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CURRENT MEDICAL RESEARCH AND OPINION� 0300-7995

VOL. 25, NO. 10, 2009, 2361–2371 doi:10.1185/03007990903156111

� 2009 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted

ORIGINAL ARTICLE

Efficacy and safety of thedipeptidyl peptidase-4 inhibitoralogliptin added to pioglitazonein patients with type 2 diabetes:a randomized, double-blind,placebo-controlled study*Richard E. Pratleya, Jane E.-B. Reuschb, Penny R. Fleckc,Craig A. Wilsonc and Qais Mekkic on behalf of theAlogliptin Study 009 GroupaUniversity of Vermont College of Medicine, Burlington, VT, USAbUniversity of Colorado Health Sciences Center, Denver, CO, USAcTakeda Global Research & Development Center, Inc., Deerfield, IL, USA

Address for correspondence: Richard E. Pratley, MD, Professor of Medicine, Director, Diabetesand Metabolism Translational Medicine Unit, University of Vermont College of Medicine, GivenC331, 89 Beaumont Avenue, Burlington, VT 05405, USA. Tel.: þ1 802 847 8901; Fax: þ1 802 6568031; Richard.Pratley@uvm.edu

Keywords: Alogliptin – Dipeptidyl peptidase-4 inhibitor – Glycemic control – Thiazolidinedione –Type 2 diabetes

ABSTRACT

Objectives: To evaluate the efficacy and safety of alogliptin in

patients with type 2 diabetes inadequately controlled by therapywith 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., glyco-sylated hemoglobin [HbA1c] 7.0–10.0%) despite ongoing treat-

ment with a TZD were randomly assigned (2:2:1) to treatmentwith pioglitazone plus alogliptin 12.5 mg, alogliptin 25 mg or

placebo once daily. Concomitant therapy with metformin orsulfonylurea at prestudy doses was permitted.

Main outcome measures: The primary efficacy endpoint waschange in HbA1c from baseline to Week 26. Secondary end-

points included changes in fasting plasma glucose (FPG) andbody weight, and incidences of marked hyperglycemia

(FPG� 200 mg/dL [11.10 mmol/L]) and rescue forhyperglycemia.

Results: Least squares (LS) mean change in HbA1c was sig-nificantly (p50.001) 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 HbA1c� 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(p¼ 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 percent-

age of patients with marked hyperglycemia was significantly(p50.001) lower for alogliptin (�25.0%) than placebo

(44.3%). The incidences of overall adverse events andhypoglycemia were similar across treatment groups, but car-

diac events occurred more often with active treatment thanplacebo.

Conclusions: Addition of alogliptin to pioglitazone therapysignificantly improved glycemic control in patients with type 2

diabetes and was generally well tolerated. The study did notevaluate the effect of combination therapy on long-term clinical

outcomes and safety.Clinical trial registration: NCT00286494, clinicaltrials.gov.

*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

Article 4771/415784 2361

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Introduction

The etiology of type 2 diabetes mellitus involves a pro-

gressive loss of beta-cell function in the setting of insu-

lin resistance, resulting in increasingly poor glycemic

control1. The American Diabetes Association (ADA)

currently recommends that patients achieve a glycosy-

lated hemoglobin (HbA1c) of57.0%, if this goal can be

reached without significant risk of hypoglycemia.

Because many patients cannot reach or maintain this

goal with a single antidiabetic agent2,3, combining

drugs with complementary mechanisms of action is

an important treatment strategy2–4.

Thiazolidinediones (TZDs) and dipeptidyl pepti-

dase-4 (DPP-4) inhibitors are two classes of antidia-

betic medications that exert their effects through

different mechanisms. TZDs activate peroxisome pro-

liferator-activated receptor g (PPARg)5 and thereby

primarily improve insulin resistance6. DPP-4 inhibitors

prolong the plasma half-life of active glucagon-like pep-

tide-1 (GLP-1), an incretin hormone released from the

gut in response to food intake, which improves glyce-

mic control by stimulating insulin secretion, inhibiting

glucagon secretion and slowing gastric emptying7.

Medications that raise plasma GLP-1 levels or mimic

GLP-1 function have shown promise for the treatment

of diabetes7–9.

Alogliptin is a potent, highly selective DPP-4 inhib-

itor10. Administration of a single dose of alogliptin for

14 days to patients with type 2 diabetes resulted in

rapid and sustained inhibition of plasma DPP-4 activity

and significant decreases in postprandial plasma glucose

levels11. The combination of alogliptin and pioglitazone

significantly improved glycemic control in obese ob/obmice compared with either monotherapy12. In addi-

tion, no pharmacokinetic interaction was observed

when alogliptin and pioglitazone were coadministered

for 7 days in healthy adult subjects13. In a 14-day ran-

domized, double-blind, placebo-controlled study in

56 patients with type 2 diabetes, alogliptin dosages of

25 mg, 100 mg and 400 mg per day all were efficacious

in decreasing postprandial glucose concentrations and

HbA1c11. Monotherapy with alogliptin 12.5 mg or a

higher dose significantly reduced HbA1c in patients

with type 2 diabetes who participated in a 12-week

randomized, double-blind, placebo-controlled study

that tested alogliptin dosages of 6.25, 12.5, 25, 50

and 100 mg per day14. The safety profile was similar

for doses of 12.5 to 50 mg; HbA1c was reduced signifi-

cantly (p50.05) from baseline, versus placebo, with

alogliptin doses of 12.5 to 100 mg14.

The primary objective of the current study was to

determine whether adding alogliptin 12.5 mg and

25 mg per day to ongoing pioglitazone therapy would

significantly improve glycemic control in patients with

type 2 diabetes compared with adding placebo.

Patients and methods

Patients

Eligible patients were men and women 18–80 years old

with type 2 diabetes and a body mass index (BMI) of

23–45 kg/m2 who were treated for at least 3 months

(at a stable dose for at least the last month) with a

TZD (pioglitazone or rosiglitazone) with or without

metformin or sulfonylurea, and who were experiencing

inadequate glycemic control (HbA1c of 7.0–10.0% at

screening). C-peptide plasma concentrations were to

be �0.8 ng/mL (fasting) or �1.5 ng/mL (post challenge

by mixed-meal tolerance test, intravenous glucagon or

intravenous arginine). All patients provided written

informed consent.

Patients were excluded if they had active heart fail-

ure (New York Heart Association Class III or IV) or had

undergone an invasive coronary procedure or had a

myocardial infarction within 6 months before screen-

ing. Additional exclusion criteria were an abnormal lab-

oratory test result (i.e., creatinine42.0 mg/dL, alanine

amino transferase42.5 times the upper limit of normal,

thyroid-stimulating hormone higher than the upper

limit of normal, hemoglobin 512 g/dL for men or

510 g/dL for women or an albumin/creatinine ratio

41000 mg/mg); uncontrolled hypertension (i.e., systolic

blood pressure4180 mm Hg or diastolic blood pressure

4110 mm Hg); history of angioedema with angiotensin-

converting enzyme inhibitors or angiotensin receptor

blockers, or treated diabetic gastric paresis; laser treat-

ment for proliferative diabetic retinopathy; most can-

cers not in remission for �5 years; and pregnancy or

lactation. Use of concomitant antidiabetic agents

other than metformin and sulfonylurea, weight loss

drugs, and noninhaled glucocorticoids was not permit-

ted within 3 months before assignment or during

treatment.

The study protocol was approved by the institutional

review board or ethics committee for each study site.

This study was conducted in accordance with the

protocol, the World Medical Association Declaration

of Helsinki, the guidelines of the International

Conference on Harmonisation for good clinical prac-

tice, and the applicable laws and regulations of the

US Food and Drug Administration.

Study design and treatments

This double-blind, randomized, placebo-controlled

study was conducted at 125 sites in four regions:

(a) the United States, (b) Western Europe, Australia

2362 Alogliptin plus pioglitazone for diabetes � 2009 Informa UK Ltd - Curr Med Res Opin 2009; 25(10)

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and New Zealand, (c) Latin America, and (d) other

countries (Hungary, India and South Africa). The pri-

mary objective was to evaluate the change from base-

line in HbA1c with a combination of alogliptin and

pioglitazone compared with placebo and pioglitazone.

After a screening period of �2 weeks, eligible patients

entered a 4-week run-in (stabilization) period that

included the following: counseling on diet, exercise

and home blood glucose monitoring; instructions for

recognizing the signs and symptoms of hypoglycemia;

and maintenance of a diary of hypoglycemic events.

All patients received single-blind placebo during the

run-in period. Patients previously treated with piogli-

tazone continued with the same dose; patients who

previously received rosiglitazone switched to an

equivalent dosage of pioglitazone 30 mg or 45 mg

once daily; patients previously treated with orally

administered metformin or a sulfonylurea continued

those medications at the same dosage throughout the

study.

At the end of the run-in period, patients with HbA1c

7.0–10.0%, fasting plasma glucose (FPG)5275 mg/dL

(15.27 mmol/L) and at least 75% compliance with the

single-blind placebo regimen were eligible for random-

ization 1 week later, at the baseline visit. Patients were

randomly assigned (in a ratio of 2:2:1) to 26 weeks of

once-daily treatment with alogliptin 12.5 mg, alogliptin

25 mg or placebo with the use of a permuted block

schedule stratified for baseline HbA1c (58.0% vs.

�8.0% at Week -1), geographic region and treatment

regimen (pioglitazone, pioglitazone plus metformin or

pioglitazone plus a sulfonylurea). Randomization codes

were obtained through a 24-h automated, interactive

voice response system.

Assessments

Scheduled visits at baseline and throughout the

26-week treatment period (i.e., on the days following

1, 2, 4, 8, 12, 16, 20, and 26 weeks of treatment)

required patients to fast for at least 8 h and included

clinical examination of skin and digits; review of diaries;

and assessment of glucometer readings, hematology

data and serum chemistry parameters, including

plasma glucose concentration. HbA1c and FPG were

measured at baseline and at every visit from Week

4–26. Vital signs, concomitant medications and adverse

events (AEs) were recorded at each clinic visit. Twelve-

lead electrocardiogram recordings were obtained at

baseline, Week 12 and study end. A follow-up visit

occurred 2 weeks after study end (Week 28).

Marked hyperglycemia was defined as

FPG� 200 mg/dL (11.10 mmol/L). Rescue therapy

was initiated if a patient had FPG� 275 mg/dL

(15.27 mmol/L), �250 mg/dL (13.88 mmol/L) and

�225 mg/dL (12.49 mmol/L) between Weeks 1 and

4, 4 and 8, and 8 and 12, respectively, or an

HbA1c� 8.5% and �0.5% reduction in HbA1c after

12 weeks of treatment. A follow-up visit was per-

formed 2 weeks after rescue unless patients

entered an open-label extension study (results not

reported here). Hypoglycemia was defined as blood

glucose 560 mg/dL (3.33 mmol/L) with symptoms or

blood glucose 550 mg/dL (2.78 mmol/L) without

symptoms.

AEs were recorded at each study visit based on

assessments by the investigator. In addition, patients

could report AEs at any other time during the study.

AEs were coded by system organ class and preferred

term using the Medical Dictionary for Regulatory

Activities (MedDRA, Version 10).

Statistical analysis

The efficacy population included all randomized

patients in the safety population, which, in turn, con-

sisted of all patients who took at least one dose of study

drug. Analysis of each efficacy variable included

data from patients in the efficacy population who

had a baseline assessment and at least one post-baseline

assessment. The last-observation-carried-forward

method was used to impute missing post-baseline

values. The primary efficacy endpoint was the change

in HbA1c from baseline to Week 26. Secondary efficacy

endpoints included changes in FPG and body weight, as

well as incidences of marked hyperglycemia and rescue

for hyperglycemia. Exploratory endpoints included

changes in the plasma concentration of various lipid

parameters.

Continuous efficacy variables were evaluated by

analysis of covariance at the two-sided 0.05 signifi-

cance level. The Type 1 error for the primary analysis

was controlled with a step-down strategy; results for

the 12.5-mg dose and placebo were compared only if

the 25-mg dose results first were found to be signifi-

cantly different from placebo. Study treatment, geo-

graphic region and baseline treatment regimen were

class variables in the analysis of covariance models;

the baseline pioglitazone dose and the baseline variable

value were continuous covariates. Incidence variables

were summarized by descriptive statistics, and

treatment groups were compared with the use of non-

parametric, covariance-adjusted, extended Mantel–

Haenszel tests.

Descriptive statistics were used to summarize the

incidence of treatment-emergent AEs, clinical labora-

tory evaluations, physical examination findings, oral

temperature, vital signs, 12-lead electrocardiogram

readings and incidence of hypoglycemia.

� 2009 Informa UK Ltd - Curr Med Res Opin 2009; 25(10) Alogliptin plus pioglitazone for diabetes Pratley et al. 2363

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Results

Patients

Of the 600 patients enrolled, 107 were excluded from

the double-blind portion of the study; of these, 43 did

not meet the additional inclusion criteria after the sta-

bilization period (at Week �1), 28 withdrew volunta-

rily, 16 were excluded because of protocol deviations

and 20 were excluded for other reasons. The remaining

493 (82.2%) patients were randomly assigned to once-

daily treatment with alogliptin 12.5 mg (n¼ 197),

alogliptin 25 mg (n¼ 199) or placebo (n¼ 97)

(Figure 1). Most randomized patients (433 of 493;

87.8%) completed the study or underwent rescue for

hyperglycemia.

The proportion of patients who discontinued

double-blind treatment was similar for all three treat-

ment arms (Figure 1). The most common reasons for

discontinuation in the placebo group were investigator

discretion, loss to follow-up and AEs. The most

common reasons for discontinuation of treatment

with alogliptin were voluntary withdrawal and AEs.

Most voluntary withdrawals occurred for personal rea-

sons and were not attributable to an AE. The dose of

alogliptin had no substantial effect on the rate of or

reasons for discontinuation (Figure 1).

The demographic and baseline clinical characteristics

were similar across treatment groups (Table 1).

The study population was predominantly male

(58.2%), white (74.2%) and American (67.1%).

Nonetheless, the population contained a racially and

ethnically diverse mix of patients. Although the mean

age in all treatment groups was 55 years, a substantial

percentage (17.2%) of the study population was elderly

(�65 years). Patients generally were overweight or

obese (mean BMI432 kg/m2) and, on average, had

received the diagnosis of diabetes 7.4–7.8 years before

enrollment. In addition to pioglitazone (mean daily

dose, 34–36 mg), more than three-fourths of patients

were receiving metformin (56.2%; mean dose,

1688 mg/day) or a sulfonylurea (21.1%; mean dose,

37.3 mg/day) at baseline. Despite use of these orally

administered antidiabetic therapies, mean HbA1c base-

line values were 8.0–8.1% across treatment groups.

Efficacy

Least squares (LS) mean change in HbA1c from base-

line to Week 26 was significantly (p50.001) greater

with alogliptin 12.5 mg (�0.66%) or 25 mg (�0.80%)

than with placebo (�0.19%) (Figure 2). LS mean

HbA1c decreased rapidly during the first 12 weeks of

alogliptin treatment and remained stable during the

following 14 weeks with slightly greater decreases

observed with the higher alogliptin dose. Changes in

HbA1c from baseline to Week 26 appeared to be

Placebo + pioglitazone (97)

Alogliptin 12.5 mg + pioglitazone (197)

Randomized (493)

Discontinued study (14 [14.4%]) Voluntary withdrawal (2 [2.1%]) Adverse event (3 [3.1%]) PI discretion (5 [5.2%]) Lost to follow-up (3 [3.1%]) Protocol deviation (1 [1.0%])

Discontinued study (25 [12.7%]) Voluntary withdrawal (10 [5.1%]) Adverse event (8 [4.1%])* PI discretion (5 [2.5%]) Lost to follow-up (1 [0.5%]) Protocol deviation (1 [0.5%])

Safety analysis (97) Efficacy analysis (97)

Safety analysis (198)† Efficacy analysis (197)

Excluded (107) Inclusion criteria not met (43) Voluntary withdrawal (28) Protocol deviation (16) Other reasons (20)

Enrolled(600)

Safety analysis (199) Efficacy analysis (199)

Alogliptin 25 mg + pioglitazone (199)

Discontinued study (21 [10.6%]) Voluntary withdrawal (9 [4.5%]) Adverse event (6 [3.0%]) PI discretion (1 [0.5%]) Lost to follow-up (3 [1.5%]) Protocol deviation (2 [1.0%])

Figure 1. Patient disposition. *Two of the patients in the alogliptin 12.5 mg group who withdrew from the study did so because of

adverse events that were not treatment emergent. yOne patient discontinued participation because he was accidentally treated

with alogliptin 12.5 mg before randomization. The patient was included in the safety analysis but not in the efficacy analysis

2364 Alogliptin plus pioglitazone for diabetes � 2009 Informa UK Ltd - Curr Med Res Opin 2009; 25(10)

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independent of age (565 or �65 years), BMI (530 or

�30 kg/m2) or ethnicity (Hispanic or non-Hispanic).

Subgroup analysis by baseline HbA1c revealed

greater decreases in the �8.0% subgroup than in the

58.0% subgroup (Figure 3). As a result, the difference

in treatment effect of alogliptin versus placebo was

more pronounced within the higher baseline HbA1c

subgroup. However, differences in the HbA1c decrease

between alogliptin- and placebo-treated patients were

highly significant (p� 0.005) in both subgroups, irre-

spective of the dose used (Figure 3).

Patients treated with either dose of alogliptin were

significantly (p� 0.016) more likely to achieve the

goal of HbA1c� 7% than those treated with placebo

(Table 2).

The percentage of patients who achieved an absolute

reduction in HbA1c of�1% after 26 weeks of treatment

was approximately three times as high with alogliptin

25 mg as with placebo, and more than twice as high

with alogliptin 12.5 mg as with placebo (p50.001

with either dose). Conversely, the percentage of

patients with marked hyperglycemia was significantly

(p50.001) lower for alogliptin 12.5 mg or 25 mg than

for placebo (Table 2).

Alogliptin at either dose resulted in significant LS

mean reductions in FPG relative to that observed

with placebo; these decreases were apparent as early

as Week 1 (p50.05) and continued throughout the

study period, resulting in a statistically significant

(p¼0.003) LS mean change from baseline to Week

26 of �19.7 mg/dL (�1.09 mmol/L) for alogliptin

12.5 mg, �19.9 mg/dL (�1.10 mmol/L) for alogliptin

25 mg and �5.7 mg/dL (�0.32 mmol/L) for placebo

(Figure 4).

Alogliptin therapy was on average weight neutral in

this study population. LS mean changes in body weight

at Week 26 were approximately 1 kg in each treatment

group, with no significant differences noted between

the placebo and the two active-treatment arms

(p� 0.294). LS mean differences (95% confidence

Table 1. Demographic and baseline clinical characteristics of the randomized population (n¼ 493)

Characteristic Placeboþ

pioglitazone

(n¼ 97)

Alogliptin 12.5 mgþ

pioglitazone

(n¼ 197)

Alogliptin 25 mgþ

pioglitazone

(n¼ 199)

Overall

(N¼ 493)

Age, years

Mean (SD) 55.2 (10.8) 55.5 (9.4) 55.4 (10.2) 55.4 (10.0)

565, n (%) 83 (85.6) 165 (83.8) 160 (80.4) 408 (82.8)

�65, n (%) 14 (14.4) 32 (16.2) 39 (19.6) 85 (17.2)

Sex, n (%)

Male 53 (54.6) 109 (55.3) 125 (62.8) 287 (58.2)

Female 44 (45.4) 88 (44.7) 74 (37.2) 206 (41.8)

Race, n (%)

White 71 (73.2) 143 (72.6) 152 (76.4) 366 (74.2)

Asian 11 (11.3) 18 (9.1) 24 (12.1) 53 (10.8)

Black or African American 10 (10.3) 22 (11.2) 13 (6.5) 45 (9.1)

Other 5 (5.2) 14 (7.1) 10 (5.0) 29 (5.9)

Ethnicity, n (%)

Hispanic 10 (10.3) 37 (18.8) 33 (16.6) 80 (16.2)

Non-Hispanic 87 (89.7) 160 (81.2) 166 (83.4) 413 (83.8)

BMI, mean (SD), kg/m2 33.2 (6.2) 32.3 (5.7) 33.1 (5.4) 32.8 (5.7)

Diabetes history, mean (SD), years 7.8 (6.7) 7.7 (5.6) 7.4 (5.4) 7.6 (5.7)

Pioglitazone dose, mean (SD), mg 36.2 (8.6) 34.0 (9.3) 35.4 (9.0) 35.0 (9.1)

Other hypoglycemic agent, n (%)

Metformin 56 (57.7) 107 (54.3) 114 (57.3) 277 (56.2)

Sulfonylurea 18 (18.6) 42 (21.3) 44 (22.1) 104 (21.1)

None 23 (23.7) 48 (24.4) 41 (20.6) 112 (22.7)

HbA1c, %

Mean (SD) 8.0 (0.8) 8.1 (0.9) 8.0 (0.8) –

Median (range) 8.0 (6.6–10.3) 7.9 (6.8–12.7) 7.8 (6.8–10.3) –

58%, n (% of patients) 47 (48.5) 100 (50.8) 104 (52.3) –

�8%, n (% of patients) 50 (51.5) 97 (49.2) 95 (47.7) –

SD¼ standard deviation; HbA1c¼ glycosylated hemoglobin

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interval) versus placebo were 0.42 kg (�0.37 to

1.22 kg) for alogliptin 12.5 mg and 0.05 kg (�0.74 to

0.84 kg) for alogliptin 25 mg. Changes from baseline

in plasma concentrations of lipids also did not differ

significantly among treatment groups.

Safety

The overall incidence of treatment-emergent AEs was

slightly higher in both alogliptin groups than in the pla-

cebo group (Table 3), although the most common AEs

generally occurred with a similar incidence across

groups. Most AEs were mild or moderate in intensity

(955 of 1007 events; 94.8%). The incidence of severe

AEs, defined as those causing considerable interference

with the patient’s usual activities, was 9.0% for

†

*

‡

**

*

‡

†

†*†

***

**

7.5

8.0

8.5

9.0

9.5

10.0

Study week

FPG

, mm

ol/L

Placebo + pioglitazone

Alogliptin 12.5 mg + pioglitazone

Alogliptin 25 mg + pioglitazone

0 4 8 12 16 20 24 26

Figure 4. Time course of changes in fasting plasma glucose

(FPG) concentrations during 26 weeks of treatment with

pioglitazone plus placebo (open circles), alogliptin 12.5 mg

(filled triangles) or alogliptin 25 mg (filled squares). Shown

are least squares mean percentages at various time points,

with last observations carried forward. Baseline values are

means. Error bars represent standard errors of the mean.

*p50.001; yp50.01; zp50.05 (vs. placebo)

*

****

**

*

* * * *

7.0

7.2

7.4

7.6

7.8

8.0

8.2

Study week

HbA

1c,%

Placebo + pioglitazone

Alogliptin 12.5 mg + pioglitazone

Alogliptin 25 mg + pioglitazone

260 4 8 12 16 20 24

Figure 2. Time course of changes in glycosylated

hemoglobin (HbA1c) during 26 weeks of treatment with pio-

glitazone plus placebo (open circles), alogliptin 12.5 mg

(filled triangles) or alogliptin 25 mg (filled squares). Shown

are least squares mean percentages at various time points,

with last observations carried forward. Baseline values

are means. Error bars represent standard errors of the

mean. *p50.001 (vs. placebo)

Table 2. Results for clinical measures of glycemic control

Patients, n (%) Placeboþ

pioglitazone

(n¼ 97)

Alogliptin 12.5 mgþ

pioglitazone

(n¼ 197)

Alogliptin 25 mgþ

pioglitazone

(n¼ 199)

p-value,

alogliptin

vs. placebo

Achieved HbA1c� 7% 33 (34.0) 87 (44.2) 98 (49.2) �0.016

HbA1c reduction of �1% 12 (12.4) 64 (32.5) 73 (36.7) 50.001

Marked hyperglycemia 43 (44.3) 49 (25.0) 43 (21.7) 50.001

Hyperglycemic rescue 12 (12.4) 19 (9.7) 18 (9.0) �0.101

HbA1c¼ glycosylated hemoglobin

−1.4

−1.2

−1.0

−0.8

−0.6

−0.4

−0.2

0.0

Placebo + pioglitazoneAlogliptin 12.5 mg + pioglitazoneAlogliptin 25 mg + pioglitazone

HbA1c < 8.0 HbA1c ≥ 8.0

*†

LS

mea

n ch

ange

fro

m b

asel

ine

in H

bA1c

, %

†

†

Figure 3. Least squares (LS) mean changes from baseline

to Week 26 (last observations carried forward) in

glycosylated hemoglobin (HbA1c) in patients with baseline

values of HbA1c5 8.0 and �8.0. *p50.001; yp50.005

(vs. placebo)

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alogliptin 25 mg, 5.6% for alogliptin 12.5 mg, and 6.2%

for placebo.

The overall incidences of AEs that led to treatment

discontinuation were similar across treatment groups

(Table 3). The individual AEs that resulted in disconti-

nuation were abnormal liver function test, cellulitis,

colon cancer, congestive cardiac failure, coronary

artery disease, dermatitis, hypokalemia, increased

blood calcium, myocardial infarction, neuropathy,

orthostatic hypotension, pitting edema, pneumonia,

serum sickness, and sudden death. None of these

events led to discontinuation of more than one patient.

Adverse events by system organ class are also shown

in Table 3. Cardiac disorders occurred in a higher

percentage of patients who received alogliptin 25 mg

(6.5%) than among those who received placebo

(1.0%) or alogliptin 12.5 mg (3.0%). Six patients expe-

rienced a total of seven cardiac AEs of severe intensity

as follows: myocardial infarction (1 receiving alogliptin

12.5 mg and 2 receiving alogliptin 25 mg), coronary

artery disease (2 receiving alogliptin 12.5 mg), and con-

gestive heart failure (2 receiving alogliptin 25 mg). Two

patients (both receiving alogliptin 25 mg) experienced

cardiac AEs that were considered by the investigator to

Table 3. Treatment-emergent adverse events reported during the treatment period

Patients, n (%) Placeboþ

pioglitazone

(n¼ 97)

Alogliptin 12.5 mgþ

pioglitazone

(n¼ 198)

Alogliptin 25 mgþ

pioglitazone

(n¼ 199)

�1 AE 63 (64.9) 138 (69.7) 144 (72.4)

�1 Drug-related AE 18 (18.6) 37 (18.7) 37 (18.6)

�1 AE resulting in study discontinuationa 3 (3.1) 6 (3.0) 6 (3.0)

�1 Serious AE 4 (4.1) 5 (2.5) 13 (6.5)

�1 Drug-related serious AE 1 (1.0) 1 (0.5) 3 (1.5)

AEs reported by45% of patients in

any treatment group

Peripheral edema 7 (7.2) 12 (6.1) 11 (5.5)

Nasopharyngitis 6 (6.2) 8 (4.0) 14 (7.0)

Upper respiratory tract infection 5 (5.2) 11 (5.6) 10 (5.0)

Headache 4 (4.1) 8 (4.0) 10 (5.0)

Influenza 4 (4.1) 3 (1.5) 11 (5.5)

Sinusitis 6 (6.2) 5 (2.5) 4 (2.0)

Bronchitis 5 (5.2) 4 (2.0) 3 (1.5)

Cardiac disorders 1 (1.0) 6 (3.0) 13 (6.5)

Atrial fibrillation 0 1 (0.5) 2 (1.0)

Cardiac failure congestive 0 0 3 (1.5)b

Myocardial infarction 0 1 (0.5) 2 (1.0)

Angina pectoris 0 1 (0.5) 1 (0.5)

Coronary artery disease 0 2 (1.0) 0

Tachycardia 0 1 (0.5) 1 (0.5)

Ventricular extrasystoles 0 0 2 (1.0)

Aortic valve sclerosis 0 0 1 (0.5)

Atrioventricular block first degree 0 1 (0.5) 0

Bradycardia 0 0 1 (0.5)

Left bundle branch block 1 (1.0) 0 0

Cardiomegaly 0 1 (0.5) 0

Palpitations 0 0 1 (0.5)b

Supraventricular extrasystoles 0 0 1 (0.5)

Gastrointestinal AEs 13 (13.4) 33 (16.7) 22 (11.1)

Infection and infestation AEs 36 (37.1) 69 (34.8) 67 (33.7)

Skin and subcutaneous tissue AEs 15 (15.5) 23 (11.6) 24 (12.1)

AE¼ adverse eventaAn AE that led to treatment discontinuation or study terminationbAE in 1 patient was considered possibly drug related

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be possibly drug related. One of these was a case of

palpitations of moderate intensity. The other was a seri-

ous AE of congestive heart failure, of moderate inten-

sity, in a 61-year-old Asian woman. The incidence of

AEs of the skin and subcutaneous tissues, which were

monitored closely because of concerns regarding other

DPP-4 inhibitors, was similar between patients who

received alogliptin and those who received placebo.

The incidences of gastrointestinal AEs of any type

were similar across treatment arms, as were the inci-

dences of events in the Infections and Infestations

system organ class.

Although serious AEs (SAEs) were more common

among patients treated with alogliptin 25 mg than

among those who received alogliptin 12.5 mg or pla-

cebo, SAEs considered by investigators to be possibly

or probably drug related were rare in all three treat-

ment groups (Table 3); no SAEs were considered

definitely related. Incidences of cardiac disorder

SAEs were higher for alogliptin (1.0% for 12.5 mg

and 2.5% for 25 mg) than for placebo (no patients).

Infections classified as SAEs were more common with

alogliptin 25 mg (2.5%) than with alogliptin 12.5 mg

(no patients) or placebo (1.0%), but none of these

SAEs was considered drug related. The following

five single SAEs were considered possibly or probably

drug related by the investigator: hypokalemia (pla-

cebo), road traffic accident (alogliptin 25 mg), conges-

tive heart failure (alogliptin 25 mg), serum sickness

(alogliptin 25 mg) and sudden death (alogliptin

12.5 mg). The patient who died suddenly was a

62-year-old man who received alogliptin 12.5 mg for

42 days. During the study, he also received pioglita-

zone 30 mg/day, glyburide 2 mg/day and simvastatin

20 mg/day; he was treated with rosiglitazone 4 mg/day

before study entry. He was a former smoker with a

BMI of 29.7 kg/m2 who had been diagnosed with dia-

betes 13.3 years before enrollment. His death was

considered possibly drug related; no autopsy was

performed.

One patient treated with alogliptin 25 mg experi-

enced an AE of mild hypoglycemia. Events of hypogly-

cemia not reported as AEs occurred with similar

frequency in patients given placebo (5.2%), alogliptin

12.5 mg (5.1%) or alogliptin 25 mg (7.0%). None of

these events was severe. A post hoc subgroup analysis

of the incidence of hypoglycemia by companion oral

antidiabetic therapy indicated that incidences of

hypoglycemia were higher in patients taking a sulfony-

lurea at baseline (21 of 104 patients [20.2%]) than in

those taking metformin (8 of 277 patients [2.9%])

(Figure 5). No hypoglycemia was observed in patients

treated with pioglitazone alone at baseline (0 of 113

patients).

Discussion

This study was designed to evaluate alogliptin in a

type 2 diabetes patient population representative of

that encountered in clinical practice, including the

elderly and those with a long history of diabetes. For

most study participants, glycemic control was poor at

baseline, despite the use of one or more hypoglycemic

agents. Compared with placebo, either dose of aloglip-

tin caused significant reductions in HbA1c and FPG

when added to pioglitazone therapy with or without

metformin or a sulfonylurea. These improvements

were statistically significant at the earliest assessment

and at every subsequent measurement throughout the

26-week treatment period. Alogliptin also was signifi-

cantly more effective than placebo in reducing HbA1c

to �7.0% and in reducing the incidence of marked

hyperglycemia.

Overall, the efficacy results of this study are consis-

tent with findings of similar studies of other DPP-4

inhibitors (i.e., vildagliptin and sitagliptin)15–17. All

studies reported significant reductions in HbA1c and

FPG compared with placebo in patients treated with

pioglitazone15–17 and significant increases in the per-

centage of patients who achieved the ADA goal of

HbA1c57.0%. In this study, baseline HbA1c levels

influenced the magnitude of HbA1c reduction with

alogliptin such that greater treatment benefits were

observed among patients with higher baseline values.

Similar effects have been observed for combination

therapy with pioglitazone and vildagliptin15.

Furthermore, a meta-analysis of 61 studies, in which a

wide range of oral antidiabetic agents, including combi-

nations, were used, found significant correlations

between mean baseline FPG concentrations and mean

decrease in FPG, and between mean baseline HbA1c

and mean decrease in HbA1c18. These correlations

Placebo + pioglitazoneAlogliptin 12.5 mg + pioglitazoneAlogliptin 25 mg + pioglitazone

0

5

10

15

20

25

30

Sulfonylurea Metformin

Pat

ient

s w

ith h

ypog

lyce

mia

, %

3/56 3/107 2/114 2/18 7/42 12/44

Figure 5. Percentage of patients with events of hypoglycemia

by treatment arm and concomitant oral antidiabetic therapy.

Fractions at the bottom of each bar indicate the proportion of

patients with hypoglycemia in each subgroup

2368 Alogliptin plus pioglitazone for diabetes � 2009 Informa UK Ltd - Curr Med Res Opin 2009; 25(10)

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may account for some of the variation in absolute

HbA1c reductions observed in different studies of

DPP-4 inhibitors combined with pioglitazone15,16.

When patients with a mean baseline HbA1c of 8.1%

were treated with sitagliptin, HbA1c decreased by

0.70%, a change nearly identical to those observed in

the present study (mean baseline HbA1c, 8.0–8.1%;

mean change, �0.67 to �0.80%)16. In contrast, combi-

nation therapy with vildagliptin and pioglitazone in

patients with mean baseline HbA1c values of 8.6%

and 8.7% produced slightly larger mean reductions in

HbA1c (0.8 to 1.0%)15. HbA1c reductions up to 1.9%

were observed for vildagliptin and pioglitazone treat-

ment given as initial combination therapy17.

Consistent with clinical data indicating little or no

weight gain with other DPP-4 inhibitors used in com-

bination with pioglitazone15–17, alogliptin on average

was not associated with weight gain relative to placebo.

Patients in all three treatment groups experienced, on

average, a small increase in weight of approximately

1 kg over the treatment period of 26 weeks, but differ-

ences in weight gain between treatment groups were

not statistically significant. These results suggest that

alogliptin is a weight-neutral agent.

The combination of alogliptin and pioglitazone gen-

erally was well tolerated. Although the incidence of

reported AEs was higher with alogliptin than with pla-

cebo, the incidence of drug-related AEs was similar in

all treatment groups. Likewise, the rates of discontinua-

tion attributable to AEs were low across treatment

groups, consistent with observations for other DPP-4

inhibitors in similarly designed studies15–17. Although

not suggested in animal studies for alogliptin, such stu-

dies with other DPP-4 inhibitors have raised concerns

that some of these agents may increase the incidence of

skin-related AEs19. Results of the present study suggest

that the addition of alogliptin to therapy with pioglita-

zone does not affect the incidence of AEs of the skin

and subcutaneous tissues. The overall incidences of gas-

trointestinal disorder and infection also were similar in

all three treatment arms. Alogliptin was not associated

with an increased incidence of peripheral edema, a

common AE of TZDs. Although SAEs occurred with

greater frequency in the alogliptin 25 mg patient group

(6.5%), a dose trend was not evident because SAEs

were reported for a larger percentage of patients

given placebo (4.1%) than of those given alogliptin

12.5 mg (2.5%).

Cardiac disorders of any cause occurred more fre-

quently in patients treated with alogliptin than in

those who received placebo. However, only 2 patients

(both treated with alogliptin) experienced cardiac AEs

that were considered related, or possibly related, to

study medication. In a similarly designed study of

alogliptin therapy added to the sulfonylurea

glyburide20, no difference in the incidence of cardiac

disorders between the active and placebo treatment

arms was noted. However, in a study of alogliptin

monotherapy in patients with type 2 diabetes21, the

frequency of cardiac AEs followed a pattern similar to

that observed in the present study (data on file). A pos-

sible explanation for these different findings is that

treatment groups in the various studies may have

been unequally matched for pre-existing cardiac risk

factors. The incidence of cardiac AEs considered related

to alogliptin by blinded study investigators was 1.1% or

less in these three randomized, double-blind, placebo-

controlled studies, but no drug-related cardiac AEs

were reported for the respective placebo groups (data

on file). Because alogliptin-related cardiac AEs were

lower in the present study than in the similarly designed

alogliptin monotherapy study (data on file), it is unli-

kely that such events were the result of drug inter-

actions between alogliptin and pioglitazone. Further

study is needed to clarify the clinical importance of

these findings across diverse cardiovascular endpoints.

The utility of improving glycemic control by combin-

ing TZD therapy with modulation of the incretin

system has been demonstrated not only with DPP-4

inhibitors but also with incretin mimics of native

GLP-18. A recent 16-week study in patients with sub-

optimal glycemic control evaluated the efficacy and

safety of the incretin mimetic exenatide as add-on ther-

apy to TZDs9. This placebo-controlled study found

that exenatide, administered twice daily by subcutane-

ous injection, improved glycemic control and pro-

moted weight loss. However, the 16% discontinuation

rate attributable to AEs in the active treatment arms

was far higher than discontinuation rates observed

with alogliptin or other oral DPP-4 inhibitors15–17.

Exenatide was associated with a high incidence of

gastrointestinal AEs, particularly nausea (39.7%) and

vomiting (13.2%), compared with placebo (nausea,

15.2%; vomiting, 0.9%)9.

Alogliptin did not increase or reduce the incidence of

hypoglycemia compared with placebo. However, sub-

group analysis by concomitant oral antidiabetic therapy

(i.e., metformin or a sulfonylurea) showed that patients

without such therapy experienced no hypoglycemia at

any time during the study, irrespective of whether they

received placebo or alogliptin. This strongly suggests

that combining pioglitazone and alogliptin did not

promote hypoglycemia. Importantly, the vast majority

of cases of hypoglycemia were associated with concom-

itant use of a sulfonylurea, whereas few cases were

associated with the use of metformin. Addition of

alogliptin to therapy with pioglitazone and a sulfony-

lurea increased the incidence of hypoglycemia

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(19 of 86; 22.1%) compared with that in the group

treated with placebo, pioglitazone and a sulfonylurea

(2 of 18; 11.1%), but the small size of the latter group

does not permit conclusions regarding the clinical sig-

nificance of the results. Conversely, among patients

who used metformin as concomitant medication, and

who constituted a much larger subgroup population

than those using a sulfonylurea, the incidence of hypo-

glycemia was lower with alogliptin (5 of 221; 2.3%)

than with placebo (3 of 56; 5.4%).

The short duration of the present study places inher-

ent limitations on the interpretation of efficacy and

safety results. Larger, longer-term, open-label safety

studies may be necessary to better understand the clin-

ical significance of the increased incidence of cardiac

events associated with alogliptin therapy in the present

study. Studies that evaluate the effect of combined alo-

gliptin and pioglitazone therapy on long-term clinical

outcomes may help to determine whether alogliptin

ultimately reduces cardiovascular risk in patients with

type 2 diabetes, with or without cardiac comorbidities.

Because most patients in our study were receiving met-

formin or a sulfonylurea as a first-line medication for

diabetes, no conclusions can be drawn from this study

regarding the use of alogliptin plus pioglitazone as first-

line therapy in patients with type 2 diabetes.

Conclusions

Alogliptin significantly improved glycemic control after

26 weeks in patients with type 2 diabetes with inade-

quate glycemic control on TZD therapy alone or in

combination with metformin or a sulfonylurea.

Alogliptin was most effective in patients with relatively

poor glycemic control, as defined by baseline

HbA1c� 8%. Overall, alogliptin had no clinically signif-

icant effect on the incidence of hypoglycemia, which

occurred most often in patients who also were taking a

sulfonylurea. Alogliptin on average was weight neutral.

Although alogliptin generally was well tolerated, a low

percentage of patients given active treatment (0.5%)

experienced possibly drug-related adverse cardiac

events. However, this study found no evidence of unfa-

vorable interactions of alogliptin with pioglitazone and

no increased incidence of skin-related AEs associated

with alogliptin. In sum, the results suggest that combi-

nation therapy with alogliptin and pioglitazone may be

an effective strategy in clinical practice for improving

glycemic control in patients with type 2 diabetes

who experience inadequate control with first-line

antidiabetic medications such as metformin and

sulfonylureas.

Transparency

Declaration of fundingFinancial support for this study, analysis and manuscriptdevelopment was provided by Takeda Global Research &Development Center, Inc., Deerfield, IL, USA.

Declaration of financial/other relationshipsQ.M., P.F. and C.W. have disclosed that they are employeesof Takeda. R.E.P. has disclosed that he has received investi-gator-initiated grants from Takeda and Merck; has received‘industry-based’ clinical trial support from Pfizer, Merck,GlaxoSmithKline, Takeda, and several other pharmaceuticalcompanies; and has consulted for GSK, Takeda, Merck,Novartis, NovoNordisk, and Roche. He owns stock inNovartis. J.E.-B.R. has disclosed that she has received inves-tigator-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 andTakeda, and is on the speakers’ bureau of Merck. Q.M. hasdisclosed that he owns stock in Takeda.

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

AcknowledgmentEditorial assistance with manuscript preparation was pro-vided 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, ThomasN, Viswanathan M; Netherlands – van Leendert R; NewZealand – Dissanayake A, Scott R, Young S; Peru – GonzalesL, 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, FogelfeldL, 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, LindleyM, Lipetz R, Littlejohn T, Long W, Lowder C, Lucas J, LynnL, Mark G, Marple R, Mayeda S, Morin D, Mullen J, NorwoodP, Oates S, Odugbesan A, Phillips F, Plevin S, Popeil L, PratleyR, 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 notenroll patients and are not listed; one investigator enrolledpatients at two separate sites and is listed once.)

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CrossRef links are available in the online published version of this paper:

http://www.cmrojournal.com

Article CMRO-4771_3, Accepted for publication: 1 July 2009

Published Online: 3 August 2009

doi:10.1185/03007990903156111

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