• Change in HbA1c at end of study.
  

The purpose of the study is to evaluate the efficacy of the addition of SYR-322 versus increasing dose of pioglitazone HCl in subjects with type 2 diabetes mellitus who are inadequately controlled on a combination of metformin and pioglitazone HCl therapy. Subjects will undergo necessary evaluations to determine eligibility for the study during a Screening period, and eligible subjects will participate in a Stabilization period. Randomized subjects will receive treatment with SYR-322 plus pioglitazone HCl placebo or SYR-322 placebo plus pioglitazone HCl (in addition to metformin), followed by a Follow-Up period.

Inclusion Criteria:

• The subject is male or female, 18 to 80 years of age, with a historical diagnosis of type 2 diabetes mellitus.
• The subject’s diabetes is inadequately controlled on a stable dose of metformin plus pioglitazone HCl.
• Female subjects of childbearing potential (ie, not surgically sterile and/or not postmenopausal) must be practicing adequate contraception.

Exclusion Criteria:

• The subject has a urine albumin/creatine ratio of greater then 100 µg/mg (113 mg/mmol).
• The subject has a history of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening.
• The subject has had gastric bypass surgery.
• The subject has New York Heart Association Class III or IV heart failure regardless of therapy. Currently treated subjects who are stable at class I or II are candidates for the study.