycemia occurred in 5% of the patients receiving glimepiride. Small decreases in mean body weight were observed with the three linagliptin doses (0.15–1.27 kg).21

Taskinen et al. evaluated the safety and efficacy of linagliptin as add-on therapy to metformin in patients with type-2 diabetes with inadequate glycemic control.22 A total of 701 patients receiving metformin (1,500 mg/day or more) were randomly assigned to additional treatment with linagliptin 5 mg (n = 524) or placebo (n = 177) once daily. The primary endpoint was the change from baseline in HbA1c at 24 weeks.

Linagliptin plus metformin provided significant (P < 0.001) changes from baseline versus placebo plus metformin in adjusted mean HbA1c (–0.49% vs. +0.15%, respectively), fasting plasma glucose (–0.59 vs. +0.58 mmol/L), and 2-hour postprandial glucose (–2.7 vs. +1.0 mmol/L).22

Hypoglycemia occurred in three subjects (0.6%) in the linagliptin/metformin group and in five patients (2.8%) in the placebo/metformin group. Body weight did not change significantly from baseline (–0.4 kg) among patients treated with linagliptin.22

Add-on Combination Therapy With Pioglitazone

Gomis et al. conducted a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type-2 diabetes.23 A total of 707 patients were assigned to receive linagliptin 5 mg plus pioglitazone 30 mg once daily (n = 259) or placebo plus pioglitazone 30 mg once daily (n = 130).

The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment.

Among patients receiving the linagliptin/pioglitazone combination, the adjusted mean change from baseline in HbA1c was −1.06%, compared with a mean change of −0.56% among those receiving placebo and pioglitazone (P < 0.0001).

The combination of linagliptin and pioglitazone also provided a significant decrease in fasting plasma glucose levels compared with placebo and pioglitazone (1.8 vs. 1.0 mmol/L, respectively; P < 0.0001). Mild hypoglycemic episodes occurred in 1.2% of the linagliptin/pioglitazone group, compared with 0% in the group receiving the placebo/pioglitazone combination.23

Add-on Combination Therapy With a Sulfonylurea

The labeling for linagliptin includes data from an 18-week, randomized, double-blind, placebo-controlled study that assessed the efficacy of linagliptin in combination with a sulfonylurea in patients with type-2 diabetes.6 Patients receiving sulfonylurea monotherapy or a sulfonylurea plus an additional oral anti-hypertensive agent were as signed to receive the addition of linagliptin 5 mg or placebo, each given once daily. The linagliptin/sulfonylurea group included 158 evaluable patients, and the placebo/sulfonylurea group included 82 evaluable patients.

In combination with a sulfonylurea, linagliptin provided a statistically significant improvement from baseline in HbA1c levels, compared with placebo and a sulfonylurea at 18 weeks (adjusted means, −0.5% vs. −0.1%, respectively; P value not stated). Moreover, the linagliptin/sulfonylurea combination lowered fasting plasma glucose levels by 8.2 mg/dL from baseline, compared with a decrease of 1.8 mg/dL with placebo/sulfonylurea; this difference was not statistically significant.6

Add-on Combination Therapy With Metformin and a Sulfonylurea

The labeling for linagliptin also includes data from a 24-week, randomized, double-blind, placebo-controlled study of linagliptin in combination with a sulfonylurea and metformin in patients with type-2 diabetes.6 The most commonly used sulfonylureas were glimepiride, 31%; glibenclamide, also known as glyburide (Micronase, Pfizer), 26%; and gliclazide (not available in the U.S.), 26%. A total of 1,058 patients receiving a sulfonylurea and metformin were randomly assigned to additional treatment with linagliptin or placebo. The two treatment groups consisted of 778 and 262 evaluable patients, respectively.

The combination of a sulfonylurea, metformin, and linagliptin significantly reduced HbA1c from baseline compared with a sulfonylurea, metformin, and placebo at 24 weeks (0.7% vs. 0.1%, respectively; P value not stated). The addition of linagliptin to a sulfonylurea and metformin also significantly lowered fasting plasma glucose levels from baseline (by 4.6 mg/dL), compared with the addition of placebo (by 8.1 mg/dL; P value not stated).6

Rescue therapy was required by 5.8% of the linagliptin group and by 13.0% of the placebo group. Changes in body weight from baseline did not differ significantly between treatment groups.6

CLINICAL SAFETY

Early safety data for linagliptin were provided by several dose-ranging studies.10,1317 Evaluating the safety and tolerability of linagliptin in healthy male volunteers, Hüttner et al. found that linagliptin was well tolerated up to doses of 600 mg.16 The incidence of drug-related AEs was similar for linagliptin and placebo (30% vs. 31%, respectively). Linagliptin (1, 2.5, 5, or 10 mg) was also well tolerated in a study of men with type-2 diabetes.10 In this study, the rate of AEs was lower for linagliptin than for placebo (54% vs. 75%, respectively), and no serious AEs or hypoglycemic episodes occurred in either treatment group. Similarly, in a study of linagliptin (1–10 mg) in healthy Japanese men, no AEs were considered to be drug-related, and there were no episodes of hypoglycemia.17

The clinical safety of linagliptin has been assessed more than 4,000 patients who had type-2 diabetes.6 In placebo-controlled trials, nasopharyngitis was an AE that occurred in at least 5% of the linagliptin patients (n = 2,566) and more frequently than in the placebo patients (n = 1,183) (5.8% vs. 5.5%, respectively). Other AEs reported in clinical studies of linagliptin included hypersensitivity and myalgia. In the linagliptin clinical trial program, pancreatitis occurred in 8 of 4,687 patients receiving linagliptin and in none of the 1,183 patients receiving placebo.6

Hypoglycemia

Hypoglycemia rarely occurs during treatment with linagliptin. According to the product labeling, the incidence of - hypoglycemia was similar for linagliptin and placebo when linagliptin was administered as monotherapy or in combination with metformin or pioglitazone in placebo-controlled trials.6 In a study of monotherapy with linagliptin (5 mg) in patients with inadequately controlled type-2 diabetes, 0.6% of the linagliptin group and 0.3% of the placebo group experienced hypoglycemic events.19

In another placebo-controlled study of linagliptin monotherapy (1, 5, or 10 mg), no episodes of hypoglycemia were reported in patients with type-2 diabetes.10 In the study of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type-2 diabetes, 1.2% of the active-treatment group experienced hypoglycemia compared with 0% of the placebo group.23 Similarly, the study of linagliptin, when added to metformin, reported no hypoglycemic events for the linagliptin or placebo groups.21

Weight Gain

DPP-4 inhibitors appear have a neutral effect on weight.21,23 Forst et al. reported mean weight loss of 0.15, 0.57, and 1.27 kg with linagliptin 1 mg, 5 mg, and 10 mg, respectively.21 Conversely, in a study by Gomis et al., combination therapy with linagliptin and pioglitazone caused significantly greater weight gain over 24 weeks of treatment compared with placebo plus pioglitazone (+2.3 vs. +1.2 kg, respectively; P = 0.01); however, the changes from baseline were minimal.23 A similar decrease in body weight was observed for linagliptin/metformin versus placebo/metformin in a 24-week study.6 Further, there were no significant differences in body weight between linagliptin plus a sulfonylurea, compared with a placebo plus a sulfonylurea in an 18-week study.6

QT Interval Prolongation

No significant changes in electrocardiographic parameters were observed in clinical studies of linagliptin.17,2123

In a randomized, placebo-controlled, double-blind, four-period crossover study, Ring et al. evaluated the potential for linagliptin to prolong the QT interval at therapeutic and supratherapeutic doses.24 A total of 44 patients were assigned to receive a single dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin (Avelox, Merck) 400 mg, or placebo. Neither the 5-mg dose nor the 100-mg dose of linagliptin increased the QT interval, corrected for heart rate.

Linagliptin was well tolerated, and there were no clinically relevant electrocardiographic (ECG) changes or relevant changes in other safety parameters.

CONTRAINDICATIONS

Linagliptin should not be prescribed for patients with a history of a hypersensitivity reaction to this drug, such as urticaria, angioedema, or bronchial hyperreactivity.6

DOSAGE AND ADMINISTRATION

The recommended dosage of linagliptin is 5 mg once daily.6 The tablets may be taken with or without food.6 No dosage adjustments are necessary for patients with renal or hepatic impairment.6,25

Dosing schedules for the three available DPP-4 inhibitors are presented in Table 2.68

DRUG INTERACTIONS

The efficacy of linagliptin may be reduced when the drug is coadministered with a strong CYP3A4 or P-glycoprotein inducer (e.g., rifampin). Therefore, the use of alternative treatments is strongly recommended.6 Sulfonylureas should be used with caution during treatment with linagliptin.26

The pharmacokinetic characteristics of linagliptin were not altered by the concomitant administration of simvastatin (Zocor, Merck), digoxin (Lanoxin, Glaxo-SmithKline), glyburide, warfarin (Coumadin), metformin, or pioglitazone.2732

COST

The average wholesale price (AWP) of linagliptin is $8.12 per tablet; therefore, the estimated cost of a 30-day supply is $243.60. The AWP of a 30-day supply of sitagliptin or saxagliptin is similar to that of linagliptin.33

P&T COMMITTEE CONSIDERATIONS

Linagliptin is the latest DPP-4 inhibitor to be approved for the treatment of type-2 diabetes. It provides prolonged inhibition of the DPP-4 enzyme (more than 80% at 24 hours after dosing).10 However, the clinical effect of such prolonged inhibition is unknown.

Linagliptin is associated with only moderate reductions in HbA1c (by 0.4% and 0.69% in pivotal clinical studies)6,19 and is more suitable as add-on combination therapy than as single-agent treatment. The HbA1c reductions noted with linagliptin monotherapy are similar to those observed with saxagliptin and sitagliptin.7,8

Unlike saxagliptin and sitagliptin, linagliptin does not necessitate dosage adjustments in patients with renal impairment. Moreover, dosage adjustments with linagliptin and saxagliptin are not required in hepatic impairment, but they are necessary for sitagliptin. Because the dosage of linagliptin does not need to be adjusted in patients with renal or hepatic dysfunction, only one dosage strength is required in the health care setting. Theoretically, this should result in fewer medication errors, which could otherwise occur when a drug is available in several different strengths.

Linagliptin’s potential for drug–drug interactions with strong CYP3A4 and P-glycoprotein inducers may limit its clinical use. The current product labeling, however, does not include recommendations for adjusting the dosage when linagliptin is taken with strong CYP3A4 or P-glycoprotein inducers.6

Like the other DPP-4 inhibitors, linagliptin is a Pregnancy Category B drug, and it should be used during pregnancy only if it is clearly needed. The safety and effectiveness of linagliptin have not been established in patients 18 years of age and younger.6 The long-term safety of the currently available DPP-4 inhibitors has not been determined.

CONCLUSION

Diabetes is associated with significant morbidity and mortality, and some patients might not be able to achieve glycemic control despite appropriate diet and exercise. Linagliptin, a new DPP-4 inhibitor, offers another option for the treatment of inadequately controlled type-2 diabetes in patients who are already receiving metformin or a sulfonylurea.

Linagliptin lowers HbA1c values by 0.4% to 0.7% as monotherapy or in combination with metformin, a sulfonylurea, or pioglitazone. This decrease is similar to the reductions observed with sitagliptin and saxagliptin. The reductions in HbA1c achieved with linagliptin, however, are less than those achieved with metformin, a sulfonylurea, or pioglitazone.

Dosage adjustments for renal or hepatic impairment are not necessary with linagliptin. In addition, linagliptin has a long half-life (above 100 hours), which results in a 24-hour DPP-4 inhibition profile. Hypoglycemia rarely develops in patients with type-2 diabetes during treatment with linagliptin, and the drug has a neutral effect on weight. No clinically significant drug interactions were observed when linagliptin was coadministered with warfarin, digoxin, or simvastatin.

Additional clinical trials are needed to further delineate the clinical profile of linagliptin in combination therapy. The drug may be an appropriate option, however, in patients who are being treated with metformin or a sulfonylurea, in those who require glycemic control, or in those who desire a weight-neutral agent. Linagliptin can also be used in patients with renal or hepatic impairment.

Figure and Tables

Chemical structure of linagliptin. (From package insert.6)

Key Pharmacokinetic Characteristics of the DPP-4 Inhibitors

Linagliptin Saxagliptin Sitagliptin
Brand name Tradjenta Onglyza Januvia
Bioavailability 30% Data not available (50%–75% in animals)18 Approximately 87%
Cmax 1.5 hours Saxagliptin: 2 hours;
5-hydroxy saxagliptin: 4 hours
1–4 hours
Protein binding 70%–80%; concentration-dependent Negligible 38%
Half-life Therapeutic: approximately 12 hours; terminal (DPP-4 saturable binding): 100 hours Saxagliptin: 2.5 hours;
5-hydroxy saxagliptin: 3.1 hours
12 hours
Metabolism Not extensively metabolized Hepatic via CYP3A4/5 to 5-hydroxy saxagliptin (active; approximately half the potency of parent compound) Not extensively metabolized; minor metabolism via CYP3A4 and CYP2C8 to metabolites (inactive) suggested by in vitro studies
CYP 450 enzyme involvement CYP3A4 inhibitor (moderate), P-glycoprotein Substrate of CYP3A4 (major), P-glycoprotein Substrate of CYP2C8 (minor), CYP3A4 (minor), P-glycoprotein
Elimination Feces: 80% unchanged;
urine: 5% unchanged
Urine: 75% (24% of total dose as saxagliptin, 36% of total dose as 5-hydroxy saxagliptin); feces: 22% Urine: 87% (79% as unchanged drug; 16% as metabolites); feces: 13%

Cmax = maximum plasma concentration; CYP = cytochrome P450.

From linagliptin, saxagliptin, and sitagliptin package inserts;68 and Fura et al. Drug Metab Dispos 2009;37:1164–1171.18

Comparative Dosing Schedules of the DPP-4 Inhibitors

Linagliptin Saxagliptin Sitagliptin
Brand name Tradjenta Onglyza Januvia
Dose 5 mg
  • 2.5–5 mg
  • Concomitant use with strong CYP3A4/5 inhibitor: 2.5 mg
  • Concomitant use with insulin secretagogue: reduced dose of secretagogue may be required
100 mg
Frequency Once daily Once daily Once daily
Food May be administered with or without food May be administered with or without food May be administered with or without food
Renal impairment No dosage adjustment required
  • CrCl > 50 mL/minute: no dosage adjustment required
  • CrCl ≤ 50 mL/minute: 2.5 mg once daily
  • ESRD requiring hemodialysis: 2.5 mg once daily, administered after dialysis
  • Peritoneal dialysis: not studied
  • CrCl ≥ 50 mL/minute: no dosage adjustment required
  • CrCl ≥ 30 to < 50 mL/minute: 50 mg once daily
  • SCr: men > 1.7 to ≤ 3.0 mg/dL and women > 1.5 to ≤ 2.5 mg/dL: 50 mg once daily
  • CrCl < 30 mL/minute: 25 mg once daily
  • Scr: men > 3.0 mg/dL and women > 2.5 mg/dL: 25 mg once daily
  • ESRD requiring hemodialysis or peritoneal dialysis: 25 mg once daily, administered without regard to timing of hemodialysis
Hepatic impairment No dosage adjustment required No dosage adjustment required
  • Mild-to-moderate impairment (Child–Pugh score, 7–9): no dosage adjustment required
  • Severe impairment (Child–Pugh score > 9): not studied

CrCl = creatinine clearance; CYP = cytochrome P450; ESRD = end-stage renal disease; Scr = serum creatinine.

From linagliptin, saxagliptin, and sitagliptin package inserts.68

References

  1. 2011 National Diabetes Fact Sheet. Available at: www.cdc.gov/diabetes/pubs/factsheet11.htm. Accessed July 2, 2011.
  2. Kim S. Burden of hospitalizations primarily due to uncontrolled diabetes: Implications of inadequate primary health care in the United States. Diabetes Care 2007;30:1281–1282.
  3. Executive summary: Standards of medical care in diabetes, 2011. Diabetes Care 2011;34;(Suppl 1):S11–S61.
  4. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type-2 diabetes mellitus: Progressive requirement for multiple therapies (UKPDS 49). JAMA 1999;281:2005–2012.
  5. FDA. FDA approves new treatment for type-2 diabetes. May 22011;Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm253501.htm. Accessed August 15, 2011.
  6. Tradjenta (linagliptin), package insert Ridgefield, Conn.: Boehringer Ingelheim. July 2011;Available at: http://bidocs.boehringer-ingelheim.com. Accessed July 1, 2011.
  7. Onglyza (saxagliptin), package insert Princeton, N.J.: Bristol-Myers Squibb. February 2011;Available at: http://pack-ageinserts.bms.com/pi/pi_onglyza.pdf. Accessed May 31, 2011.
  8. Januvia (sitagliptin), package insert Whitehouse Station, N.J.: Merck. April 2011;Available at: www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf. Accessed May 31, 2011.
  9. Gerich J. DPP-4 inhibitors: What may be the clinical differentiators?. Diabetes Res Clin Pract 2010;90:131–140.
  10. Heise T, Graefe-Mody EU, Huttner S, et al. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor, in male type-2 diabetes patients. Diabetes Obesity Metab 2009;11:786–794.
  11. Thomas L, Eckhardt M, Langkopf E, et al. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther 2008;325:175–182.
  12. Deacon CF, Holst JJ. Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor with an unusual profile for the treatment of type-2 diabetes. Exp Opin Invest Drugs 2010;19:133–140.
  13. Retlich S, Duval V, Ring A, et al. Pharmacokinetics and pharmacodynamics of single rising intravenous doses (0.5 mg–10 mg) and determination of absolute bioavailability of dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) in healthy male subjects. Clin Pharmacokinet 2010;49:829–840.
  14. Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, et al. The metabolism and disposition of oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos 2010;38:667–678.
  15. Retlich R, Duval V, Graefe-Mody U, et al. Impact of target-mediated drug disposition on linagliptin pharmacokinetics and DPP-4 inhibition in type-2 diabetic patients. J Clin Pharmacol 2010;50:873–885.
  16. Hüttner S, Graefe-Mody EU, Withopf B, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of B1 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers. J Clin Pharmacol 2008;48:1171–1178.
  17. Sarashina A, Sesoko S, Nakashima M, et al. Linagliptin, a dipeptidyl peptidase-4 inhibitor in development for the treatment of type-2 diabetes mellitus: A phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male Japanese subjects. Clin Ther 2010;32:1188–1204.
  18. Fura A, Khanna A, Vyas V, et al. Pharmacokinetics of the dipeptidyl peptidase 4 inhibitor saxagliptin in rats, dogs, and monkeys and clinical projections. Drug Metab Dispos 2009;37:1164–1171.
  19. Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type-2 diabetes: A randomized controlled trial. Diabetes Obesity Metab 2011;13:258–267.
  20. Rendell M, Chrysant SG. Review of the safety and efficacy of linagliptin as add-on therapy to metformin in patients with type-2 diabetes: A randomized, double-blind, placebo-controlled study. Postgrad Med 2011;123:183–186.
  21. Forst T, Uhlig-Laske B, Ring A, et al. Linagliptin (BI 1256), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled type-2 diabetes. Diabetic Med 2010;27:1409–1419.
  22. Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type-2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obesity Metab 2011;13:65–74.
  23. Gomis R, Espadero RM, Jones R, et al. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type-2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obesity Metab 2011;13:653–661.
  24. Ring A, Port A, Graefe-Mody EU, et al. The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses. Br J Clin Pharmacol 2011;72:39–50.
  25. Graefe-Mody U, Friedrich C, Port A, et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obesity Metab 2011;13;(10):939–946.
  26. Drug interactions between glipizide XL and linagliptin Available at: www.drugs.com/drug-interactions/glipizide-xl-with-linagliptin-1179-3473-3322-0.html. Accessed October 12, 2011.
  27. Graefe-Mody U, Rose P, Ring A, et al. Assessment of the pharmacokinetic interaction between the novel DPP-4 inhibitor linagliptin and a sulfonylurea, glyburide, in healthy subjects. Drug Metab Pharmacokinet 2011;26:123–129.
  28. Scheen AJ. Dipeptidylpeptidase-4 inhibitors (gliptins): Focus on drug–drug interactions. Clin Pharmacokinet 2010;49:573–588.
  29. Graefe-Mody EU, Padula S, Ring A, et al. Evaluation of the potential for steady-state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects. Curr Med Res Opin 2009;25:1963–1972.
  30. Graefe-Mody EU, Brand T, Ring A, et al. Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. Int J Clin Pharmacol Ther 2011;49:300–310.
  31. Friedrich C, Ring A, Brand T, et al. Evaluation of the pharmacokinetic interaction after multiple oral doses of linagliptin and digoxin in healthy volunteers. Eur J Drug Metab Pharmacokinet 2011;36:17–24.
  32. Graefe-Mody U, Huettner S, Stähle H, et al. Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin. Int J Clin Pharmacol Ther 2010;48:367–374.
  33. Red Book Online via Micromedex. Available at: www.thomsonhc.com and www.redbook.com. Accessed July 2, 2011.