Non-alcoholic Fatty Liver DiseasePhase 1SMASHNCT02696941
SGLT2 Inhibitors and Metformin on Metabolism and Non-Alcoholic SteatoHepatitis
A Phase 1 study testing Metformin and SGLT2 inhibitor in people with Non-alcoholic Fatty Liver Disease, run by University of Oxford at 1 site in United Kingdom.
Trial summary
SGLT2 inhibitors have been proven to be effective in several preclinical rodent models of non-alcoholic fatty liver disease (NAFLD). Using a choline deficient diet to recapitulate some of the histological features of human non-alcoholic steatohepatitis (NASH), it was found that 5 weeks of SGLT2 inhibition led to… Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Non-alcoholic Fatty Liver Disease
- What is being tested?
- Metformin and SGLT2 inhibitor
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Feb 2016to 1 Apr 2018
- Phase
- Phase 1
- 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 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Arm 1: SGLT2 inhibitors
- Volunteers with diagnosis of Type 2 Diabetes on oral anti-diabetic therapy at a stable dose for ≥3 months including one of the following:
- Metformin monotherapy ii. Sulphonylurea monotherapy iii. Metformin and Sulphonylurea dual therapy
- All volunteers will be due to start SGLT2 inhibitor therapy for inadequate glycaemic control and it will be prescribed according to licensed indications.
- Arm 2: metformin
- Insulin resistant treatment naive individuals as defined by fasting insulin and / or glucose in top 10th percentile
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- Both arms:
- Participant is willing and able to give informed consent for participation in the study.
- Male or Female, aged between 18 years and 70 years.
- BMI: 25-45 kg/m2
- HbA1C: 42-86mmol/mol
- Normal renal function
Who cannot join
- Arm 1: SGLT2 inhibitors Volunteers taking insulin, glucagon-like peptide 1 analogues, thiazolidinediones, or dipeptidyl peptidase IV inhibitors
- Arm 2: metformin Volunteers taking insulin, glucagon-like peptide 1 analogues, thiazolidinediones, SGLT2 inhibitors, metformin or dipeptidyl peptidase IV inhibitors
- Both arms
- Age <18 or >70 years
- Body mass index <25 or >45kg/m2
- A blood haemoglobin <120mg/dL
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- History of alcoholism or a greater than recommended alcohol intake (Recommendations > 21 drinks on average per week in men and > 14 drinks on average per week in women)
- Pregnant or nursing mothers
- History of severe claustrophobia
- Presence of metallic implants, pacemaker
- Haemorrhagic disorders
- Anticoagulant treatment
- History of albumin allergy
Trial locations and contacts
1 site in 1 country.
About this study
SGLT2 inhibitors have been proven to be effective in several preclinical rodent models of non-alcoholic fatty liver disease (NAFLD). Using a choline deficient diet to recapitulate some of the histological features of human non-alcoholic steatohepatitis (NASH), it was found that 5 weeks of SGLT2 inhibition led to significant reductions in hepatic triglyceride content and improved markers of liver fibrosis. Similarly, 4 weeks of treatment in obese mice led to improved glucose tolerance, reduced hepatic steatosis and reduced markers of liver oxidative stress in a dose dependent manner. These findings corresponded with an improvement in traditional liver function tests including the aminotransferases (ALT and AST). The widely used antidiabetic agent metformin has been shown in rodent models to increase hepatic insulin sensitivity and lower liver fat content which is in contrast to the findings in humans where metformin increases hepatic insulin sensitivity, reduces body weight but does not decrease liver fat content. The reason for the discrepancy between the animal and human studies, with regards to liver fat content remains unclear.
The investigators hypothesise the following:
Read more
- SGLT2 Inhibitors have the potential to decrease lipid accumulation in the liver through reduced de novo lipogenesis (DNL)
- There will be no decrease in endogenous lipid synthesis (DNL) with metformin and thus no change in liver fat content.
There are two arms to this study.
- Arm 1: x10 participants with poorly controlled type 2 Diabetes (T2DM) who have been recommended to start an SGLT2 inhibitor called dapagliflozin will be recruited.
- Arm 2: x13 participants with insulin resistance who have not yet started any diabetic medication will be recruited and will be prescribed metformin at standard clinical doses.
The two arms will run in parallel and all participants will undergo identical investigations before and after 3 months of treatment with either dapagliflozin or metformin. Investigations will include liver magnetic resonance imaging/spectroscopy, fat biopsy, fat microdialysis sampling, two-step hyperinsulinaemic euglycaemic clamp, breath sampling and stable glucose and palmitate isotope infusions.
The investigators aim to show that SGLT2 inhibition decreases liver fat whereas we aim to demonstrate why liver fat remains unchanged in humans, treated with metformin. These data will provide the first evidence for the use SGLT2 inhibitors in NAFLD, and will be highly informative for the design of future clinical studies. Moreover, the data gained from the metformin arm of the study will provide the first mechanistic evidence in humans of the effects of metformin on hepatic fatty acid metabolism.
- Conditions
- Non-alcoholic Fatty Liver Disease
- Being tested
- Metformin, SGLT2 inhibitor
- Medical subject headings
- Non-alcoholic Fatty Liver Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Metformin 500mg once daily and titrated weekly to a dose of 1000mg twice daily for 3 months
SGLT2 inhibitorDrug
SGLT2 inhibitor has been recommended to be started as part of routine clinical care
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | Participants with insulin resistance who have not yet started any diabetic medication will be recruited and will be prescribed metformin at standard clinical doses. Receives: Drug: Metformin |
| SGLT2 | Experimental | Participants with poorly controlled type 2 Diabetes (T2DM) who have been recommended to start an SGLT2 inhibitor will be recruited. Receives: Drug: SGLT2 inhibitor |
What is being measured
The primary outcome is the main question the study is designed to answer.
Hepatic steatosis
Liver fat measured by magnetic resonance imaging / spectroscopy (MRI/S)
Measured: 3 months
Secondary outcomes (4)
% contribution of newly synthesised lipid to circulating triglyceride levels
deuterated water incorporation into palmitate
Measured: 3 months
Global insulin sensitivity
two-step hyperinsulinaemic-euglycaemic clamp
Measured: 3 months
Hepatic insulin sensitivity
two-step hyperinsulinaemic-euglycaemic clamp
Measured: 3 months
Intrabdominal fat
Intrabdominal fat depot measured at level of L4-L5, visible on liver MRI.
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Mar 2016 (estimated)
- Study startFeb 2016
- Primary completion1 Apr 2018
- Study completion1 Apr 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Non-alcoholic Fatty Liver DiseaseStudies of the same condition, open and under way.
- More trials run by University of OxfordThe 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 1
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jeremy W Tomlinson, MD PhD, Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02696941
- Sponsor's protocol ID
- 11693
- Acronym
- SMASH
- Status last verified
- May 2018
- First submitted
- 12 Feb 2016
- Last updated
- 4 May 2018
- Results posted
- No
- Data monitoring committee
- No
Publications
Marjot T, Green CJ, Charlton CA, Cornfield T, Hazlehurst J, Moolla A, White S, Francis J, Neubauer S, Cobbold JF, Hodson L, Tomlinson JW. Sodium-glucose cotransporter 2 inhibition does not reduce hepatic steatosis in overweight, insulin-resistant patients without type 2 diabetes. JGH Open. 2019 Nov 5;4(3):433-440. doi: 10.1002/jgh3.12274. eCollection 2020 Jun.
PubMed 32514450
Study at a glance
From the registry record, last updated by the sponsor on 4 May 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- SGLT2 Inhibitors and Metformin on Metabolism and Non-Alcoholic SteatoHepatitis
- ClinicalTrials.gov ID
- NCT02696941
- Acronym / sponsor ID
- SMASH / 11693
- Conditions
- Non-alcoholic Fatty Liver Disease
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Study start
- Feb 2016
- Primary completion
- 1 Apr 2018 (actual)
- Study completion
- 1 Apr 2018 (actual)
- First posted
- 2 Mar 2016 (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.
SGLT2 inhibitors have been proven to be effective in several preclinical rodent models of non-alcoholic fatty liver disease (NAFLD). Using a choline deficient diet to recapitulate some of the histological features of human non-alcoholic steatohepatitis (NASH), it was found that 5 weeks of SGLT2 inhibition led to significant reductions in hepatic triglyceride content and improved markers of liver fibrosis. Similarly, 4 weeks of treatment in obese mice led to improved glucose tolerance, reduced hepatic steatosis and reduced markers of liver oxidative stress in a dose dependent manner. These findings corresponded with an improvement in traditional liver function tests including the aminotransferases (ALT and AST). The widely used antidiabetic agent metformin has been shown in rodent models to increase hepatic insulin sensitivity and lower liver fat content which is in contrast to the findings in humans where metformin increases hepatic insulin sensitivity, reduces body weight but does not decrease liver fat content. The reason for the discrepancy between the animal and human studies, with regards to liver fat content remains unclear.
The investigators hypothesise the following:
- SGLT2 Inhibitors have the potential to decrease lipid accumulation in the liver through reduced de novo lipogenesis (DNL)
- There will be no decrease in endogenous lipid synthesis (DNL) with metformin and thus no change in liver fat content.
There are two arms to this study.
- Arm 1: x10 participants with poorly controlled type 2 Diabetes (T2DM) who have been recommended to start an SGLT2 inhibitor called dapagliflozin will be recruited.
- Arm 2: x13 participants with insulin resistance who have not yet started any diabetic medication will be recruited and will be prescribed metformin at standard clinical doses.
The two arms will run in parallel and all participants will undergo identical investigations before and after 3 months of treatment with either dapagliflozin or metformin. Investigations will include liver magnetic resonance imaging/spectroscopy, fat biopsy, fat microdialysis sampling, two-step hyperinsulinaemic euglycaemic clamp, breath sampling and stable glucose and palmitate isotope infusions.
The investigators aim to show that SGLT2 inhibition decreases liver fat whereas we aim to demonstrate why liver fat remains unchanged in humans, treated with metformin. These data will provide the first evidence for the use SGLT2 inhibitors in NAFLD, and will be highly informative for the design of future clinical studies. Moreover, the data gained from the metformin arm of the study will provide the first mechanistic evidence in humans of the effects of metformin on hepatic fatty acid metabolism.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: MetforminParticipants with insulin resistance who have not yet started any diabetic medication will be recruited and will be prescribed metformin at standard clinical doses. |
| SGLT2 | Experimental | Drug: SGLT2 inhibitorParticipants with poorly controlled type 2 Diabetes (T2DM) who have been recommended to start an SGLT2 inhibitor will be recruited. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Arm 1: SGLT2 inhibitors
- Volunteers with diagnosis of Type 2 Diabetes on oral anti-diabetic therapy at a stable dose for ≥3 months including one of the following:
- All volunteers will be due to start SGLT2 inhibitor therapy for inadequate glycaemic control and it will be prescribed according to licensed indications.
- Arm 2: metformin
- Insulin resistant treatment naive individuals as defined by fasting insulin and / or glucose in top 10th percentile
Key exclusion criteria (13 listed)
- Arm 1: SGLT2 inhibitors Volunteers taking insulin, glucagon-like peptide 1 analogues, thiazolidinediones, or dipeptidyl peptidase IV inhibitors
- Arm 2: metformin Volunteers taking insulin, glucagon-like peptide 1 analogues, thiazolidinediones, SGLT2 inhibitors, metformin or dipeptidyl peptidase IV inhibitors
- Both arms
- Age <18 or >70 years
- Body mass index <25 or >45kg/m2
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 |
|---|---|---|
| MetforminMetformin 500mg once daily and titrated weekly to a dose of 1000mg twice daily for 3 months | Drug | Metformin |
| SGLT2 inhibitorSGLT2 inhibitor has been recommended to be started as part of routine clinical care | Drug | SGLT2 |
Primary outcome
Hepatic steatosis
Time frame: 3 months
Liver fat measured by magnetic resonance imaging / spectroscopy (MRI/S)
4 secondary outcomes
% contribution of newly synthesised lipid to circulating triglyceride levels
Time frame: 3 months
Global insulin sensitivity
Time frame: 3 months
Hepatic insulin sensitivity
Time frame: 3 months
Intrabdominal fat
Time frame: 3 months
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 4 May 2018.
- Derived from this study: PubMed 32514450Marjot T, Green CJ, Charlton CA, Cornfield T, Hazlehurst J, Moolla A, White S, Francis J, Neubauer S, Cobbold JF, Hodson L, Tomlinson JW. Sodium-glucose cotransporter 2 inhibition does not reduce hepatic steatosis in overweight, insulin-resistant patients without type 2 diabetes. JGH Open. 2019 Nov 5;4(3):433-440. doi: 10.1002/jgh3.12274. eCollection 2020 Jun.
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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.
Jeremy W Tomlinson, MD PhD principal investigator
University of Oxford
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Metformin and SGLT2 inhibitor in people with Non-alcoholic Fatty Liver Disease, run by University of Oxford at 1 site in United Kingdom.
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 12 inclusion and 13 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 4 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 United Kingdom. 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. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Hepatic steatosis (time frame: 3 months). 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 NCT02696941, which also lists 1 linked publication.
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 4 May 2018.