Included Studies

Three randomized controlled trials (RCTs) met the criteria for inclusion in this review: Studies 008 (N = 500), 305 (N = 2,639) and 302 (N = 784). Of these, 008 and 305 were considered pivotal trials by Health Canada. Studies 008 and 302 were superiority studies of alogliptin/metformin versus placebo/metformin, while Study 305 was a non-inferiority trial comparing alogliptin/metformin with glipizide/metformin. None of the included studies employed ALO/MET FDC, and only Study 302 co-administered alogliptin and metformin in a manner that corresponded with the strengths of ALO/MET FDC available in Canada.

Study 008 was a 26-week, double-blind, placebo-controlled, three-group, multi-centre RCT that compared metformin plus alogliptin 12.5 mg or 25 mg daily versus metformin plus placebo. Enrolled patients had T2DM and inadequate glycemic control metformin monotherapy. The primary outcome was change from baseline in A1C.

Study 305 was a 104-week, double-blind, active-controlled, three-group, multi-centre RCT that compared metformin plus alogliptin 12.5 mg or 25 mg daily with metformin plus glipizide up to 20 mg daily; metformin doses were > 1,500 mg daily or maximum tolerated dose. Patients had T2DM with inadequate glycemic control on previous metformin monotherapy. The primary outcome of this study was change from baseline A1C at 52 or 104 weeks, and the trial was powered to confirm non-inferiority of alogliptin versus glipizide with a non-inferiority margin of 0.3%.

Study 302 was a 26-week, placebo-controlled, seven-group, multi-centre RCT. Patients had T2DM with inadequate glycemic control when treated with diet and exercise for at least two months prior to screening. Patients were randomized to one of seven treatment groups: alogliptin/metformin 12.5 mg/500 mg twice a day, alogliptin/metformin 12.5 mg/1,000 mg twice daily, alogliptin 12.5 mg twice daily, alogliptin 25 mg once daily, metformin 500 mg twice daily, metformin 1,000 mg twice daily or placebo twice daily. The primary outcome of this study was change from baseline A1C at 26 weeks.

While the included trials demonstrated a number of methodological strengths, some limitations were also identified. In Study 305, glipizide appeared to be titrated in a relatively conservative fashion, and the mean doses achieved (5.2 mg daily) were relatively low. This could have biased results in favour of a finding of non-inferiority between alogliptin and glipizide. As well, a large proportion of patients (44% to 51%) withdrew prematurely from this study either because of hyperglycemic rescue or premature discontinuation, which may introduce biases arising from potential imbalances between treatment groups during the course of the study.

Efficacy

None of the included studies evaluated outcomes related to macrovascular or microvascular complications of T2DM, or quality of life. The latter was identified as an important outcome in patient group input received by CADTH on this submission.

In Study 008, alogliptin 12.5 mg and 25 mg daily, both in combination with metformin, demonstrated superiority compared with placebo on A1C at 26 weeks in the full analysis set (FAS) analysis (least squares mean difference [LSMD] = −0.4%; 95% confidence interval [CI], −0.6 to −0.2%, and LSMD = −0.5%; 95% CI, −0.7 to −0.3%, respectively). Alogliptin 12.5 mg and 25 mg also demonstrated statistically significantly greater decreases in fasting plasma glucose (FPG) when compared with placebo (LSMD = −1.04 mmol/L; 95% CI, −1.51 to −0.57, and LSMD = −0.97 mmol/L; 95% CI, −1.44 to −0.49], respectively). Adjusted mean changes from baseline body weight at 26 weeks were −0.4 kg to −0.7 kg and −0.4 kg for the alogliptin 12.5 mg, alogliptin 25 mg, and placebo groups, respectively. There were no statistically significant differences between alogliptin 12.5 mg and placebo (LSMD = 0.0 kg; 95% CI, −0.7 to 0.7). However, the difference between alogliptin 25 mg and placebo was statistically significant (LSMD = −0.3 kg; 95% CI, −0.9 to 0.4).

In Study 305, alogliptin 12.5 mg and 25 mg daily, both in combination with metformin, demonstrated non-inferiority on A1C at 52 weeks compared with glipizide/metformin based on the per-protocol set (PPS) analysis (LSMD = −0.09%; one-sided 98.75% CI, 0.03%, and LSMD = −0.03%; one-sided 98.75% CI, 0.06%, respectively). Similarly, at 104 weeks, alogliptin 12.5 mg and 25 mg daily demonstrated non-inferiority compared with glipizide (LSMD = −0.09%; one-sided 98.75% CI, 0.04, and LSMD = −0.13%; one-sided 98.75% CI, −0.01, respectively). At both 52 and 104 weeks, alogliptin 12.5 mg and 25 mg daily demonstrated statistically significantly greater reductions in FPG compared with glipizide. Adjusted mean changes from baseline body weight at 52 weeks were −0.65 kg to −0.71 kg, and 0.86 kg for the alogliptin 12.5 mg, alogliptin 25 mg and glipizide groups, respectively. Adjusted mean differences between alogliptin 12.5 mg and 25 mg versus glipizide were statistically significant (LSMD = −1.51 kg; 95% CI, −1.79 to −1.231, and LSMD = −1.58 kg; 95% CI, −1.86 to −1.30, respectively). Results were similar at week 104.

In Study 302, both alogliptin/metformin 12.5 mg/500 mg twice daily and 12.5 mg/1,000 mg twice daily were associated with statistically significantly greater reductions from baseline A1C at 26 weeks versus the respective doses of metformin monotherapy (LSMD = −0.6%; 95% CI, −0.9 to −0.3, and LSMD = −0.4%; 95% CI, −0.7 to −0.2%, respectively). Both dual therapy regimens were also associated with statistically significant reductions in FPG compared with the respective metformin monotherapy regimens. Adjusted mean differences in FPG between twice-daily alogliptin/metformin 12.5 mg/500 mg and twice-daily 12.5 mg/1,000 mg versus the respective metformin monotherapy doses were not statistically significant.

Harms

In Study 008, eight patients in the alogliptin 12.5 mg group (3.9%), six patients in the alogliptin 25 mg group (2.8%), and four patients (3.8%) in the placebo group experienced a serious adverse event (SAE). There was one death in Study 008, in the alogliptin 12.5 mg group. In Study 008, two patients (0.9%) in the alogliptin 12.5 mg group, no patients in the alogliptin 25 mg group and three patients (2.9%) in the placebo experienced at least one episode of hypoglycemia.

In Study 305, 11% of patients in the alogliptin 25 mg group, 9.9% in the alogliptin 12.5 mg group, and 9.3% in the glipizide group experienced an SAE. There were 11 deaths in Study 305, three in the alogliptin 12.5 group (0.3%), three in the alogliptin 25 mg group (0.3%) and five in the glipizide group (0.6%). Twenty-two patients (2.5%) in the alogliptin 12.5 mg group, 12 patients (1.4%) in the alogliptin 25 mg group and 202 patients (23.2%) in the placebo glipizide group experienced at least one episode of hypoglycemia.

In Study 302, the proportions of patients with an SAE were similar among the dual therapy and metformin monotherapy groups. Two patients in the alogliptin/metformin 12.5 mg/500 mg twice-daily group (1.9%), two patients in the alogliptin/metformin 12.5 mg/1,000 mg twice-daily group (1.8%), two patients in the metformin 500 mg group (1.8%), two patients in the metformin 1,000 mg group (1.8%), and three patients (2.8%) in the placebo group experienced an SAE. There were no deaths in this study. Alogliptin/metformin dual therapy tended to be associated with more withdrawals due to adverse effects (WDAEs) than metformin alone: the proportions were 4.7% in the alogliptin/metformin 12.5 mg/500 mg twice-daily group and 9.6% in the alogliptin/metformin 12.5 mg/1,000 mg twice-daily group, compared with 2.8% and 1.8% in the respective metformin monotherapy groups. Hypoglycemia occurred in two (1.9%), six (5.3%), seven (6.3%), two (1.8%), and one (1.8%) in the twice-daily alogliptin/metformin 12.5 mg/500 mg, 12.5 mg/1,000 mg, metformin 1,000 mg, metformin 500 mg, and placebo groups, respectively.

All of the DPP-4 inhibitors approved for use in Canada carry a warning regarding the risk of pancreatitis in their respective product monographs. There were no cases of pancreatitis reported in Study 008, and isolated cases only in the other two studies with no apparent association with alogliptin. Recent comprehensive assessments from the FDA and EMA concluded that the currently available data did not support a causal association between incretin-based drugs and pancreatitis or pancreatic cancer.

Bioequivalence

A key consideration in the assessment of ALO/MET FDC is its comparative bioavailability with ALO and MET administered as separate dosage forms. The pharmacokinetic characteristics of ALO/MET FDC were compared with co-administration of the single-drug tablets in two phase 1 studies of healthy volunteers (MET-103 and MET-101). The 90% CIs for the area under the curve (AUC) and maximum concentrations (Cmax) for ALO/MET FDC 12.5 mg/500 mg and ALO/MET FDC 12.5 mg/1,000 mg, versus ALO and MET co-administered at the same doses separately, were within the EMA-specified bioequivalence range of 80% to 125%.

Comparative Efficacy and Safety of Alogliptin and Other DPP-4 Inhibitors

There were no trials comparing alogliptin with other DPP-4 inhibitors available in Canada; however, the manufacturer submitted a network meta-analysis (NMA) to assess comparative efficacy and safety between DPP-4 inhibitors in the monotherapy, dual therapy (with metformin or sulfonylurea), and triple therapy (with metformin and a sulfonylurea) setting. The NMA did not find evidence of differences in glycemic control, weight gain, or hypoglycemia risk between alogliptin and the other DPP-4 inhibitors in the dual therapy setting; however, the analysis did not allow for a conclusion of non-inferiority or similarity across drugs. A second NMA submitted by the manufacturer assessed the relative efficacy and safety of alogliptin versus other DPP-4 inhibitors for dual therapy (i.e., in combination with metformin when a sulfonylurea (SU) is not appropriate, or in combination with SU when metformin is not appropriate). The results were similar to the original analysis in that there were no significant differences in A1C change from baseline. However, this analysis went further to show that there was a high probability (ranging from 64% to 100%, depending on the comparison and whether a fixed- or random-effects model was used) that alogliptin has similar effects on A1C as the other DPP-4 inhibitors within a margin of 0.3%. Alogliptin/metformin dual therapy also demonstrated favourable results with respect to weight gain against saxagliptin, and with respect to hypoglycemia against sitagliptin and saxagliptin. But all other comparisons of alogliptin with other DPP-4 inhibitors on these outcomes were not statistically significant.

Cardiovascular Safety

The Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE) study (N = 5,380) compared alogliptin with placebo in combination with standard of care among individuals with type 2 diabetes mellitus (T2DM) and acute coronary syndrome (ACS). The primary objective of this study was to demonstrate non-inferiority of alogliptin versus placebo with respect to a composite of major adverse cardiac events (MACE) in high-risk T2DM patients. The hazard ratio for the primary MACE composite outcome confirmed the non-inferiority hypothesis (hazard ratio [one-sided 95% CI] 0.96 [1.16]). The LSMD in change from baseline A1C between the alogliptin and placebo groups was −0.4% (95% CI, −0.4 to −0.3). The overall safety profile of alogliptin was similar to placebo during the course of the study, and there were no apparent differences in the rates of SAEs between the two groups.

Alogliptin Triple Therapy With Metformin and a Sulfonylurea

In the absence of a specific trial of alogliptin as triple therapy with metformin and sulfonylurea, the manufacturer provided a post hoc exploratory subgroup analysis of patients treated with triple therapy in the EXAMINE trial. In the subgroup of patients receiving metformin and sulfonylurea at baseline, the adjusted mean difference on A1C between alogliptin and placebo ▬▬▬▬ was ▬▬▬▬. The alogliptin and placebo groups ▬▬▬▬ with respect to the incidence of overall adverse events (▬▬▬▬) in the metformin/sulfonylurea subgroup. The incidence of hypoglycemia was ▬▬▬▬. These findings should be interpreted with caution given the post hoc nature of the analysis.