Diabetes Mellitus Type 2Phase 3DapaNCT02383238
Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content
A Phase 3 study testing Dapagliflozin in people with Diabetes Mellitus Type 2, run by University of Erlangen-Nürnberg Medical School at 1 site in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Diabetes Mellitus Type 2
- What is being tested?
- Dapagliflozin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 59 participants
- Where
- 1 siteGermany
- Study dates
- Mar 2014to Oct 2015
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Type 2 diabetes
- HbA1c > 6.5%
- age > 18 years
- male and females
Who cannot join
- age > 75 years
- HbA1c > 10 %,
- reduced renal function (eGFR < 60 ml/min/1.73 m²).
- insulin therapy, or any antidiabetic medication other than metformin.
- uncontrolled hypertension (> 180/>110 mmHg)
- cardiovascular event within the last 3 months
- Use of loop diuretics
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Randomized, Placebo Controlled, Crossover Clinical Study to Analyse the Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content
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.
Read the 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.
- Conditions
- Diabetes Mellitus Type 2
- Being tested
- Dapagliflozin, Placebo
- Keywords
- Dapagliflozin, diabetes mellitus, vascular
- Medical subject headings
- Diabetes Mellitus, Type 2, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DapagliflozinDrug
Also called Forxiga
10 mg, oral for 6 weeks
PlaceboDrug
oral for 6 weeks
| Study group | Role | What they receive |
|---|---|---|
| Dapagliflozin | Active comparator | Dapagliflozin, 10 mg/day, oral administration, 6 weeks Receives: Drug: Dapagliflozin |
| Placebo | Placebo comparator | Placebo, oral administration, 6 weeks Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Microcirculation
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.
Measured: 6 weeks
Secondary outcomes (1)
Macrovascular circulation
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.
Measured: 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Mar 2015 (estimated)
- Study startMar 2014
- Primary completionOct 2015
- Study completionOct 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus Type 2Studies of the same condition, open and under way.
- More trials run by University of Erlangen-Nürnberg Medical SchoolThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 59 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Erlangen-Nürnberg Medical School
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Roland E. Schmieder, University of Erlangen-Nürnberg Medical School
- Investigators
- Roland Schmieder, Prof., Principal investigator, Department of Medicine 4, University of Erlangen-Nuernberg
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02383238
- Sponsor's protocol ID
- MB102-210
- Acronym
- Dapa
- Status last verified
- May 2018
- First submitted
- 24 Jul 2014
- Last updated
- 11 May 2018
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 29301520Zimmer KB, Gessner A, Kannenkeril D, Bosch A, Strobel A, Schmieder RE, Maas R. Effects of SGLT-2 Inhibitors on Plasma Concentrations and Renal Clearance of the Risk Marker Trimethylamine-N-Oxide in Patients With Type-2 Diabetes. Endocrinol Diabetes Metab. 2026 Nov;9(6):e70318. doi: 10.1002/edm2.70318.
PubMed 42817074Gessner A, Kannenkeril D, Bosch A, Harazny JM, Fromm MF, Klinkhammer H, Staerk C, Mayr A, Schmieder RE, Maas R. Treatment with dapagliflozin and empagliflozin reduces concentrations of N4-acetylcytidine in plasma, a biomarker associated with vascular damage. Cardiovasc Diabetol. 2026 Jul 24;25(1):210. doi: 10.1186/s12933-026-03292-z.
PubMed 42498959Staef M, Ott C, Kannenkeril D, Striepe K, Schiffer M, Schmieder RE, Bosch A. Determinants of arterial stiffness in patients with type 2 diabetes mellitus: a cross sectional analysis. Sci Rep. 2023 Jun 2;13(1):8944. doi: 10.1038/s41598-023-35589-4.
PubMed 37268640Gessner A, Gemeinhardt A, Bosch A, Kannenkeril D, Staerk C, Mayr A, Fromm MF, Schmieder RE, Maas R. Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers. Cardiovasc Diabetol. 2022 Jan 6;21(1):4. doi: 10.1186/s12933-021-01436-x.
PubMed 34991562Kannenkeril D, Jung S, Harazny J, Striepe K, Ott C, Dahlmann A, Kopp C, Schiffer M, Linz P, Nagel AM, Uder M, Schmieder RE. Tissue sodium content correlates with hypertrophic vascular remodeling in type 2 diabetes. J Diabetes Complications. 2021 Dec;35(12):108055. doi: 10.1016/j.jdiacomp.2021.108055. Epub 2021 Sep 29.
PubMed 34620556Kannenkeril 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.
PubMed 30231923Ott 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.
PubMed 28231831
Study at a glance
From the registry record, last updated by the sponsor on 11 May 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized, Placebo Controlled, Crossover Clinical Study to Analyse the Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content
- ClinicalTrials.gov ID
- NCT02383238
- Acronym / sponsor ID
- Dapa / MB102-210
- Conditions
- Diabetes Mellitus Type 2
- Keywords
- Dapagliflozin, diabetes mellitus, vascular
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 59 participants (actual)
- Lead sponsor
- University of Erlangen-Nürnberg Medical SchoolUniversity, hospital or other
- Study start
- Mar 2014
- Primary completion
- Oct 2015 (actual)
- Study completion
- Oct 2015 (actual)
- First posted
- 9 Mar 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Dapagliflozin | Active comparator | Drug: DapagliflozinDapagliflozin, 10 mg/day, oral administration, 6 weeks |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo, oral administration, 6 weeks |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Type 2 diabetes
- HbA1c > 6.5%
- age > 18 years
- male and females
Key exclusion criteria (7 listed)
- age > 75 years
- HbA1c > 10 %,
- reduced renal function (eGFR < 60 ml/min/1.73 m²).
- insulin therapy, or any antidiabetic medication other than metformin.
- uncontrolled hypertension (> 180/>110 mmHg)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DapagliflozinAlso: Forxiga10 mg, oral for 6 weeks | Drug | Dapagliflozin |
| Placebooral for 6 weeks | Drug | Placebo |
Primary outcome
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.
1 secondary outcome
Macrovascular circulation
Time frame: 6 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 May 2018.
- Results publication: PubMed 29301520Karg 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.
- Derived from this study: PubMed 42817074Zimmer KB, Gessner A, Kannenkeril D, Bosch A, Strobel A, Schmieder RE, Maas R. Effects of SGLT-2 Inhibitors on Plasma Concentrations and Renal Clearance of the Risk Marker Trimethylamine-N-Oxide in Patients With Type-2 Diabetes. Endocrinol Diabetes Metab. 2026 Nov;9(6):e70318. doi: 10.1002/edm2.70318.
- Derived from this study: PubMed 42498959Gessner A, Kannenkeril D, Bosch A, Harazny JM, Fromm MF, Klinkhammer H, Staerk C, Mayr A, Schmieder RE, Maas R. Treatment with dapagliflozin and empagliflozin reduces concentrations of N4-acetylcytidine in plasma, a biomarker associated with vascular damage. Cardiovasc Diabetol. 2026 Jul 24;25(1):210. doi: 10.1186/s12933-026-03292-z.
- Derived from this study: PubMed 37268640Staef M, Ott C, Kannenkeril D, Striepe K, Schiffer M, Schmieder RE, Bosch A. Determinants of arterial stiffness in patients with type 2 diabetes mellitus: a cross sectional analysis. Sci Rep. 2023 Jun 2;13(1):8944. doi: 10.1038/s41598-023-35589-4.
- Derived from this study: PubMed 34991562Gessner A, Gemeinhardt A, Bosch A, Kannenkeril D, Staerk C, Mayr A, Fromm MF, Schmieder RE, Maas R. Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers. Cardiovasc Diabetol. 2022 Jan 6;21(1):4. doi: 10.1186/s12933-021-01436-x.
- Derived from this study: PubMed 34620556Kannenkeril D, Jung S, Harazny J, Striepe K, Ott C, Dahlmann A, Kopp C, Schiffer M, Linz P, Nagel AM, Uder M, Schmieder RE. Tissue sodium content correlates with hypertrophic vascular remodeling in type 2 diabetes. J Diabetes Complications. 2021 Dec;35(12):108055. doi: 10.1016/j.jdiacomp.2021.108055. Epub 2021 Sep 29.
- Derived from this study: PubMed 30231923Kannenkeril 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.
- Derived from this study: PubMed 28231831Ott 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Roland Schmieder, Prof. principal investigator
Department of Medicine 4, University of Erlangen-Nuernberg
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Dapagliflozin in people with Diabetes Mellitus Type 2, run by University of Erlangen-Nürnberg Medical School at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 May 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Microcirculation (time frame: 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02383238, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 May 2018.