Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study

ABSTRACT

Objectives: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD).

Research design and methods: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18–80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA_1c] 7.0–10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5 mg, alogliptin 25 mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted.

Main outcome measures: The primary efficacy endpoint was change in HbA_1c from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG ≥ 200 mg/dL [11.10 mmol/L]) and rescue for hyperglycemia.

Results: Least squares (LS) mean change in HbA_1c was significantly (p < 0.001) greater for alogliptin 12.5 mg (−0.66%) or 25 mg (−0.80%) than for placebo (−0.19%). A significantly (p ≤ 0.016) larger proportion of patients achieved HbA_1c ≤ 7% with alogliptin 12.5 mg (44.2%) or 25 mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p = 0.003) greater with alogliptin 12.5 mg (−19.7 mg/dL [−1.09 mmol/L]) or 25 mg (−19.9 mg/dL [−1.10 mmol/L]) than with placebo (−5.7 mg/dL [−0.32 mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p < 0.001) lower for alogliptin (≤25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo.

Conclusions: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety.

Clinical trial registration: NCT00286494, clinicaltrials.gov.

Keywords: :

• Alogliptin
• Dipeptidyl peptidase-4 inhibitor
• Glycemic control
• Thiazolidinedione
• Type 2 diabetes

Transparency

Declaration of funding

Financial support for this study, analysis and manuscript development was provided by Takeda Global Research & Development Center, Inc., Deerfield, IL, USA.

Declaration of financial/other relationships

Q.M., P.F. and C.W. have disclosed that they are employees of Takeda. R.E.P. has disclosed that he has received investigator-initiated grants from Takeda and Merck; has received ‘industry-based’ clinical trial support from Pfizer, Merck, GlaxoSmithKline, Takeda, and several other pharmaceutical companies; and has consulted for GSK, Takeda, Merck, Novartis, NovoNordisk, and Roche. He owns stock in Novartis. J.E.-B.R. has disclosed that she has received investigator-initiated grants from Takeda and that she has received ‘industry-based’ clinical trial support from Pfizer, Merck, GSK, and Takeda. She has consulted for GSK, BMS and Takeda, and is on the speakers’ bureau of Merck. Q.M. has disclosed that he owns stock in Takeda.

All peer reviewers receive honoraria from CMRO for their review work. Peer reviewer 1 has disclosed that he/she is a minor stockholder in Merck. The other reviewer has disclosed that he/she has no relevant financial relationships.

Acknowledgment

Editorial assistance with manuscript preparation was provided by Scientific Connexions, Newtown, PA, USA.

Alogliptin Study 009 Group Investigators: Argentina – Castano P, Cuadrado J, Maffei L, Sposetti G, Ulla M; Australia – Allan C, dEmden M, Oneal D, Roberts A; Brazil – Chrisman C, Gross J, Hayashida C, Rea R; Germany – Derwahl K, Hensen J, Klausmann G, Laus S, Lehmann R, von Behren V; Guatemala – Granandos-Fuentes A, Turcios-Juarez E; Hungary – Koranyi L, Nagy K; India – Bantwal G, Chowdhury S, Prasanna Kumar K, Thomas N, Viswanathan M; Netherlands – van Leendert R; New Zealand – Dissanayake A, Scott R, Young S; Peru – Gonzales L, Molina G, More L; South Africa – Ellis G, Seeber M; Spain – De Teresa L, Moreiro J; United States – Barrera J, Behnke A, Bonabi G, Broker R, Caos A, Chappel C, Cheatham W, Cohen L, Corder C, Curtis W, Davis P, Dunn L, Earl J, Elliott S, Fidelholtz J, Fishman N, Fitz-Patrick D, Fogelfeld L, Glenn S, Guevara A, Hassman M, Herring C, Hurley D, Jones C, Kang J, Kerwin E, Kipnes M, Koppel W, Krasner J, Landgarten S, Lerman S, Levenson D, Liljenquist J, Lindley M, Lipetz R, Littlejohn T, Long W, Lowder C, Lucas J, Lynn L, Mark G, Marple R, Mayeda S, Morin D, Mullen J, Norwood P, Oates S, Odugbesan A, Phillips F, Plevin S, Popeil L, Pratley R, Pudi K, Raad G, Reed J, Rendell M, Riff D, Rock K, Rosenstock J, Sall K, Sargent E, Seidner M, Smith T, Soboeiro M, Sotsky M, Sparks J, Stegemoller R, Stoner C, Taber L, Tamayo R, Tarshis G, Touger M, Wahle J, Weinstein R, Wiker J. (Ten study investigators did not enroll patients and are not listed; one investigator enrolled patients at two separate sites and is listed once.)

Notes

* The results of this study were presented at the 68th Annual Scientific Sessions of the American Diabetes Association, in San Francisco, CA, USA, 6–10 June 2008, and at the 44th European Association for the Study of Diabetes Annual Meeting, in Rome, Italy, 7–11 September 2008