Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Takeda Pharma A/S, Delta Park 45, 2665 Vallensbaek Strand, Denmark medinfoEMEA@takeda.com
Pharmacotherapeutic group: Drugs used in diabetes; dipeptidyl peptidase 4 (DPP-4) inhibitors
ATC code: A10BH04
Alogliptin is a potent and highly selective inhibitor of DPP-4, >10,000-fold more selective for DPP-4 than other related enzymes including DPP-8 and DPP-9. DPP-4 is the principal enzyme involved in the rapid degradation of the incretin hormones, glucagon-like peptide-1 (GLP-1) and GIP (glucose-dependent insulinotropic polypeptide), which are released by the intestine and levels are increased in response to a meal. GLP-1 and GIP increases insulin biosynthesis and secretion from pancreatic beta cells, while GLP-1 also inhibits glucagon secretion and hepatic glucose production. Alogliptin therefore improves glycaemic control via a glucose-dependent mechanism, whereby insulin release is enhanced and glucagon levels are suppressed when glucose levels are high.
Alogliptin has been studied as monotherapy, as initial combination therapy with metformin or a thiazolidinedione, and as add-on therapy to metformin, or a sulphonylurea, or a thiazolidinedione (with or without metformin or a sulphonylurea), or insulin (with or without metformin).
Administration of 25 mg alogliptin to patients with type 2 diabetes mellitus produced peak inhibition of DPP-4 within 1 to 2 hours and exceeded 93% both after a single 25 mg dose and after 14 days of once-daily dosing. Inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing. When the 4-hour postprandial glucose concentrations were averaged across breakfast, lunch and dinner, 14 days of treatment with 25 mg alogliptin resulted in a mean placebo-corrected reduction from baseline of -35.2 mg/dL.
Both 25 mg alogliptin alone and in combination with 30 mg pioglitazone demonstrated significant decreases in postprandial glucose and postprandial glucagon whilst significantly increasing postprandial active GLP-1 levels at Week 16 compared to placebo (p<0.05). In addition, 25 mg alogliptin alone and in combination with 30 mg pioglitazone produced statistically significant (p<0.001) reductions in total triglycerides at Week 16 as measured by postprandial incremental AUC(0-8) change from baseline compared to placebo.
A total of 14,779 patients with type 2 diabetes mellitus, including 6,448 patients treated with 25 mg alogliptin and 2,476 patients treated with 12.5 mg alogliptin, participated in one phase 2 or 13 phase 3 (including the cardiovascular outcomes study) double-blind, placebo- or active-controlled clinical studies conducted to evaluate the effects of alogliptin on glycaemic control and its safety. In these studies, 2,257 alogliptin-treated patients were ≥65 years old and 386 alogliptin-treated patients were ≥75 years old. The studies included 5,744 patients with mild renal impairment, 1,290 patients with moderate renal impairment and 82 patients with severe renal impairment/end-stage renal disease treated with alogliptin.
Overall, treatment with the recommended daily dose of 25 mg alogliptin improved glycaemic control when given as monotherapy and as initial or add-on combination therapy. This was determined by clinically relevant and statistically significant reductions in glycosylated haemoglobin (HbA1c) and fasting plasma glucose compared to control from baseline to study endpoint. Reductions in HbA1c were similar across different subgroups including renal impairment, age, gender and body mass index, while differences between races (e.g. White and non-White) were small. Clinically meaningful reductions in HbA1c compared to control were also observed with 25 mg alogliptin regardless of baseline background treatment. Higher baseline HbA1c was associated with a greater reduction in HbA1c. Generally, the effects of alogliptin on body weight and lipids were neutral.
Treatment with 25 mg alogliptin once daily resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose compared to placebo-control at Week 26 (Table 2).
The addition of 25 mg alogliptin once daily to metformin hydrochloride therapy (mean dose = 1,847 mg) resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose at Week 26 when compared to the addition of placebo (Table 2). Significantly more patients receiving 25 mg alogliptin (44.4%) achieved target HbA1c levels of ≤7.0% compared to those receiving placebo (18.3%) at Week 26 (p<0.001).
The addition of 25 mg alogliptin once daily to metformin hydrochloride therapy (mean dose = 1,835 mg) resulted in improvements from baseline in HbA1c at Week 52 and Week 104. At Week 52, the HbA1c reduction by 25 mg alogliptin plus metformin (-0.76%, Table 3) was similar to that produced by glipizide (mean dose = 5.2 mg) plus metformin hydrochloride therapy (mean dose = 1,824 mg, -0.73%). At Week 104, the HbA1c reduction by 25 mg alogliptin plus metformin (-0.72%, Table 3) was greater than that produced by glipizide plus metformin (-0.59%). Mean change from baseline in fasting plasma glucose at Week 52 for 25 mg alogliptin and metformin was significantly greater than that for glipizide and metformin (p<0.001). By Week 104, mean change from baseline in fasting plasma glucose for 25 mg alogliptin and metformin was -3.2 mg/dL compared with 5.4 mg/dL for glipizide and metformin. More patients receiving 25 mg alogliptin and metformin (48.5%) achieved target HbA1c levels of ≤7.0% compared to those receiving glipizide and metformin (42.8%) (p=0.004).
The addition of 25 mg alogliptin once daily to glyburide therapy (mean dose = 12.2 mg) resulted in statistically significant improvements from baseline in HbA1c at Week 26 when compared to the addition of placebo (Table 2). Mean change from baseline in fasting plasma glucose at Week 26 for 25 mg alogliptin showed a reduction of 8.4 mg/dL compared to an increase of 2.2 mg/dL with placebo. Significantly more patients receiving 25 mg alogliptin (34.8%) achieved target HbA1c levels of ≤7.0% compared to those receiving placebo (18.2%) at Week 26 (p=0.002).
The addition of 25 mg alogliptin once daily to pioglitazone therapy (mean dose = 35.0 mg, with or without metformin or a sulphonylurea) resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose at Week 26 when compared to the addition of placebo (Table 2). Clinically meaningful reductions in HbA1c compared to placebo were also observed with 25 mg alogliptin regardless of whether patients were receiving concomitant metformin or sulphonylurea therapy. Significantly more patients receiving 25 mg alogliptin (49.2%) achieved target HbA1c levels of ≤7.0% compared to those receiving placebo (34.0%) at Week 26 (p=0.004).
The addition of 25 mg alogliptin once daily to 30 mg pioglitazone and metformin hydrochloride therapy (mean dose = 1,867.9 mg) resulted in improvements from baseline in HbA1c at Week 52 that were both non-inferior and statistically superior to those produced by 45 mg pioglitazone and metformin hydrochloride therapy (mean dose = 1,847.6 mg, Table 3). The significant reductions in HbA1c observed with 25 mg alogliptin plus 30 mg pioglitazone and metformin were consistent over the entire 52-week treatment period compared to 45 mg pioglitazone and metformin (p<0.001 at all time points). In addition, mean change from baseline in fasting plasma glucose at Week 52 for 25 mg alogliptin plus 30 mg pioglitazone and metformin was significantly greater than that for 45 mg pioglitazone and metformin (p<0.001). Significantly more patients receiving 25 mg alogliptin plus 30 mg pioglitazone and metformin (33.2%) achieved target HbA1c levels of ≤7.0% compared to those receiving 45 mg pioglitazone and metformin (21.3%) at Week 52 (p<0.001).
The addition of 25 mg alogliptin once daily to insulin therapy (mean dose = 56.5 IU, with or without metformin) resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose at Week 26 when compared to the addition of placebo (Table 2). Clinically meaningful reductions in HbA1c compared to placebo were also observed with 25 mg alogliptin regardless of whether patients were receiving concomitant metformin therapy. More patients receiving 25 mg alogliptin (7.8%) achieved target HbA1c levels of ≤7.0% compared to those receiving placebo (0.8%) at Week 26.
Table 2. Change in HbA1c (%) from baseline with alogliptin 25 mg at Week 26 by placebo-controlled study (FAS, LOCF):
| Study | Mean baseline HbA1c (%) (SD) | Mean change from baseline in HbA1c (%)† (SE) | Placebo-corrected change from baseline in HbA1c ()† (2-sided 95 CI) |
|---|---|---|---|
| Monotherapy placebo-controlled study | |||
| Alogliptin 25 mg once daily (n=128) | 7.91 (0.788) | -0.59 (0.066) | -0.57* (-0.80, -0.35) |
| Add-on combination therapy placebo-controlled studies | |||
| Alogliptin 25 mg once daily with metformin (n=203) | 7.93 (0.799) | -0.59 (0.054) | -0.48* (-0.67, -0.30) |
| Alogliptin 25 mg once daily with a sulphonylurea (n=197) | 8.09 (0.898) | -0.52 (0.058) | -0.53* (-0.73, -0.33) |
| Alogliptin 25 mg once daily with a thiazolidinedione ± metformin or a sulphonylurea (n=195) | 8.01 (0.837) | -0.80 (0.056) | -0.61* (-0.80, -0.41) |
| Alogliptin 25 mg once daily with insulin + metformin (n=126) | 9.27 (1.127) | -0.71 (0.078) | -0.59* (-0.80, -0.37) |
FAS = full analysis set
LOCF = last observation carried forward
† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline values
* p<0.001 compared to placebo or placebo+combination treatment
Table 3. Change in HbA1c (%) from baseline with alogliptin 25 mg by active-controlled study (PPS, LOCF):
| Study | Mean baseline HbA1c (%) (SD) | Mean change from baseline in HbA1c (%)† (SE) | Treatment-corrected change from baseline in HbA1c (%)† (1-sided CI) |
|---|---|---|---|
| Add-on combination therapy studies | |||
| Alogliptin 25 mg once daily with metformin vs a sulphonylurea + metformin | |||
| Change at Week 52 (n=382) | 7.61 (0.526) | -0.76 (0.027) | -0.03 (-infinity, 0.059) |
| Change at Week 104 (n=382) | 7.61 (0.526) | -0.72 (0.037) | -0.13* (-infinity, -0.006) |
| Alogliptin 25 mg once daily with a thiazolidinedione + metformin vs a titrating thiazolidinedione + metformin | |||
| Change at Week 26 (n=303) | 8.25 (0.820) | -0.89 (0.042) | -0.47* (-infinity, -0.35) |
| Change at Week 52 (n=303) | 8.25 (0.820) | -0.70 (0.048) | -0.42* (-infinity, -0.28) |
PPS = per protocol set
LOCF = last observation carried forward
* Non inferiority and superiority statistically demonstrated
† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline values
The efficacy and safety of the recommended doses of alogliptin were investigated separately in a subgroup of patients with type 2 diabetes mellitus and severe renal impairment/end-stage renal disease in a placebo-controlled study (59 patients on alogliptin and 56 patients on placebo for 6 months) and found to be consistent with the profile obtained in patients with normal renal function.
The efficacy of alogliptin in patients with type 2 diabetes mellitus and ≥ 65 years old across a pooled analysis of five 26-week placebo-controlled studies was consistent with that in patients <65 years old.
In addition, treatment with 25 mg alogliptin once daily resulted in improvements from baseline in HbA1c at Week 52 that were similar to those produced by glipizide (mean dose = 5.4 mg). Importantly, despite alogliptin and glipizide having similar HbA1c and fasting plasma glucose changes from baseline, episodes of hypoglycaemia were notably less frequent in patients receiving 25 mg alogliptin (5.4%) compared to those receiving glipizide (26.0%).
In a pooled analysis of the data from 13 studies, the overall incidences of cardiovascular death, non fatal myocardial infarction and non-fatal stroke were comparable in patients treated with 25 mg alogliptin, active control or placebo.
In addition, a prospective randomised cardiovascular outcomes safety study was conducted with 5,380 patients with high underlying cardiovascular risk to examine the effect of alogliptin compared with placebo (when added to standard of care) on major adverse cardiovascular events (MACE) including time to the first occurrence of any event in the composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke in patients with a recent (15 to 90 days) acute coronary event. At baseline, patients had a mean age of 61 years, mean duration of diabetes of 9.2 years, and mean HbA1c of 8.0%.
The study demonstrated that alogliptin did not increase the risk of having a MACE compared to placebo [Hazard Ratio: 0.96; 1-sided 99% Confidence Interval: 0-1.16]. In the alogliptin group, 11.3% of patients experienced a MACE compared to 11.8% of patients in the placebo group.
Table 4. MACE Reported in cardiovascular outcomes study:
| Number of Patients (%) | ||
|---|---|---|
| Alogliptin 25 mg | Placebo | |
| N=2,701 | N=2,679 | |
| Primary Composite Endpoint [First Event of CV Death, Nonfatal MI and Nonfatal Stroke] | 305 (11.3) | 316 (11.8) |
| Cardiovascular Death* | 89 (3.3) | 111 (4.1) |
| Nonfatal Myocardial Infarction | 187 (6.9) | 173 (6.5) |
| Nonfatal Stroke | 29 (1.1) | 32 (1.2) |
* Overall there were 153 subjects (5.7%) in the alogliptin group and 173 subjects (6.5%) in the placebo group who died (all-cause mortality).
There were 703 patients who experienced an event within the secondary MACE composite endpoint (first event of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and urgent revascularization due to unstable angina). In the alogliptin group, 12.7% (344 subjects) experienced an event within the secondary MACE composite endpoint, compared with 13.4% (359 subjects) in the placebo group [Hazard Ratio = 0.95; 1-sided 99% Confidence Interval: 0-1.14].
In a pooled analysis of the data from 12 studies, the overall incidence of any episode of hypoglycaemia was lower in patients treated with 25 mg alogliptin than in patients treated with 12.5 mg alogliptin, active control or placebo (3.6%, 4.6%, 12.9% and 6.2%, respectively). The majority of these episodes were mild to moderate in intensity. The overall incidence of episodes of severe hypoglycaemia was comparable in patients treated with 25 mg alogliptin or 12.5 mg alogliptin, and lower than the incidence in patients treated with active control or placebo (0.1%, 0.1%, 0.4% and 0.4%, respectively). In the prospective randomised controlled cardiovascular outcomes study, investigator reported events of hypoglycemia were similar in patients receiving placebo (6.5%) and patients receiving alogliptin (6.7%) in addition to standard of care.
In a clinical study of alogliptin as mono-therapy, the incidence of hypoglycaemia was similar to that of placebo, and lower than placebo in another study as add-on to a sulphonylurea.
Higher rates of hypoglycaemia were observed with triple therapy with thiazolidinedione and metformin and in combination with insulin, as observed with other DPP-4 inhibitors.
Patients (≥65 years old) with type 2 diabetes mellitus are considered more susceptible to episodes of hypoglycaemia than patients <65 years old. In a pooled analysis of the data from 12 studies, the overall incidence of any episode of hypoglycaemia was similar in patients ≥65 years old treated with 25 mg alogliptin (3.8%) to that in patients <65 years old (3.6%).
A double-blind, randomized, placebo-controlled, multinational (6 countries, 37 sites), study was conducted in paediatric patients (10 to 17 years old) with type 2 diabetes mellitus with insufficient glycemic control, despite dietary treatment and/or exercise therapy, with or without metformin and/or insulin background therapy. A total of 151 patients (including 27 without background therapy, 124 with metformin and/or insulin therapy) were randomized 1:1 and received treatment with either alogliptin 25 mg (n=75) or placebo (n=76) once daily. No statistically significant difference was observed between treatment with 25 mg alogliptin compared with placebo for the primary efficacy endpoint of HbA1c change from Baseline to Week 26 among subjects for the Full Analysis Set (FAS) or Per Protocol Set (PPS), the sensitivity analysis of the FAS, or any subgroups including the patients without background antidiabetic therapy and patients on background therapy of metformin and/or insulin. Similar results were observed for the secondary endpoints of HbA1c change from Baseline at Weeks 12, 18, 39, and 52 among subjects in the FAS and the PPS.
The results of this study are presented in Table 5.
Table 5. HbA1c Change from Baseline at Week 26 in Pediatric Patients (10-17 years) with Type 2 Diabetes Mellitus Administered Alogliptin 25 mg or Placebo once daily:
| Treatment Group | HbA1c (%)* | Difference in HbA1c (%) Alogliptin vs. Placebo* |
|---|---|---|
| alogliptin 25 mg | 0.091 ± 0.288 (n=54) | 0.102 [-0.627, 0.831] |
| Placebo | -0.011 ± 0.281 (n=56) |
* Least squares mean ± S.E.
[ ] shows two-sided 95% confidence interval
S.E. = Standard Error
The pharmacokinetics of alogliptin has been shown to be similar in healthy subjects and in patients with type 2 diabetes mellitus.
The absolute bioavailability of alogliptin is approximately 100%.
Administration with a high-fat meal resulted in no change in total and peak exposure to alogliptin. Vipidia may, therefore, be administered with or without food.
After administration of single, oral doses of up to 800 mg in healthy subjects, alogliptin was rapidly absorbed with peak plasma concentrations occurring 1 to 2 hours (median Tmax) after dosing.
No clinically relevant accumulation after multiple dosing was observed in either healthy subjects or in patients with type 2 diabetes mellitus.
Total and peak exposure to alogliptin increased proportionately across single doses of 6.25 mg up to 100 mg alogliptin (covering the therapeutic dose range). The inter-subject coefficient of variation for alogliptin AUC was small (17%).
Following a single intravenous dose of 12.5 mg alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L indicating that the active substance is well distributed into tissues.
Alogliptin is 20-30% bound to plasma proteins.
Alogliptin does not undergo extensive metabolism, 60-70% of the dose is excreted as unchanged active substance in the urine. Two minor metabolites were detected following administration of an oral dose of [14C] alogliptin, N-demethylated alogliptin, M-I (<1% of the parent compound), and N-acetylated alogliptin, M-II (<6% of the parent compound). M-I is an active metabolite and is a highly selective inhibitor of DPP-4 similar to alogliptin; M-II does not display any inhibitory activity towards DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin.
In vitro studies indicate that alogliptin does not induce CYP1A2, CYP2B6 and CYP2C9 and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 at concentrations achieved with the recommended dose of 25 mg alogliptin. Studies in vitro have shown alogliptin to be a mild inducer of CYP3A4, but alogliptin has not been shown to induce CYP3A4 in studies in vivo.
In studies in vitro, alogliptin was not an inhibitor of the following renal transporters; OAT1, OAT3 and OCT2.
Alogliptin exists predominantly as the (R)-enantiomer (>99%) and undergoes little or no chiral conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at therapeutic doses.
Alogliptin was eliminated with a mean terminal half-life (T1/2) of approximately 21 hours.
Following administration of an oral dose of [14C] alogliptin, 76% of total radioactivity was eliminated in the urine and 13% was recovered in the faeces.
The average renal clearance of alogliptin (170 mL/min) was greater than the average estimated glomerular filtration rate (approx. 120 mL/min), suggesting some active renal excretion.
Total exposure (AUC(0-inf)) to alogliptin following administration of a single dose was similar to exposure during one dose interval (AUC(0-24)) after 6 days of once daily dosing. This indicates no time-dependency in the kinetics of alogliptin after multiple dosing.
A single-dose of 50 mg alogliptin was administered to 4 groups of patients with varying degrees of renal impairment (CrCl using the Cockcroft-Gault formula): mild (CrCl = >50 to ≤80 mL/min), moderate (CrCl = ≥30 to ≤50 mL/min), severe (CrCl = <30 mL/min) and end-stage renal disease on haemodialysis.
An approximate 1.7-fold increase in AUC for alogliptin was observed in patients with mild renal impairment. However, as the distribution of AUC values for alogliptin in these patients was within the same range as control subjects, no dose adjustment for patients with mild renal impairment is necessary (see section 4.2).
In patients with moderate or severe renal impairment, or end-stage renal disease on haemodialysis, an increase in systemic exposure to alogliptin of approximately 2- and 4-fold was observed, respectively. (Patients with end-stage renal disease underwent haemodialysis immediately after alogliptin dosing. Based on mean dialysate concentrations, approximately 7% of the active substance was removed during a 3-hour haemodialysis session.) Therefore, in order to maintain systemic exposures to alogliptin that are similar to those observed in patients with normal renal function, lower doses of alogliptin should be used in patients with moderate or severe renal impairment, or end-stage renal disease requiring dialysis (see section 4.2).
Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment compared to healthy control subjects. The magnitude of these reductions was not considered to be clinically relevant. Therefore, no dose adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh scores of 5 to 9). Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh score >9, see section 4.2).
Age (65-81 years old), gender, race (white, black and Asian) and body weight did not have any clinically relevant effect on the pharmacokinetics of alogliptin. No dose adjustment is necessary (see section 4.2).
The pharmacokinetics of alogliptin following oral doses of alogliptin benzoate were evaluated in children with type 2 diabetes mellitus aged 10 to 17 years. Based on the population pharmacokinetic analysis, the mean paediatric exposures were modestly lower i.e. less than 25% difference with AUCτ and Cmax of adult exposures following multiple daily 25 mg doses (see section 4.2). The body weight range was from 54.5 to 195 kg in children and from 71.7 to 130 kg in adults.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and toxicology.
The no-observed-adverse-effect level (NOAEL) in the repeated dose toxicity studies in rats and dogs up to 26 and 39 weeks in duration, respectively, produced exposure margins that were approximately 147- and 227-fold, respectively, the exposure in humans at the recommended dose of 25 mg alogliptin.
Alogliptin was not genotoxic in a standard battery of in vitro and in vivo genotoxicity studies.
Alogliptin was not carcinogenic in 2-year carcinogenicity studies conducted in rats and mice. Minimal to mild simple transitional cell hyperplasia was seen in the urinary bladder of male rats at the lowest dose used (27 times the human exposure) without establishment of a clear NOEL (no observed effect level).
No adverse effects of alogliptin were observed upon fertility, reproductive performance, or early embryonic development in rats up to a systemic exposure far above the human exposure at the recommended dose. Although fertility was not affected, a slight, statistical increase in the number of abnormal sperm was observed in males at an exposure far above the human exposure at the recommended dose.
Placental transfer of alogliptin occurs in rats.
Alogliptin was not teratogenic in rats or rabbits with a systemic exposure at the NOAELs far above the human exposure at the recommended dose. Higher doses of alogliptin were not teratogenic but resulted in maternal toxicity, and were associated with delayed and/or lack of ossification of bones and decreased foetal body weights.
In a pre- and postnatal development study in rats, exposures far above the human exposure at the recommended dose did not harm the developing embryo or affect offspring growth and development. Higher doses of alogliptin decreased offspring body weight and exerted some developmental effects considered secondary to the low body weight.
Studies in lactating rats indicate that alogliptin is excreted in milk.
No alogliptin-related effects were observed in juvenile rats following repeat-dose administration for 4 and 8 weeks.
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