Inhibition of Urinary Angiotensinogen and the Reduction of Blood Pressure by SGLT2 Inhibition in Patients With Type 2 Diabetes
Condition: Type 2 Diabetes; Hypertension
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      To assess the effect of sodium-glucose cotransporter 2 (SGLT-2) inhibitors on blood pressure
      and urinary angiotensinogen. This is a cross over study design, where 40 subjects will
      receive Dapagliflozin for 6 weeks followed by placebo for 6 weeks, or placebo for 6 weeks
      followed by Dapagliflozin for 6 weeks. In addition there will be an arm of 10 subjects who
      will receive sulfonylurea in an open label as a comparative to the cross over subjects to
      assess if the effect of Dapagliflozin may also be in part due to improved glycemic control.
    

Detailed description: 
      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.

        1. Type 2 diabetes with hypertension and on renin-angiotensin-aldosterone system (RAAS)
           blocking drugs with stable blood pressure on therapy; n= 20

        2. 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.
    

Intervention name(s): Dapagliflozin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 5mg pill taken once daily; 5mg pill taken once daily- placebo of Dapagliflozin
Intervention MeSH terms: Dapagliflozin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: SGLT-2 inhibitor; urinary angiotensinogen