Inhibition of Urinary Angiotensinogen and the Reduction of Blood Pressure by SGLT2 Inhibition in Patients With Type 2 Diabetes

Clinical trials of two SGLT2 inhibitors, canagliflozin and dapagliflozin, have reported drops in systolic blood pressure of ~5 mmHg. Inappropriate activation of intrarenal renin-angiotensin system (RAS) is a major contributor to the increased arterial pressure and tissue injury including diabetic nephropathy. A key factor in the intrarenal RAS activation is stimulation of intrarenal angiotensinogen (AGT) which is the precursor of angiotensin peptides. From previous studies, it has been shown that high blood sugars in patients with type1 and type 2 diabetes mellitus is accompanied by elevated intrarenal AGT and urinary AGT levels. High glucose results in stimulation of AGT production. The high glucose levels augments intrarenal AGT levels in diabetes mellitus leading to the development of high blood pressure and diabetic nephropathy.

The investigators propose to conduct a single-center randomized, double blind, cross over study of the effect of Dapagliflozin over 6 weeks, followed by placebo over 6 weeks on the other treatment allocation (those getting placebo first will cross over to Dapagliflozin and vice versa). Treatment will be stratified according to the underlying presence or absence of hypertension.

• Type 2 diabetes with hypertension and on renin-angiotensin-aldosterone system (RAAS) blocking drugs with stable blood pressure on therapy; n= 20
• Type 2 diabetes without hypertension and not on RAAS blocking drugs n=10

If unable to recruit 10 participants without hypertension the investigators will increase the number with hypertension for a total of 30. Stratification by hypertension status will remain and is important in understanding the effect of SGLT2 inhibition in patients not on BP lowering drugs.

In addition a Sulfonylurea (SU) arm will also be included - 10 participants who are on metformin and other background therapy (with the exclusion of SGLT-2 inhibitor and sulfonylurea) will be recruited. This will be an open-labeled arm. Participants will assessed at baseline. Participants will then receive usual care for 6 weeks. At the end of 6 weeks, participants will then undergo another assessment before being provided SU for 6 weeks. At the end of 6 weeks, participants will undergo assessment again. The aim is to determine whether any effects seen with Dapagliflozin are specific to that drug or related simply to improved glycemic control.

Inclusion criteria

• Type 2 diabetes with hypertension and on RAAS blocking drugs OR
• Type 2 diabetes without hypertension and not on RAAS blocking drugs
• Hemoglobin A1c between 7% and 9% (inclusive)
• Estimated glomerular filtration rate (eGFR) ≥60 ml/min
• Capacity to understand and sign informed consent

Exclusion criteria

• Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3x upper limit of normal (ULN)
• Total bilirubin >2.0 mg/dL
• Positive serologic evidence of current infectious liver disease, including Hepatitis B viral antibody immunoglobulin M (IGM), Hepatitis B surface antigen, and Hepatitis C virus antibody
• Estimated glomerular filtration rate (eGFR) <60 ml/min
• Recent cardiovascular events with the last 2 months: acute coronary syndrome (ACS), hospitalization for unstable angina or acute myocardial infarction, acute stroke or transient ischemic attack (TIA), or post coronary artery revascularization
• Congestive Heart Failure defined as New York Heart Association (NYHA) class IV, unstable or acute congestive heart failure
• Pregnant or breastfeeding patients
• Patients who, in the judgement of the investigator, may be at risk for dehydration
• Blood pressure at enrollment: Systolic ≥165 mmHg and/or Diastolic ≥110 mmHg; At randomization: Systolic ≥160 mmHg and/or Diastolic ≥100 mmHg
• Use of SGLT-2 inhibitor class drugs is an exclusion for all patients. For patients in the sulfonylurea arm, use of sulfonylurea class drugs is an exclusion.