Metformin And Cardiovascular Effectiveness vs SGLT2 (MACES)

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.

Study Overview

• Status: Unknown
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: 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.

• Study Type: Observational
• Enrollment (Anticipated): 20000

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02130
      • Division of Pharmacoepidemiology and Pharmacoeconomics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

1

Cohorts and Interventions

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 Names: 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 Names: All doses will be included. Metformin is an oral medication.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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 Measures

Outcome Measure	Measure Description	Time Frame
Harms: Hypoglycemia	Hypoglycemia: identified using ICD9 and ICD10 codes and reported as rates	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	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	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	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	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.	Follow-up will begin one day after cohort entry and cost analysis will end 1 year thereafter

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tracer outcomes	The outcome will be identified using ICD9 and ICD10 codes and reported as rates (1) Cellulitis	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

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2018
• Primary Completion (Anticipated): August 1, 2020
• Study Completion (Anticipated): August 1, 2020

Study Registration Dates

• First Submitted: July 30, 2018
• First Submitted That Met QC Criteria: August 8, 2018
• First Posted (Actual): August 13, 2018

Study Record Updates

• Last Update Posted (Actual): August 13, 2019
• Last Update Submitted That Met QC Criteria: August 10, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin; Metformin; Empagliflozin; Canagliflozin
• Other Study ID Numbers: 123 (Giresun University Scientific Research Project)

Drug and device information, study documents

• 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