Type 2 diabetes is a national epidemic. Diabetes has undesirable effects on blood vessels which may contribute to heart disease. Endothelial Progenitor Cells (EPCs) are found in the blood. Research has shown that improving the survival of these special blood cells may decrease the harmful effects of diabetes on blood vessels and reduce or reverse heart disease. Linagliptin is an Food and Drug Administration (FDA) approved prescription medicine used along with insulin or with oral medications to lower blood sugar in people with Type 2 diabetes. It is in a class of diabetes medication called Dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4 inhibitors have been shown to increase EPCs in patients with Type 2 diabetes.

Hypothesis: Both type 2 diabetes and Chronic Kidney Disease (CKD) are associated with poor stem cell number and function. Poor viability and function of EPCs in CKD and diabetes The investigators hypothesize that use of Linagliptin (along with Insulin) may help reduce cardiovascular risk by improving EPC survival and function above and beyond adequate glucose metabolism control

Type 2 diabetes is a national epidemic with significant macro and microvascular complications. Insulin resistance in pre-diabetes and overt diabetes are associated with endothelial dysfunction.

A few studies indicate that stem cells particularly EPCs can act as a suitable bio-marker for monitoring cardiovascular morbidity. In this proposal the investigators suggest that EPCs or CD34 positive cells (defined as CD34/vascular endothelial growth factor receptor 2 (VEGFR2+) cells) can act as a suitable cellular biomarker for estimating and following endothelial dysfunction in early type 2 diabetes patients with CKD. EPCs have been shown to be dysfunctional in both CKD patients and type 2 Diabetes Mellitus (DM) patients.

Linagliptin (TRADJENTA) tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. No dose adjustment is recommended for patients with renal impairment.

EPCs have been used as a regenerative tool in ischemic myocardium and diabetic wound healing. Endothelial dysfunction with associated inflammation may be a consequence of excess intra-cellular super-oxide presence in a setting of diabetes which is a pro-oxidative stress condition ultimately leading to poor EPC function and senescence.

Though lifestyle modification has been proposed as a main stay for prevention and treatment of early type 2 diabetes, several new therapies for diabetes have been developed in recent years. Incretins and incretin mimetics appear to hold promise. Mechanism of positive effect of exercise and oral hypoglycemic agents can be very different.

DPP-4 inhibitors have been shown to increase EPCs in patients with type 2 diabetes reportedly via stromal cell-derived factor 1 (SDF-1) alpha up-regulation. Interestingly, up-regulation of SDF-1 alpha and vascular endothelial growth factor (VEGF), both chemotactic factors increase mobilization and recruitment of EPCs in the face of acute ischemic injury for repair and regeneration.

Several studies have shown positive effect of incretins (Glucagon like peptide, GLP-1) and incretin receptor agonists (GLP-1 receptor agonists) on cardiovascular risk factors in type 2 diabetes patients and even in patients with chronic heart failure and left ventricular dysfunction who do not have diabetes.

DPP-4 Inhibitors may have cardio-protective effects of their own, as they increase bio-availability of endogenous GLP-1. They improve blood flow and nitric oxide production in endothelium. These are unique properties not demonstrated by other oral diabetes medications. The mechanism underlying these effects may be mediated by increased nitric oxide bioavailability but is not completely known. However these beneficial effects appear to be independent of glycemia reduction.

It is however unknown whether Linagliptin will have any positive effect on human EPC function where two prominent cardiovascular risk factors co-exist such as CKD and type 2 diabetes.

Therefore the investigators plan to investigate if Linagliptin can alter function and gene expression of CD34+ cells in a setting of CKD and type 2 diabetes. The investigators choose to look at non geriatric adult population with early type 2 diabetes (less than 10 years of duration) at an early phase of renal impairment (stages 1-3).

Inclusion Criteria:

• Adults aged 30-70 years
• Diagnosis of type 2 diabetes within the previous 15 years using criteria of the American Diabetes Association
• Currently being treated with 1-2 grams/day of metformin, or insulin or both stably
• Hemoglobin A1c (HbA1C) between 6.5% to 10.0% (both inclusive)
• Body Mass Index (BMI) between 25 and 39.9 kg/m2 (both inclusive)
• Chronic Kidney disease (CKD) Stages 1-3, Creatinine clearance (CrCl) less than 90 and more than 29

Exclusion Criteria:

• Type 1 diabetes
• History of Diabetic Ketoacidosis (DKA) or hyperosmolar nonketotic coma
• Hemoglobinopathies with low hematocrit (Below 28 Units)
• History of pancreatitis
• History of cancer within the past 5 years (except basal cell carcinoma)
• Previous cardiovascular or cerebrovascular event within 6 months of screening or active or clinically significant coronary and/or Peripheral Vascular Disease (PVD)
• Statin use started in the last 3 month
• Current use of oral or injectable anti-diabetic medication other than Metformin and insulin
• Consistent use of steroids within the last 3 months
• Any active wounds, or surgery within the past 3 months
• Inflammatory disease, or the chronic use of anti-inflammatory drugs within the past 3 months
• Untreated hyper/hypothyroidism
• Contraindications to moderate exercise
• Implanted devices that might interact with the tanita scale
• Pre-existing liver disease and/or Alanine aminotransferase (ALT) and Aspartate Aminotransferase (AST) > 2.5 times Under the Normal Limits (UNL)
• Untreated Systolic blood pressure > 140 mmHg or diastolic blood pressure> 90 mmHg
• Serum creatinine levels ≥ 2.0
• CKD Stages 4 and 5 (estimated CrCl <30 mL/min)
• Triglycerides > 450 mg/dL
• Known allergies or hypersensitivities to Linagliptin or Dipeptidyl peptidase-4 (DDP-4) inhibitors
• Treatment with cytochrome p450 (CYP 3A4) inhibitors
• Women of child bearing age who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study
• Prisoners or subjects that are involuntarily incarcerated
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness
• Additionally, patients who are active smokers, patients who are pregnant, nursing women, and post-menopausal women who are on hormone replacement therapy will be excluded.

There is no current plan to share IPD with other researchers.

Adverse event data was collected from signing of informed consent to 30 days post final visit (approximately 16 weeks)

The adverse events that occurred during the duration of the study were isolated incidents, therefore, do not have any relation to the study intervention or medication regiment.

Limitations may include the relatively short duration of 12-week Linagliptin therapy. Limitations also arise because of the small sample size, and due to the difficulty in obtaining all cellular outcome measures, in some patients, due to low total CD34+ cell numbers. Further studies with a larger population and longer duration may be helpful to further define the mechanisms behind our findings.