Anti-Inflammatory Small Drug Adjunctive Therapy for Type 2 Diabetes

INCLUSION CRITERIA 1. Patients 21-75 years of age inclusive who meet the American Diabetes Association standard criteria for type 2 diabetes mellitus (T2D). 2. Subjects are currently on metformin (at least 1000 mg per day) for a minimum period of 4 weeks prior to screening visit alone, or in combination with any of the following diabetes medications or combinations: 1. DPPIV inhibitor (any dose level/frequency) 2. Sulfonylurea (any dose level/frequency) 3. GLP1 agonist (any dose level/frequency) 4. Sulfonylurea (any dose level/frequency) + GLP1 agonist (any dose level/frequency) 5. Meglitinide (any dose level/frequency) 6. SGLT2 inhibitor (any dose level/frequency) 3. Patients must have a body-to-mass index (BMI) of greater than or equal to 27 kg/m2. 4. Patients exhibit glycated HbA1c between 7.3-11.0 during eligibility screening and then \<=8.5 at final run-in visit. 5. Willingness to replace current diabetes therapies (listed in inclusion 2) with metformin and saxagliptin and to adjust metformin dose during run-in period. 6. Subjects present adequate immune competence as assessed by immunoreactivity to viral antigens (CEF Pool Assay) in vitro at the time of screening. 7. Participants of childbearing potential must agree to practice an effective form of birth control which may include any one of the following: barrier method, oral contraception, or surgery. These measures must be maintained throughout the study. 8. Subjects must have good peripheral venous access for the hyperinsulinemic-euglycemic clamp and the 3-hr. OGTT procedures. 9. Patients understand the study procedures, alternative treatments available, risks involved in the study, and voluntarily agree to participate by giving informed and signed written consent for screening and enrollment. 10. Participants can be on anti-inflammatory therapies that are not diabetes-focused (e.g. non-salicylate anti-inflammatory therapies, non-salicylate NSAIDs) and/or anti-hypertensive medicaments or statins. EXCLUSION CRITERIA 1. Patients with type 1 diabetes mellitus as defined by the American Diabetes Association criteria or a history of ketoacidosis, or the patients are assessed by the study team as possibly having type 1 diabetes mellitus confirmed with the presence of at least one of the typical autoantibodies (insulin, GAD65, IA-2, ZnT8) AND a serum C-peptide level of \<0.7 ng/mL. 2. Patients have been treated with any therapies specific for their diabetes (other than those listed in the inclusion criteria) within 4 weeks of the screening visit. 3. Patients have been treated with insulin within 2 months of the screening visit. 4. Patients are currently participating in or have participated in another study with an investigational compound or device within the prior 12 weeks of signing the informed consent or do not agree to refrain from participating in any other study while participating in this study. 5. Patients have a history of hypersensitivity or any contraindication to DPPIV inhibitors, including saxagliptin (Onglyza), or metformin based upon the labels of the USA. 6. Patients are on a weight loss medication (such as orlistat, phentermine, Qsymia, or Belviq) within the prior 6 weeks. 7. Patients are required by treating physicians to remain on any one of these agents during the trial: macrolide antibiotics, cisapride, anti-arrhythmics, steroids, rifampicin, phenobarbital, phenytoin, secobarbital, carbamazepine, norethindrone, isoniazid. AZD9668 is metabolized by CYP3A4, 3A5, and 2B6. SAXA is metabolized by CYP3A4 and 3A5, potentially leading to drug-drug interactions with hypothetical adverse events in patients on the above agents. Also, AZD9668 causes weak inhibition of CYP2C9 and therefore patients on fluconazole, amiodarone, fenofibrate, fluvoxamine, phenylbutazone, probenecid, sertraline, will also be excluded to avoid the hypothetical adverse events due to this effect. 8. Patients have undergone major surgery within the 6 weeks prior to signing consent or have any type or form of major surgery planned during the study (at the discretion of the physician). 9. Patients are on or are likely to require treatment with 14 consecutive days or repeated courses of pharmacologic doses of corticosteroids or any other immunomodulatory agent. For example, patients requiring chronic systemic corticosteroids (does not include topical or inhaled corticosteroids). Exceptions are over the counter non-salicylate NSAIDs. 10. Enrollment or history of enrollment in a drug, or biologic therapy clinical trial that affects the immune system within the past 12 months (e.g., systemic immunosuppressive pharmacologics, immunosuppressive cytokines, therapeutic immunomodulating antibodies, therapeutic immunomodulating fusion proteins and/or cytokine receptor decoys as well as any intervention and/or non-intervention induced immunodeficiencies). 11. Prior history of coronary artery disease (defined as myocardial infarction, angina, bypass surgery, or angioplasty) 12. Prior history of arrhythmia (excludes premature beats) 13. Prior history of heart failure defined as i) symptomatic OR ii) pulmonary edema, leg edema or low ejection fraction (\<40%) 14. Evidence of refractory chronic migraine (defined in ICHD-3 and Martelletti et al.). 15. History of persistent bradycardia within the last year prior screening visit (more than three episodes in a calendar year of a heart rate \<60 beats per minute that required hospitalization on each of these occasions). 16. Leukopenia (\<3000 leukocytes/microliter), neutropenia (1500 neutrophils/microliter), lymphopenia (\<800 lymphocytes/microliter), or thrombocytopenia (\<125000 platelets/microliter),. any other clinically relevant abnormal hematology value. 17. Positivity for HIV, active CMV, chlamydia, any evidence of serious fungal infection, active HSV1and/or HSV2 (determined as IgM positivity of 2 standard deviations higher than the highest value of the test reference range), hepatitis B or C, at screening. Minor skin fungus, or minor candidiasis is not an enrollment or treatment exclusion criterion. Also, with the exception of HIV history, hepatitis B and C, successfully-treated, disease-free individuals (\> 6 months between time of successful treatment confirmation and time at screening) would be eligible for enrollment in this trial. 18. Patients are required by treating physician to remain on any medications listed in inclusion #2 that directly affect glucose metabolism such as, but not limited to thiazolidinediones, pramlintide, or amylin. 19. Vaccination with any form of live vaccine product within the last 3 months prior to initiation of study agent administration. 20. Any chronic disease that in the opinion of the investigators would affect the patient's safety and/or the integrity of the study outcome. This does not include dyslipidemia, patients on statin or anti- hypertension treatment, or patients with well-controlled hypo- or hyperthyroidism 21. Any other disease or disorder requiring chronic drug therapy except for treated hypothyroidism (T4 and TSH should be within the normal reference range adjusted for age), celiac disease, or statin- maintained, uncomplicated lipidemia. 22. Evidence of liver dysfunction, with ALT or AST\> 1.5 times the upper limit of normal. 23. Evidence of renal insufficiency as indicated by blood creatinine of \> 2 times the upper limit of normal at baseline screening OR an eGFR \< 45 mL/min. OR A past history or current clinical evidence of renal failure or low creatinine clearance at screening. 24. Females who are pregnant at the time of screening or unwilling to defer pregnancy during the study period. 25. Lactating women. 26. Poor accessibility to veins for the 3-hour OGTT and hyperinsulinemic-euglycemic clamp procedures. 27. The following therapies cannot be administered while patients are undergoing treatment on this protocol: i) radiation therapy; ii) chemotherapy; iii) corticosteroids (except for very short courses of topical or inhaled); iv) agents used to treat attention deficit and hyperactivity disorder (ADHD); v) rifampicin or phenytoin; vi) other protein, particle or cell vaccine immunomodulation therapies. If these therapies are essential for treatment of other conditions, participation in this study will be terminated. 28. A condition which interferes with the ability to accurately determine glycated HbA1c. Examples include: Genetic variants (e.g. HbS trait, HbC trait), elevated fetal hemoglobin (HbF) and chemically modified derivatives of hemoglobin (e.g. carbamylated Hb in patients with renal failure); Any condition that shortens erythrocyte survival or decreases mean erythrocyte age (e.g., recovery from acute blood loss, hemolytic anemia); Iron deficiency anemia, iron replacement therapy 29. Subjects who cannot tolerate at least 1000 mg daily of immediate or extended release metformin by the time of final run-in will be excluded from further participation. 30. Subjects who do not exhibit a glycated HbA1c level \<=8.5 by the end of the run-in period.