Introduction
Diabetes is a chronic metabolic disease with significant health impacts on individuals and societies. The prevalence of diabetes in Canada was 6.8% (2.4 million Canadians) in 2009 and is expected to rise to 3.7 million people by 2019. Ninety per cent of people with diabetes have type 2 diabetes mellitus, which is characterized by increased hepatic glucose output, reduced insulin secretion, and insulin resistance. People with diabetes are at risk of microvascular complications such as diabetic nephropathy and retinopathy, macrovascular complications such as cardiovascular disease, and premature mortality. Improved glycemic control reduces the risk of microvascular complications and possibly of macrovascular complications. Current guideline recommendations specify a target for glycated hemoglobin (A1C) of 7% or less for most patients with type 2 diabetes.
There are currently 11 classes of antihyperglycemic drugs approved for use in Canada for type 2 diabetes: metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 analogues, sodium-glucose cotransporter-2 inhibitors, basal insulins, bolus insulins, and biphasic insulins. Alogliptin is the fourth DPP-4 inhibitor to be introduced in Canada after sitagliptin, saxagliptin, and linagliptin. Upon submission, the manufacturer requested listing of alogliptin in a manner similar to other DPP-4 inhibitors in Canada. Based on consideration of listing criteria across Canada for existing DPP-4 inhibitors, and in consultation with the manufacturer, the following two of the six approved indications for alogliptin were reviewed by the CADTH Common Drug Review (CDR):
in combination with metformin when diet and exercise plus metformin alone do not provide adequate glycemic control
in combination with a sulfonylurea when diet and exercise plus a sulfonylurea alone do not provide adequate glycemic control.
Upon review of the draft CDR clinical and pharmacoeconomic reports, the manufacturer asked that the requested listing criteria be modified to reflect the two indications under review.
Of note, the Canadian Drug Expert Committee recommendations for the existing DPP-4 inhibitors have recommended listing for patients with inadequate glycemic control on metformin and a sulfonylurea who are unable to use insulin. However, alogliptin is not approved for use in combination with metformin and a sulfonylurea.
Results and Interpretation
Included studies
Four randomized controlled trials (RCTs) met the criteria for inclusion in this review: Studies 007 (N = 500), 008 (N = 500), 305 (N = 2,639), and 302_MET (N = 784). Of these, Studies 007, 008, and 305 were considered pivotal trials by Health Canada. Studies 007, 008, and 302_MET were superiority studies of alogliptin 12.5 mg and 25 mg daily versus placebo, while Study 305 was a non-inferiority trial comparing alogliptin 12.5 mg and 25 mg daily with glipizide. Studies 007 and 008 were 26-week, double-blind, placebo-controlled, three-group, multi-centre RCTs of similar design; 007 compared dual therapies alogliptin + glyburide and placebo + glyburide, while 008 compared alogliptin + metformin and placebo + metformin. Enrolled patients had type 2 diabetes and inadequate glycemic control on sulfonylurea (007) or metformin (008) monotherapy. The primary outcome in both studies was change from baseline in A1C.
Study 305 was a 104-week, double-blind, active-controlled, three-group, multi-centre RCT. Patients had type 2 diabetes with inadequate glycemic control on previous metformin monotherapy. The study compared alogliptin 12.5 mg daily, alogliptin 25 mg daily, and glipizide up to 20 mg daily, all in combination with metformin > 1,500 mg daily or maximum tolerated dose. 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_MET was a 26-week, placebo-controlled, seven-group, multi-centre RCT. Patients had type 2 diabetes with inadequate glycemic control when treated with diet and exercise for at least two months before screening. Patients were randomized to one of seven treatment groups: alogliptin 12.5 mg twice daily + metformin 500 mg twice daily, alogliptin 12.5 mg twice daily + metformin 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 have introduced biases arising from potential imbalances between treatment groups over the course of the study.
Efficacy
None of the included studies evaluated outcomes related to macrovascular or microvascular complications of type 2 diabetes, or related to quality of life. The latter was identified as an important outcome in patient group input received by CADTH for this submission.
Sulfonylurea combination therapy: In Study 007, alogliptin 12.5 mg and 25 mg daily, both in combination with glyburide, demonstrated superiority in terms of A1C level achieved at 26 weeks compared with placebo + glyburide in the full analysis set (FAS) analysis (least squares mean differences [LSMD] were −0.4%; 95% confidence interval [CI], −0.6% to −0.2% for alogliptin 12.5 mg versus placebo and −0.5%; 95% CI, −0.7% to −0.3% for alogliptin 25 mg versus placebo). However, alogliptin 12.5 mg and alogliptin 25 mg did not demonstrate statistically significantly greater decreases in fasting plasma glucose (FPG) compared with placebo.
Patient group input submitted to CADTH for this submission indicated that increases in body weight represented an important limitation of some antihyperglycemic therapies. In Study 007, adjusted mean changes from baseline at 26 weeks were 0.6 kg, 0.7 kg, and 0.2 kg for the alogliptin 12.5 mg, alogliptin 25 mg, and placebo groups, respectively. Mean differences between alogliptin 12.5 mg and 25 mg and placebo were statistically significant (LSMD = 0.8 kg; 95% CI, 0.14 kg to 1.46 kg and LSMD = 0.9 kg; 95% CI, 0.21 kg to 1.54 kg, respectively).
Metformin combination therapy: In Study 008, alogliptin 12.5 mg and 25 mg daily, both in combination with metformin, demonstrated superiority to placebo in terms of A1C level achieved at 26 weeks in the FAS analysis (LSMD = −0.4%; 95% 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 FPG when compared with placebo (LSMD = −1.04 mmol/L; 95% CI, −1.51 mmol/L to −0.57 mmol/L and LSMD = −0.97; 95% CI, −1.44 mmol/L to −0.49 mmol/L, respectively). Adjusted mean changes from baseline body weight at 26 weeks were −0.4 kg, −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 in body weight change between alogliptin 12.5 mg and placebo (LSMD = 0.0 kg; 95% CI, −0.7 kg to 0.7 kg), and alogliptin 25 mg and placebo (LSMD = −0.3 kg; 95% CI, −0.9 kg to 0.4 kg).
In Study 305, alogliptin 12.5 mg and 25 mg daily, both in combination with metformin, demonstrated non-inferiority in terms of A1C level achieved at 52 weeks compared with glipizide + metformin based on the PPS analysis (LSMD = −0.09%; one-sided 98.75% CI, 0.03% and LSMD = −0.03%; one-sided 95% CI, 0.06%, respectively). Similarly, at 104 weeks, alogliptin 12.5 mg and 25 mg daily demonstrated non-inferiority to 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 than placebo. Adjusted mean changes from baseline body weight at 52 weeks were −0.65 kg, −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 kg to −1.231 kg and LSMD = −1.58 kg; 95% CI, −1.86 kg to −1.30 kg, respectively). Results were similar at week 104.
In Study 302_MET, both alogliptin 12.5 mg twice daily + metformin 500 mg twice daily and alogliptin 12.5 mg twice daily + metformin 1,000 mg twice daily were associated with statistically significantly greater reductions in A1C from baseline 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 between alogliptin 12.5 mg twice daily + metformin 500 mg twice daily and alogliptin 12.5 mg twice daily + metformin 1,000 mg twice daily versus the respective metformin monotherapy doses were not statistically significant.
Harms
Sulfonylurea combination therapy: In Study 007, 11 patients in both the alogliptin 12.5 mg (5.4%) and 25 mg (5.6%) groups experienced a serious adverse event (SAE), compared with two patients in the placebo group (2.0%). There were no deaths in Study 007. Hypoglycemia was identified as a significant barrier to achieving glycemic control in the patient group input received by CDR. Thirty-two patients (15.8%) in the alogliptin 12.5 mg group, 19 patients (9.6%) in the alogliptin 25 mg group, and 11 patients (11.1%) in the placebo group experienced at least one episode of hypoglycemia.
Metformin combination therapy: In Study 008, eight patients (3.9%) in the alogliptin 12.5 mg group, six patients (2.8%) in the alogliptin 25 mg group, and four patients (3.8%) in the placebo group experienced an 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 group 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 (0.3%) in the alogliptin 12.5 group, three (0.3%) in the alogliptin 25 mg group, and five (0.6%) in the glipizide group. 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 glipizide group experienced at least one episode of hypoglycemia.
In Study 302_MET, the percentages of patients with an SAE were similar among the dual-therapy and metformin monotherapy groups. Two patients (1.9%) in the alogliptin 12.5 mg twice daily + metformin 500 mg twice daily group, two patients (1.8%) in the alogliptin 12.5 mg twice daily + metformin 1,000 mg twice daily group, two patients (1.8%) in the metformin 500 mg group, two patients (1.8%) in the metformin 1,000 mg group, 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 WDAEs than metformin alone: the percentages were 4.7% in the alogliptin 12.5 mg twice daily + metformin 500 mg twice daily group and 9.6% in the alogliptin 12.5 mg twice daily + metformin 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 alogliptin 12.5 mg twice daily + metformin 500 mg twice daily, alogliptin 12.5 mg twice daily + metformin 1,000 mg twice daily, metformin 1,000 mg twice daily, metformin 500 mg twice daily, 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 Studies 007 and 008 and isolated cases in the other two studies with no apparent association with alogliptin. Recent comprehensive assessments from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) concluded that the currently available data did not support a causal association between incretin-based drugs and pancreatitis or pancreatic cancer.
Other considerations
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 among DPP-4 inhibitors in monotherapy, dual-therapy (with metformin or sulfonylurea), and triple-therapy (with metformin and a sulfonylurea) regimens. The NMA did not show evidence of differences in glycemic control, weight gain, or hypoglycemia risk between alogliptin and the other DPP-4 inhibitors in dual-therapy regimens; however, the analysis did not allow for a conclusion of non-inferiority or similarity among 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 is not appropriate, or in combination with a sulfonylurea when metformin is not appropriate). The results were similar to the original analysis, showing 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 upon the comparison and whether a fixed- or random-effects model was used) that alogliptin has effects on A1C similar to those of the other DPP-4 inhibitors, within a margin of 0.3%. Alogliptin + metformin dual therapy also demonstrated favourable results with respect to weight gain compared with saxagliptin, and with respect to hypoglycemia compared with sitagliptin and saxagliptin, but all other comparisons of alogliptin with other DPP-4 inhibitors on these outcomes were statistically non-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 and acute coronary syndrome. The primary objective of this study was to demonstrate non-inferiority of alogliptin to placebo with respect to a composite of major adverse cardiac events (MACE) in high-risk type 2 diabetes patients. The hazard ratio for the primary MACE composite outcome (0.96; one-sided 95% CI, 1.16) confirmed the non-inferiority hypothesis. 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 over 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 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 did not differ significantly 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.
Conclusions
Four double-blind, placebo- or active-controlled RCTs were included in this review of alogliptin add-on therapy to metformin or a sulfonylurea. In all trials, the addition of alogliptin was associated with modest but clinically relevant improvements in A1C, ranging from 0.4% to 0.6%. In the only active-controlled trial in dual-therapy regimens, alogliptin + metformin dual therapy was demonstrated to be non-inferior to glipizide + metformin, although there was some concern that the conservative titration algorithm and relatively low mean doses of glipizide in this study may have biased results toward a finding of non-inferiority. There were no data available from the included trials regarding the long-term complications of diabetes or quality of life. Alogliptin add-on therapy resulted in modest weight gain compared with placebo when added to a sulfonylurea, was weight-neutral versus placebo when added to metformin, and was associated with lower weight gain than sulfonylurea when either was added to metformin. Alogliptin was not associated with a higher risk of hypoglycemia than placebo when added to either metformin or a sulfonylurea, but was associated with lower risk of hypoglycemia versus a sulfonylurea in dual therapy with metformin. There were no apparent associations between alogliptin and other adverse effects. The EXAMINE trial, which was designed to confirm the cardiovascular safety of alogliptin added to various existing antidiabetes therapies, reported that alogliptin was non-inferior to placebo on MACE.
There was no direct comparative evidence for alogliptin versus other DPP-4 inhibitors available in Canada in the context of metformin or sulfonylurea dual therapy. The manufacturer-submitted NMAs suggested that there are no differences among DPP-4 inhibitors in relation to A1C, body weight, and hypoglycemia, and that alogliptin as dual therapy with either metformin or sulfonylurea has a high probability of producing reductions in A1C (within a margin of 0.3%) similar to those of other DPP-4 inhibitors available in Canada.
Summary of Efficacy Results.
