Metformin And Cardiovascular Effectiveness vs SGLT2 (MACES)
Metformin And Cardiovascular Effectiveness vs SGLT2 (MACES)
Sponsors
Source
Brigham and Women's Hospital
Oversight Info
Has Dmc
No
Is Fda Regulated Drug
Yes
Is Fda Regulated Device
No
Is Us Export
No
Brief 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.
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.
Overall Status
Active, not recruiting
Start Date
2018-09-01
Completion Date
2020-08-01
Primary Completion Date
2020-08-01
Study Type
Observational
Primary Outcome
Measure |
Time Frame |
|
Cardiovascular composite (stroke, myocardial infarction, heart failure) |
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 Outcome
Measure |
Time Frame |
|
Harms: Hypoglycemia |
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 |
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 |
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 |
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 |
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 |
Follow-up will begin one day after cohort entry and cost analysis will end 1 year thereafter |
Number Of Groups
1
Enrollment
20000
Condition
Intervention
Intervention Type
Drug
Intervention Name
Description
All SGLT2 medications approved prior to 2017 will be included (Canagliflozin, empagliflozin, dapagliflozin (all doses, all of the medications are oral)
Arm Group Label
Truven
Other Name
Canagliflozin, empagliflozin, dapagliflozin (all doses, all of the medications are oral)
Intervention Type
Drug
Intervention Name
Description
Metformin is the main comparator of interest. In a secondary analysis GLP1 will be the comparator
Arm Group Label
Truven
Other Name
All doses will be included. Metformin is an oral medication.
Eligibility
Study Pop
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.
Sampling Method
Non-Probability Sample
Criteria
INCLUSION:
- 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)
EXCLUSION:
- 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
Gender
All
Minimum Age
18 Years
Maximum Age
N/A
Healthy Volunteers
No
Location
Facility |
|
Division of Pharmacoepidemiology and Pharmacoeconomics Boston Massachusetts 02130 United States |
Location Countries
Country
United States
Verification Date
2019-08-01
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Principal Investigator
Investigator Affiliation
Brigham and Women's Hospital
Investigator Full Name
Michael Fralick
Investigator Title
Principal investigator
Has Expanded Access
No
Condition Browse
Intervention Browse
Mesh Term
Metformin
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Empagliflozin
Canagliflozin
Arm Group
Arm Group Label
Truven
Description
NOTE: In the case there are not enough patients/events data will be included from other databases (e.g., Optum, Medicare)
Firstreceived Results Date
N/A
Other Outcome
Measure
Tracer outcomes
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
Description
The outcome will be identified using ICD9 and ICD10 codes and reported as rates (1) Cellulitis
Firstreceived Results Disposition Date
N/A
Study Design Info
Observational Model
Cohort
Time Perspective
Retrospective
Study First Submitted
July 30, 2018
Study First Submitted Qc
August 8, 2018
Study First Posted
August 13, 2018
Last Update Submitted
August 10, 2019
Last Update Submitted Qc
August 10, 2019
Last Update Posted
August 13, 2019
ClinicalTrials.gov processed this data on December 11, 2019
Conditions
Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov,
conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.