This is a phase IV study that will explore the mechanisms of action of a drug (dapagliflozin) that is already commercially available in the country where the study will be conducted (Greece). The drug will be used according to its approved clinical indications (as add-on treatment in patients failed to achieve glycemic targets on metformin monotherapy) and in the approved posology (10 mg/day). Additionally, although there is limited data on the coadministration of dapagliflozin with thiazides, the excellent safety profile of the drug even when it is used in combination with drugs that induce significant volume depletion (such as loop diuretics) suggests that, in properly selected patients, the possibility of important adverse events during the coadministration of dapagliflozin with chlorthalidone is very low. All patients will give written informed consent prior to their enrollment in the study. The study protocol will be approved by the scientific committee of the University Hospital of Ioannina.

Fifty patients with type 2 diabetes on metformin monotherapy with HbA1c > 7% and blood pressure > 140/90 mmHg will be included. All eligible patients will be given dapagliflozin 10 mg qd for 3 months. Routine laboratory parameters that will be measured on each visit include: 1) for serum samples: glucose, urea, creatinine, uric acid, electrolytes (sodium, potassium, chloride, calcium, phosphate and magnesium and 2) for urine samples: glucose, urea, creatinine, uric acid, electrolytes (sodium, potassium, chloride, calcium, phosphate and magnesium) and alpha-1 microglobulin. It is well known that alpha-1 microglobulin is a low-molecular weight protein that is normally filtered by renal glomeruli and reabsorbed by the proximal tubular cells. Increased excretion of alpha1-microglobulin has been proposed as a non-invasive marker for the diagnosis and monitoring of early tubular disorders such as diabetic nephropathy. In addition, the fractional excretion values (FE) of the electrolytes will be calculated using the formula: FEA(%) = (UrineA/SerumA) /(UrineCr/SerumCr) × 100.

The 1HΝMR spectra of urine samples will be recorded on a 500 MHz spectrometer. In the present study, the main low molecular weight (LMW) constituents of urine that will be quantified are 1) metabolites such as glucose, creatinine, creatine, choline, taurine, dimethylamine, betaine, trimethylaminoxide 2) amino acids such as glycine, valine, alanine, leucine, histidine, lysine, threonine and 3) organic acids such as citrate, hippurate, lactate, acetate, succinate, and formate. In addition, 1HNMR methodology allows for the detection of changes in the concentrations of hundreds of metabolites. These substances are normally present in traces, whereas in pathological conditions their concentrations can be found increased.

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures
2. Female and/or male aged 18-70 years. Women with childbearing potential can only be included in the study if a serological pregnancy test is negative and a safe contraception method is used throughout the study.
3. Uncontrolled type 2 diabetes mellitus (HbA1c > 7%) on metformin monotherapy (≥ 2000 mg qd or maximum tolerated dose)
4. Stage 1 hypertension (BP 140-159/90-99 mmHg)

Exclusion Criteria:

1. Known primary kidney disease (eGFR < 60 ml/min)
2. History of cardiovascular disease
3. Type 1 diabetes
4. History of heart failure
5. Diseases that shorten the life expectancy (cancers, degenerative neurological disorders etc.)
6. Pregnancy-lactation
7. Patients with eGFR values lower than 45 ml/min (on repeated measurements) during the study period will be excluded