Linagliptin's Effect on CD34+ Stem Cells

Role of Linagliptin in Improving Renal Failure by Improving CD34+ Stem Cell Number, Function and Gene Expression in Renal Function Impaired Type 2 Diabetes Patients.

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).

Diabetes Mellitus, Type 2, Endothelial cells, Cellular biomarker, endothelial dysfunction, CD34+, Impaired renal function

The investigators will use participants' peripheral blood derived CD34+ cells looking at number, function, and gene expression. Post Linagliptin will be compared to pre Linagliptin measurements. Here we report fold changes in protein populations as determined by ELISA.

Glycemic control is evaluated by measuring HbA1c levels to gauge changes in blood sugar control over last ~90 days

Measured via blood biochemistry eGFR, an alternative measurement to spot urine urine microalbumin/creatinine ratio presented above

Vessel health is assessed by looking at Arterial stiffness. Augmentation index (AI) is defined as the ratio of the augmentation pressure to the pulse pressure, times 100, to give a percentage. Augmentation index 75 normalizes this value to an estimate of the AI at a heart rate of 75bpm. We used Vascular Flow and wave measurement equipment, SphygmoCor Central Pressure system from AtCor.

Vessel health is assessed by looking at Arterial stiffness. Pulse wave velocity (PWV) measures the delay between the pulse registered at the femoral artery from the pulse at the carotid. The difference in distance between these two measurement points from the aortic notch is divided by this delay to give a speed. In stiffer, less healthy vessels, the PWV is increased. We used Vascular Flow and wave measurement equipment, SphygmoCor Central Pressure system from AtCor to perform this calculation.

(RMR, similar to Resting Energy expenditure measurement): Evaluation of changes in Basal Metabolic Rate

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.

Awal HB, Nandula SR, Domingues CC, Dore FJ, Kundu N, Brichacek B, Fakhri M, Elzarki A, Ahmadi N, Safai S, Fosso M, Amdur RL, Sen S. Linagliptin, when compared to placebo, improves CD34+ve endothelial progenitor cells in type 2 diabetes subjects with chronic kidney disease taking metformin and/or insulin: a randomized controlled trial. Cardiovasc Diabetol. 2020 Jun 3;19(1):72. doi: 10.1186/s12933-020-01046-z.