Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content (Dapa)

• ClinicalTrials.gov Identifier: NCT02383238
• Recruitment Status: Completed
• First Posted: March 9, 2015
• Last Update Posted: May 11, 2018
• Sponsor: University of Erlangen-Nürnberg Medical School
• Information provided by (Responsible Party): Roland E. Schmieder, University of Erlangen-Nürnberg Medical School

Tracking Information

• First Submitted Date: July 24, 2014
• First Posted Date: March 9, 2015
• Last Update Posted Date: May 11, 2018
• Study Start Date: March 2014
• Actual Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 2, 2015)

Microcirculation [ Time Frame: 6 weeks ]

To analyse the effects after 6 weeks of treatment with dapagliflozin on retinal capillary flow (given as AU) as the key measurement of vascular remodeling in the microcirculation compared to placebo.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 2, 2015)

Macrovascular circulation [ Time Frame: 6 weeks ]

To analyse the effects after 6 weeks of treatment with dapagliflozin on central (aortic) systolic pressure, central (aortic) pulse pressure and augmentation pressure, on retinal capillary flow after flicker light exposure, parameters that all are determined by pulse wave reflection (i.e. arterial wall properties) in the arterial tree compared to placebo.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content
• Official Title: Randomized, Placebo Controlled, Crossover Clinical Study to Analyse the Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content
• Brief Summary: Dapagliflozin leads to improved vascular function in the micro- and macrocirculation by action on various cardiovascular risk factors, in particular by effectively controlling hyperglycemia, arterial hypertension and reducing whole sodium content amongst others.

Detailed Description

Diabetes mellitus, considered at the beginning as a metabolic disorder, mutates into a predominantly vascular disease, once its duration extends over several years or/and when additional cardiovascular risk factors coexist, in particular arterial hypertension. In accordance, patients with type 2 diabetes die because of microvascular and macrovascular complications, and only rarely because of hypoglycaemic or hyperglycaemic shock syndromes [1]. As a consequence, treatment of type 2 diabetes should focus not only on metabolic control but also on improving the global vascular risk. Analyses that have compared the importance of the various cardiovascular risk factors concluded that reductions of blood pressure and lipid levels are significantly more important than reduction of hyperglycemia [2]. Of course, a multidisciplinary approach is desirable and the STENO-2 study has clearly indicated that in mid-term microvascular complications and in long-term macrovascular complications can be prevented in type 2 diabetes [3].

Vascular changes occurring in the course of type 2 diabetes, arterial hypertension and elevated global cardiovascular risk can now reliably assessed non-invasively, and already at the very early stage of vascular remodeling processes. For example, the guidelines of the European Society of Hypertension recommend several vascular

#0284 CSP 130911 v1.4.docx 8 parameters to be assessed already at the diagnosis of the disease in order to analyze early organ damage of the arteries [4]. The measurement of pulse wave velocity, pulse wave analysis, central (aortic) systolic pressure and pulse pressure are tools to detect early vascular changes in the large arteries related to a faster wave reflection in the arterial tree [5]. Wall to lumen ratio of retinal arteries, retinal capillary flow and flow mediated vasodilation are tools to detect changes in the microvascular circulation [6]. These parameters are only infrequently measured in studies with type 2 diabetes, mainly due to lack of awareness that the vascular changes are the key prognostic factor in type-2 diabetes that ultimately determine the fate of the patient.

Dapagliflozin is a novel selective SLGT-2 inhibitor that has been shown to improve glycaemic control after 2, 12, and 24 weeks as well as after 1 and 2 years. Dapagliflozin produced dose dependent increases in glucosuria and clinically meaningful changes of glycemic parameters in type 2 diabetes in addition to weight loss. Most striking, dapagliflozin was also found to lower systolic blood pressure by 5 mmHg. This reduction in blood pressure might be related to weight loss or/and concomitant loss of total body sodium content. However, the precise mechanism of the blood pressure reduction needs to be elucidated. Loss of sodium would lead to a less reactive contraction of the small arteries in response to increased sympathetic activity, angiotensin II [7] and catecholamines.

In summary, dapagliflozin exert beneficial effects on a variety of cardiovascular risk factors, such as hyperglycaemia, hypertension and obesity. These changes should lead (so the hypothesis) to improved vascular function in the micro- and macrocirculation. Moreover, increased total body content of sodium that now can be measured in humans by a specific MRI technique [8] may also be reduced by dapagliflozin that may lead to less vasoreactive responses since the tubular SGLT-2 mediated glucose uptake is sodium related, i.e. blockade should lead to sodium loss. However, the latter is nothing more than hypothesis and requires clear proof by clinical studies in patients with type 2 diabetes.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Diabetes Mellitus Type 2

Intervention

• Drug: Dapagliflozin
  10 mg, oral for 6 weeks
  Other Name: Forxiga
• Drug: Placebo
  oral for 6 weeks

Study Arms

• Active Comparator: Dapagliflozin
  Dapagliflozin, 10 mg/day, oral administration, 6 weeks
  Intervention: Drug: Dapagliflozin
• Placebo Comparator: Placebo
  Placebo, oral administration, 6 weeks
  Intervention: Drug: Placebo

Publications *

• Karg MV, Bosch A, Kannenkeril D, Striepe K, Ott C, Schneider MP, Boemke-Zelch F, Linz P, Nagel AM, Titze J, Uder M, Schmieder RE. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial. Cardiovasc Diabetol. 2018 Jan 4;17(1):5. doi: 10.1186/s12933-017-0654-z.
• Kannenkeril D, Bosch A, Harazny J, Karg M, Jung S, Ott C, Schmieder RE. Early vascular parameters in the micro- and macrocirculation in type 2 diabetes. Cardiovasc Diabetol. 2018 Sep 19;17(1):128. doi: 10.1186/s12933-018-0770-4.
• Ott C, Jumar A, Striepe K, Friedrich S, Karg MV, Bramlage P, Schmieder RE. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc Diabetol. 2017 Feb 23;16(1):26. doi: 10.1186/s12933-017-0510-1.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 9, 2018): 59
• Original Estimated Enrollment (submitted: March 2, 2015): 63
• Actual Study Completion Date: October 2015
• Actual Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Type 2 diabetes
2. HbA1c > 6.5%
3. age > 18 years
4. male and females

Exclusion Criteria:

1. age > 75 years
2. HbA1c > 10 %,
3. reduced renal function (eGFR < 60 ml/min/1.73 m²).
4. insulin therapy, or any antidiabetic medication other than metformin.
5. uncontrolled hypertension (> 180/>110 mmHg)
6. cardiovascular event within the last 3 months
7. Use of loop diuretics

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT02383238
• Other Study ID Numbers: MB102-210
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Roland E. Schmieder, University of Erlangen-Nürnberg Medical School
• Study Sponsor: University of Erlangen-Nürnberg Medical School
• Collaborators: Not Provided

Investigators

• Principal Investigator: Roland Schmieder, Prof.; Department of Medicine 4, University of Erlangen-Nuernberg

• PRS Account: University of Erlangen-Nürnberg Medical School
• Verification Date: May 2018