Hypertension, Type 2 Diabetes
Conditions
Keywords
SGLT-2 inhibitor, urinary angiotensinogen
Brief 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.
Interventions
DRUGDapagliflozin
5mg pill taken once daily
DRUGPlacebo
5mg pill taken once daily- placebo of Dapagliflozin
Sponsors
AstraZeneca
Tulane University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Blood Pressure From Baseline to 6 Weeks Measured by ABPM | Baseline to 6 weeks | Blood pressure was measured at baseline with a 24 hour ambulatory blood pressure machine (ABPM), and again after 6 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Urinary AGT Levels From Baseline to 6 Weeks | Baseline to 6 weeks | Urinary Angiotensinogen (AGT) was measured through the collection of 24 hour urine at baseline and again after 6 weeks of treatment. Angiotensinogen was normalized to creatinine. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin First Then Placebo Participants underwent 6 weeks of Dapagliflozin (washout period for 2 weeks) and then crossed over to 6 weeks of placebo.
Dapagliflozin: 5mg pill taken once daily
Placebo: 5mg pill taken once daily. | 8 |
| Placebo First Then Dapagliflozin Participants underwent 6 weeks of placebo (washout period for 2 weeks) and then crossed over to 6 weeks of Dapagliflozin.
Placebo: 5mg pill taken once daily
Dapagliflozin: 5mg pill taken once daily | 3 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 0 |
Baseline characteristics
| Characteristic | Placebo First Then Dapagliflozin | Dapagliflozin First Then Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 7 Participants | 10 Participants |
| Age, Continuous | 52.7 Years STANDARD_DEVIATION 6.7 | 56.5 Years STANDARD_DEVIATION 7.8 | 55.5 Years STANDARD_DEVIATION 7.4 |
| angiotensin converting enzyme (ACE)-I/ angiotensin receptor blocker (ARB) | 3 Participants | 6 Participants | 9 Participants |
| Average Diastolic blood pressure | 79.3 mmHg STANDARD_DEVIATION 7.1 | 74.0 mmHg STANDARD_DEVIATION 4.1 | 75.4 mmHg STANDARD_DEVIATION 5.3 |
| Average Heart Rate | 76.5 bpm STANDARD_DEVIATION 13.3 | 83.1 bpm STANDARD_DEVIATION 10.9 | 81.3 bpm STANDARD_DEVIATION 11.3 |
| Average Systolic Blood pressure | 121.3 mmHg STANDARD_DEVIATION 19.1 | 119.0 mmHg STANDARD_DEVIATION 8.5 | 119.6 mmHg STANDARD_DEVIATION 11.2 |
| B-blockers | 1 Participants | 2 Participants | 3 Participants |
| BMI | 38.2 Kg/m^2 STANDARD_DEVIATION 8.4 | 32.6 Kg/m^2 STANDARD_DEVIATION 7.4 | 34.1 Kg/m^2 STANDARD_DEVIATION 7.7 |
| Calcium antagonists | 1 Participants | 2 Participants | 3 Participants |
| Diuretics | 2 Participants | 3 Participants | 5 Participants |
| Estimated glomerular filtration rate (eGFR) | 89.0 mL/min/1.73m2 STANDARD_DEVIATION 5.6 | 93.0 mL/min/1.73m2 STANDARD_DEVIATION 15.4 | 91.9 mL/min/1.73m2 STANDARD_DEVIATION 13.3 |
| Glucagon-like peptide-1 (GLP-1)/Dipeptidyl Peptidase-4 (DPP-4) | 1 Participants | 2 Participants | 3 Participants |
| HbA1c | 7.9 HbA1c % STANDARD_DEVIATION 0.8 | 8.0 HbA1c % STANDARD_DEVIATION 1.3 | 8.0 HbA1c % STANDARD_DEVIATION 1.1 |
| HDL Cholesterol | 43.3 mg/dL STANDARD_DEVIATION 4 | 55.3 mg/dL STANDARD_DEVIATION 17.6 | 52.0 mg/dL STANDARD_DEVIATION 15.8 |
| Insulin | 0 Participants | 3 Participants | 3 Participants |
| LDL Cholesterol | 78.3 mg/dL STANDARD_DEVIATION 8.4 | 80.6 mg/dL STANDARD_DEVIATION 15.5 | 79.9 mg/dL STANDARD_DEVIATION 13.3 |
| Metformin | 3 Participants | 8 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 3 participants | 8 participants | 11 participants |
| Sex: Female, Male Female | 1 Participants | 7 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
| Statins | 3 Participants | 7 Participants | 10 Participants |
| Sulfonylurea | 1 Participants | 2 Participants | 3 Participants |
| Total Cholesterol | 141.3 mg/dL STANDARD_DEVIATION 11.4 | 175.4 mg/dL STANDARD_DEVIATION 43.8 | 166.1 mg/dL STANDARD_DEVIATION 40.3 |
| Triglycerides | 111.0 mg/dL STANDARD_DEVIATION 57.4 | 192.8 mg/dL STANDARD_DEVIATION 184.5 | 170.5 mg/dL STANDARD_DEVIATION 161.1 |
| Weight | 114.5 Kg STANDARD_DEVIATION 14.9 | 89.3 Kg STANDARD_DEVIATION 17.6 | 96.2 Kg STANDARD_DEVIATION 20 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 3 |
| other Total, other adverse events | 0 / 8 | 0 / 3 |
| serious Total, serious adverse events | 0 / 8 | 0 / 3 |
Outcome results
Primary
Change in Blood Pressure From Baseline to 6 Weeks Measured by ABPM
Blood pressure was measured at baseline with a 24 hour ambulatory blood pressure machine (ABPM), and again after 6 weeks of treatment.
Time frame: Baseline to 6 weeks
Population: Out of the 8 participants who completed the study, 5 Participants had full data analyzed for this outcome measure, where three participants had the ABPM missing, so they were excluded from the final data analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Change in Blood Pressure From Baseline to 6 Weeks Measured by ABPM | Systolic Blood pressure | -10.72 mmHg | Standard Deviation 6.17 |
| Dapagliflozin | Change in Blood Pressure From Baseline to 6 Weeks Measured by ABPM | Diastolic blood pressure | -3.34 mmHg | Standard Deviation 4.2 |
| Placebo | Change in Blood Pressure From Baseline to 6 Weeks Measured by ABPM | Systolic Blood pressure | 1.94 mmHg | Standard Deviation 17.01 |
| Placebo | Change in Blood Pressure From Baseline to 6 Weeks Measured by ABPM | Diastolic blood pressure | 1.56 mmHg | Standard Deviation 15.05 |
Secondary
Change in Urinary AGT Levels From Baseline to 6 Weeks
Urinary Angiotensinogen (AGT) was measured through the collection of 24 hour urine at baseline and again after 6 weeks of treatment. Angiotensinogen was normalized to creatinine.
Time frame: Baseline to 6 weeks
Population: Out of the 8 participants who completed the study, 5 Participants had full data analyzed for this outcome measure, where three participants had the AGT data missing, so they were excluded from the final data analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Change in Urinary AGT Levels From Baseline to 6 Weeks | 53.85 ng/mg | Standard Deviation 98.79 |
| Placebo | Change in Urinary AGT Levels From Baseline to 6 Weeks | 39.69 ng/mg | Standard Deviation 58.37 |