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Metformin And Cardiovascular Effectiveness vs SGLT2 (MACES)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03627039
Recruitment Status : Active, not recruiting
First Posted : August 13, 2018
Last Update Posted : August 13, 2019
Sponsor:
Information provided by (Responsible Party):
Michael Fralick, Brigham and Women's Hospital

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.


Condition or disease Intervention/treatment
Diabetes Mellitus, Type 2 Drug: SGLT2 Drug: Metformin

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.

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Study Type : Observational
Estimated Enrollment : 20000 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Metformin And Cardiovascular Effectiveness vs SGLT2 (MACES)
Actual Study Start Date : September 1, 2018
Estimated Primary Completion Date : August 1, 2020
Estimated Study Completion Date : August 1, 2020

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Truven
NOTE: In the case there are not enough patients/events data will be included from other databases (e.g., Optum, Medicare)
Drug: SGLT2
All SGLT2 medications approved prior to 2017 will be included (Canagliflozin, empagliflozin, dapagliflozin (all doses, all of the medications are oral)
Other Name: Canagliflozin, empagliflozin, dapagliflozin (all doses, all of the medications are oral)

Drug: Metformin
Metformin is the main comparator of interest. In a secondary analysis GLP1 will be the comparator
Other Name: All doses will be included. Metformin is an oral medication.




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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 ]
    Hypoglycemia: identified using ICD9 and ICD10 codes and reported as rates

  2. 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 ]
    Diabetic ketoacidosis: identified using ICD9 and ICD10 codes and reported as rates

  3. 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 ]
    Lactic acidosis: identified using ICD9 and ICD10 codes and reported as rates

  4. 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 ]
    Acute kidney injury: identified using ICD9 and ICD10 codes and reported as rates

  5. 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 ]
    Genital infection: identified using ICD9 and ICD10 codes and reported as rates

  6. Costs [ Time Frame: Follow-up will begin one day after cohort entry and cost analysis will end 1 year thereafter ]
    Costs of metformin compared to SGLT2. Estimates for costs associated with the individual outcomes.


Other Outcome Measures:
  1. 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 ]
    The outcome will be identified using ICD9 and ICD10 codes and reported as rates (1) Cellulitis



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
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.
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03627039


Locations
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United States, Massachusetts
Division of Pharmacoepidemiology and Pharmacoeconomics
Boston, Massachusetts, United States, 02130
Sponsors and Collaborators
Brigham and Women's Hospital
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Responsible Party: Michael Fralick, Principal investigator, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT03627039    
Other Study ID Numbers: 123
First Posted: August 13, 2018    Key Record Dates
Last Update Posted: August 13, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Empagliflozin
Canagliflozin
Hypoglycemic Agents
Physiological Effects of Drugs
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action