Diabetes Mellitus, Type 2NCT03627039
Metformin And Cardiovascular Effectiveness vs SGLT2 (MACES)
An observational study of Diabetes Mellitus, Type 2, run by Brigham and Women's Hospital at 1 site in United States.
Trial summary
The objective of this study was to compare the effectiveness of sodium glucose co-transporter 2 (SGLT2) inhibitors relative to metformin for reducing subsequent cardiovascular events in patients with type 2 diabetes mellitus. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Diabetes Mellitus, Type 2
- What is being tested?
- SGLT2 and Metformin
- Type of treatment
- Pill or oral medicine
- How many people
- 20,000 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Sep 2018to 1 Aug 2020
- Phase
- Observational
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: We will conduct a population-based, new-user, longitudinal-cohort study using the nationwide US commercial insurance claims database. This database provides patient demographics and longitudinal, individual-level data on healthcare utilization, inpatient and outpatient diagnoses, diagnostic tests, clinical procedures, outpatient laboratory results, and pharmacy dispensing of drugs.
Who may be able to join
- all patients newly prescribed an SGLT2 or metformin between March 29, 2013 to January 1st, 2017 with at least 6 months of continuous enrollment (1 year in a sensitivity analysis)
Who cannot join
- age < 18 years
- previous use of any diabetes medication
- lack of a diagnosis of type 2 diabetes mellitus
- history of malignant neoplasm
- dialysis
- type 1 diabetes
Trial locations and contacts
1 site in 1 country.
United States1 site
Division of Pharmacoepidemiology and Pharmacoeconomics
Boston, Massachusetts, 02130
About this study
The objective of this study was to compare the effectiveness of sodium glucose co-transporter 2 (SGLT2) inhibitors relative to metformin for reducing subsequent cardiovascular events in patients with type 2 diabetes mellitus.
The investigators will conduct a population-based, new-user, longitudinal-cohort study using a nationwide US commercial insurance claims database. The investigators will compare adults with diabetes mellitus type 2 over the age of 18 who were newly prescribed an SGLT2 inhibitor or metformin between March 29, 2013 (date of US approval of first SGLT2) and January 1st, 2017 (most recent available data). Patients with diabetes mellitus type 2 will be identified using the International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes. Cohort entry date will be the date of the first prescription for an SGLT2 or metformin. New users of SGLT2 or metformin will be defined as those without a prior prescription for either class of medications, or any other medication for diabetes, in the preceding 180 days.
Read the detailed description
Baseline Covariates: All covariates will be assessed prior to cohort entry. Covariates will reflect diagnoses and procedures recorded during health encounters, including chronic medical conditions (e.g., hypertension, coronary artery disease), diabetes severity (e.g., hemoglobin A1C, end-organ damage), overall healthcare utilization (e.g., recent hospitalization, emergency department visit), prescriber characteristics (e.g., endocrinologist, general practitioner), and medications (e.g., anti-hypertensives, diuretics).
Statistical analysis Propensity score matching will be used to adjust for confounding. The probability of initiating an SGLT2-inhibitor will be calculated through a multivariable logistic regression model containing all of the baseline covariates. Using this propensity score, patients prescribed an SGLT2 were matched 1:1 with patients prescribed metformin using a caliper of up to 0.1 on the probability scale. Covariate balance between the matched cohorts was assessed using standardized differences. Since laboratory data were not available for all patients, these were not included in the propensity score estimation.
After propensity score matching, proportional hazards models will be used to estimate the incidence rate, hazard ratios and 95% confidence intervals for the primary outcome without further adjustments. Schoenfeld residuals will be plotted to assess the proportional hazards assumption. Predefined sensitivity and subgroup analyses included an intention to treat analysis where the censoring criteria of drug discontinuation, switching or augmentation are removed. The investigators will also assess the primary risk in a cohort restricted to patients with a past-history of cardiovascular disease if our sample size allows it. To test the specificity of our findings, the investigators will also conduct a tracer analysis using cellulitis as an outcome, since cellulitis is not associated with SGLT2s or metformin.
- Conditions
- Diabetes Mellitus, Type 2
- Being tested
- SGLT2, Metformin
- Medical subject headings
- Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SGLT2Drug
Also called Canagliflozin, empagliflozin, dapagliflozin (all doses, all of the medications are oral)
All SGLT2 medications approved prior to 2017 will be included (Canagliflozin, empagliflozin, dapagliflozin (all doses, all of the medications are oral)
MetforminDrug
Also called All doses will be included. Metformin is an oral medication.
Metformin is the main comparator of interest. In a secondary analysis GLP1 will be the comparator
| Study group | Role | What they receive |
|---|---|---|
| Truven | NOTE: In the case there are not enough patients/events data will be included from other databases (e.g., Optum, Medicare) Receives: Drug: SGLT2; Drug: Metformin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Cardiovascular composite (stroke, myocardial infarction, heart failure)
The outcome will be identified using ICD9 and ICD10 codes and reported as rates of acute myocardial infarction, heart failure, stroke (they will only be analyzed individually if there are sufficient number of one of the events defined as > 30 events)
Measured: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
Secondary outcomes (6)
Harms: Hypoglycemia
Hypoglycemia: identified using ICD9 and ICD10 codes and reported as rates
Measured: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
Harms: diabetic ketoacidosis
Diabetic ketoacidosis: identified using ICD9 and ICD10 codes and reported as rates
Measured: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
Harms: lactic acidosis
Lactic acidosis: identified using ICD9 and ICD10 codes and reported as rates
Measured: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
Harms: Acute kidney injury
Acute kidney injury: identified using ICD9 and ICD10 codes and reported as rates
Measured: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
Harms: Genital infection
Genital infection: identified using ICD9 and ICD10 codes and reported as rates
Measured: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
Costs
Costs of metformin compared to SGLT2. Estimates for costs associated with the individual outcomes.
Measured: Follow-up will begin one day after cohort entry and cost analysis will end 1 year thereafter
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Aug 2018
- Study start1 Sep 2018
- Primary completion1 Aug 2020 (estimated)
- Study completion1 Aug 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- More trials run by Brigham and Women's HospitalThe 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
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 20,000 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Brigham and Women's Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Michael Fralick, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03627039
- Sponsor's protocol ID
- 123
- Status last verified
- Aug 2019
- First submitted
- 30 Jul 2018
- Last updated
- 13 Aug 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Metformin And Cardiovascular Effectiveness vs SGLT2 (MACES)
- ClinicalTrials.gov ID
- NCT03627039
- Acronym / sponsor ID
- 123
- Conditions
- Diabetes Mellitus, Type 2
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 20,000 participants (estimated)
- Lead sponsor
- Brigham and Women's HospitalUniversity, hospital or other
- Study start
- 1 Sep 2018 (actual)
- Primary completion
- 1 Aug 2020 (estimated)
- Study completion
- 1 Aug 2020 (estimated)
- First posted
- 13 Aug 2018 (actual)
- 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.
The objective of this study was to compare the effectiveness of sodium glucose co-transporter 2 (SGLT2) inhibitors relative to metformin for reducing subsequent cardiovascular events in patients with type 2 diabetes mellitus.
The investigators will conduct a population-based, new-user, longitudinal-cohort study using a nationwide US commercial insurance claims database. The investigators will compare adults with diabetes mellitus type 2 over the age of 18 who were newly prescribed an SGLT2 inhibitor or metformin between March 29, 2013 (date of US approval of first SGLT2) and January 1st, 2017 (most recent available data). Patients with diabetes mellitus type 2 will be identified using the International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes. Cohort entry date will be the date of the first prescription for an SGLT2 or metformin. New users of SGLT2 or metformin will be defined as those without a prior prescription for either class of medications, or any other medication for diabetes, in the preceding 180 days.
Detailed description
Baseline Covariates: All covariates will be assessed prior to cohort entry. Covariates will reflect diagnoses and procedures recorded during health encounters, including chronic medical conditions (e.g., hypertension, coronary artery disease), diabetes severity (e.g., hemoglobin A1C, end-organ damage), overall healthcare utilization (e.g., recent hospitalization, emergency department visit), prescriber characteristics (e.g., endocrinologist, general practitioner), and medications (e.g., anti-hypertensives, diuretics).
Statistical analysis Propensity score matching will be used to adjust for confounding. The probability of initiating an SGLT2-inhibitor will be calculated through a multivariable logistic regression model containing all of the baseline covariates. Using this propensity score, patients prescribed an SGLT2 were matched 1:1 with patients prescribed metformin using a caliper of up to 0.1 on the probability scale. Covariate balance between the matched cohorts was assessed using standardized differences. Since laboratory data were not available for all patients, these were not included in the propensity score estimation.
After propensity score matching, proportional hazards models will be used to estimate the incidence rate, hazard ratios and 95% confidence intervals for the primary outcome without further adjustments. Schoenfeld residuals will be plotted to assess the proportional hazards assumption. Predefined sensitivity and subgroup analyses included an intention to treat analysis where the censoring criteria of drug discontinuation, switching or augmentation are removed. The investigators will also assess the primary risk in a cohort restricted to patients with a past-history of cardiovascular disease if our sample size allows it. To test the specificity of our findings, the investigators will also conduct a tracer analysis using cellulitis as an outcome, since cellulitis is not associated with SGLT2s or metformin.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Truven | – | Drug: SGLT2, Drug: MetforminNOTE: In the case there are not enough patients/events data will be included from other databases (e.g., Optum, Medicare) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- We will conduct a population-based, new-user, longitudinal-cohort study using the nationwide US commercial insurance claims database. This database provides patient demographics and longitudinal, individual-level data on healthcare utilization, inpatient and outpatient diagnoses, diagnostic tests, clinical procedures, outpatient laboratory results, and pharmacy dispensing of drugs.
Key inclusion criteria (1 listed)
- all patients newly prescribed an SGLT2 or metformin between March 29, 2013 to January 1st, 2017 with at least 6 months of continuous enrollment (1 year in a sensitivity analysis)
Key exclusion criteria (6 listed)
- age < 18 years
- previous use of any diabetes medication
- lack of a diagnosis of type 2 diabetes mellitus
- history of malignant neoplasm
- dialysis
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 |
|---|---|---|
| SGLT2Also: Canagliflozin, empagliflozin, dapagliflozin (all doses, all of the medications are oral)All SGLT2 medications approved prior to 2017 will be included (Canagliflozin, empagliflozin, dapagliflozin (all doses, all of the medications are oral) | Drug | Truven |
| MetforminAlso: All doses will be included. Metformin is an oral medication.Metformin is the main comparator of interest. In a secondary analysis GLP1 will be the comparator | Drug | Truven |
Primary outcome
Cardiovascular composite (stroke, myocardial infarction, heart failure)
Time frame: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
The outcome will be identified using ICD9 and ICD10 codes and reported as rates of acute myocardial infarction, heart failure, stroke (they will only be analyzed individually if there are sufficient number of one of the events defined as > 30 events)
6 secondary outcomes
Harms: Hypoglycemia
Time frame: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
Harms: diabetic ketoacidosis
Time frame: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
Harms: lactic acidosis
Time frame: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
Harms: Acute kidney injury
Time frame: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
Harms: Genital infection
Time frame: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up
Costs
Time frame: Follow-up will begin one day after cohort entry and cost analysis will end 1 year thereafter
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Aug 2019.
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Diabetes Mellitus, Type 2, run by Brigham and Women's Hospital at 1 site in United States.
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 1 inclusion and 6 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: status not confirmed, as of the sponsor's last update on 13 Aug 2019. 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 States. 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.
Are results available for this study?
Results are not available in the source record.
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?
Cardiovascular composite (stroke, myocardial infarction, heart failure) (time frame: Follow-up will begin one day after cohort entry and continue until medication discontinuation, study outcome, or no further data. Most patients will have 200 days of follow up). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 13 Aug 2019.