The prevalence of type 2 diabetes mellitus (T2DM) in Qatar and nations worldwide has increased in recent decades into epidemic proportions. Cardiovascular (CVD) disease is the leading cause of death in T2DM patients. Approximately 80% of T2DM patients will die because of CV cause. Congestive heart failure (CHF) is a major cause of CV death in T2DM, and it also is responsible for significant morbidity and health care expenditure due to high rate of hospitalization for heart failure.

Community based studies have demonstrated similar prevalence of HF with reduced ejection fraction (HFpEF) and HF with reduced LV function (HFrEF) in patients hospitalized for CHF. Moreover, the prevalence of HFrEF is declining over the past two decades, whereas that of HFpEF is progressively increasing. Progressive increase in obesity and T2DM prevalence is likely among the principal factors responsible for the steady increase in HFpEF prevalence.

The aims of the present study are to examine whether therapies that correct the myocardial metabolic abnormalities present in subjects with T2DM and diastolic dysfunction improve myocardial diastolic dysfunction and reduce the rate of hospitalizations in patients with HFpEF

The primary objective of the study is to examine the effect of combination therapy with pioglitazone (15 mg) plus dapagliflozin (10 mg) versus placebo on hospitalization for heart failure in patients with HFpEF.

Eligible subjects, who consent for participating in the study, will be seen by the study coordinator. Medical history and physical examination will be performed. Each subject will receive the following measurements:

Medical history and physical examination including weight, height, waist, blood pressure and pulse.

Blood tests:

Screening: CBC, Blood chemistry, fasting plasma glucose concentration, HbA1c, renal and liver function, lipid profile, TSH, serum iron, iron biding capacity and ferritin.

Plasma metabolites: ketone, lactate, bicarbonate, venous PH and plasma free fatty acid.

Hormones: insulin, C-peptide, glucagon, NT proBNP, angiotensin II, plasma renin activity, and aldosterone.

Inflammatory markers: adiponectin, hsCRP, IL-2, IL-6 and IL-12, F2-isoprostane, oxidized LDL.

Vascular Measurements: Measurement of pulse wave velocity, and central aortic pulse pressure, with sphygmocor.

Measurement of total body fat mass with Bioimpedence. Echocardiography

Patients will be consented on the day of discharge or during the outpatient visit in the Cardiology Clinic. Consented patients will be referred to the CRC within one week to perform the echocardiography and vascular measurements. Patients will be asked to come to CRC after overnight fast and blood samples will be drawn for the above mentioned blood tests, after which echocardiography and vascular measurements will be performed.

Randomization and Intervention:

After completing the baseline studies, patients will be randomized into two groups to receive in a double blind fashion:

Group 1: combination of pioglitazone plus dapagliflozin, or Group 2: Placebo (Beta blockers, ACEI, ARB, and aldosterone )

Patients in both groups will be matched for age, gender, BMI, HbA1c, systolic BP and LVEF. Randomization will be made by the pharmacist at the Heart Hospital and the randomization code will be maintained at the hospital pharmacy. Patients will be randomized in blocks of 4 while the group means are matched for the above parameters

Inclusion Criteria:

1. Diagnosis of type 2 diabetes according to the ADA criteria.
2. Drug naïve or on stable dose of antidiabetic therapy (oral agents and/or insulin) for 3 months preceding recruitment.
3. Hospitalized for HFpEF (defined as hospitalization require intravenous diuresis) in the 6 months preceding recruitment.
4. eGFR >60 ml/min
5. LVEF >50%
6. Presence of LV diastolic dysfunction in echocardiography

We have limited the inclusion criteria in the present study to T2DM patients with HFpEF and evidence of diastolic dysfunction by echocardiography in order to select a homogenous group of HFpEF patients with similar etiology, likely "metabolic HFpEF". We believe that this subgroup of HFpEF will benefit most from treatment with low dose pioglitazone (15 mg) plus dapagliflozin (10 mg).

Exclusion Criteria:

1. Treatment with pioglitazone or SGLT2 inhibitor in the 3 months prior to recruitment.
2. eGFR < 60 ml/min
3. LVEF <50%;
4. Valvular heart disease, ASD, VSD
5. Chronic lung disease
6. Cancer
7. diabetes mellitus type 1
8. patients with acute coronary syndrome, stroke or transient ischemic attack in the preceding 6 months
9. pregnancy or lactation period

Random process