The hypothesis of this Phase 2, 12-week study, is that DS-8500a will improve glycemic control relative to placebo, based on changes in HbA1c, with acceptable safety and tolerability, in patients with Type 2 Diabetes Mellitus (T2DM) who are treated with metformin.

Inclusion Criteria:

• Able to provide written informed consent and adhere to the study visit schedule and treatment
• Diagnosed with Type 2 diabetes mellitus as defined in the American Diabetes Association Standards of Medical Care in Diabetes 2015
• Male or female ≥ 18 and ≤ 70 years of age
• Screening fasting C-peptide > 0.5 ng/mL
• Women of child bearing potential (WOCBP) must be willing to use double-barrier contraception for the entire study
• WOCBP must have a negative pregnancy test (human chorionic gonadotropin, beta subunit [βhCG]) before entering the Lead-in Period
• Body mass index ≥ 25 kg/m2 and ≤ 45 kg/m2 at the Screening Visit
• On stable (≥ 8 weeks) metformin monotherapy ≥ 1000 mg/day
• Screening HbA1c ≥ 7.0% and ≤ 10%
• Taking ≥ 80% and ≤ 120% of both dispensed DS-8500a placebo tablets and sitagliptin placebo capsules during the Lead-in Period

Exclusion Criteria:

• History of type 1 diabetes and/or history of ketoacidosis

• History of insulin use for > 2 weeks within 2 months prior to the Screening Visit

• Two or more readings of fasting Self-monitoring of Blood Glucose (SMBG) > 240 mg/dL or worsening symptoms of hyperglycemia with one SMBG level of > 240 mg/dL during the second week of Lead-in Period, confirmed by laboratory measurement

• Screening hemoglobin <12 g/dL for males and <11 g/dL for females

• Blood donation within 2 months prior to the Screening Visit or plans to donate blood or blood products during the study

• Subjects after bariatric surgery or any gastric bypass

• Screening thyroid stimulating hormone (TSH) levels not within normal range (based on reference laboratory values )

• Screening Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) > 2.0 x upper limit of normal (ULN), and/or total bilirubin > 1.5 x ULN. If a subject has total bilirubin > 1.5 ULN, unconjugated and conjugated bilirubin fractions should be analyzed and only subjects documented to have Gilbert's syndrome may be enrolled

• Screening Serum creatinine ≥ 1.5 mg/dL for males and ≥ 1.4 mg/dL for females, or creatinine clearance (CrCl) < 50 mL/min for both males and females

• Screening Creatine kinase (CK) > 3.0 × ULN

• History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, peripheral arterial event or any revascularization procedure during the 6 months prior to the Screening Visit or planned vascular procedures or surgery during study period

• History of congestive heart failure (CHF)

• Exclusionary concomitant medications:

  a. Eight weeks prior to screening and throughout the duration of the study:

• Any diabetes medication other than metformin; any prescription or over the counter medication for weight-loss.

• Systemic corticosteroids (including nasal and inhaled), with the exception of use of topical and ophthalmic corticosteroids.

• Rosuvastatin > 20 mg daily. b. During treatment periods, additional medications will be prohibited based on potential drug-drug interaction (DDI) (see Section 5.6)

• Subjects with anticipated interruption in metformin or study drug use during the course of the clinical trial (e.g., due to an imaging procedure involving iodinated contrast media)

• Subjects in whom treatment with sitagliptin 100 mg is contraindicated ( e.g., known hypersensitivity or intolerance to sitagliptin) or may not be medically advisable (e.g., history of pancreatitis)

• Abuse of or dependence on prescription medications, illicit drugs, or alcohol within the last 1 year

• Any history of a malignancy other than basal cell carcinoma within the past 5 years

• Pregnancy or breast-feeding, or intent to become pregnant during the study period

• Known (or evidence of) infection with human immunodeficiency virus

• Any condition, laboratory abnormality, or concomitant therapy which, in the opinion of the Investigator, might pose a risk to the subject or make participation not in the subject's best interest

• Subject is currently enrolled in or has not yet completed at least 30 days since ending another investigational device or drug study or is receiving other investigational agents

• A direct or familial relationship with the Sponsor, Investigator, or site personnel affiliated with the study

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.

Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.