Sodium-glucose Co-transporter 2 (SGLT2) Inhibitor Risk of Below-Knee Lower Extremity Amputation: A Retrospective Cohort Study Using a Large Claims Database in the United States

Study Overview
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Brief Summary
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The purpose of the study is to estimate the incidence of below-knee lower extremity amputation in type 2 diabetes mellitus (T2DM) participants newly exposed to sodium-glucose co-transporter 2 inhibitors (SGLT2i)/ non-SGLT2i antihyperglycemic agents (AHA) overall and in the subgroup with high cardiovascular (CV) risk and to compare the hazards of below-knee lower extremity amputation in canagliflozin new users versus non-SGLT2i AHA new users.

Official Title
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SGLT2 Inhibitor Risk of Below-Knee Lower Extremity Amputation: A Retrospective Cohort Study Using a Large Claims Database in the United States

Conditions
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Diabetes Mellitus, Type 2

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: First exposure to the particular drug in person's history For the initial analysis, exposure start is between April 1, 2013 and January 31, 2015. For the ongoing repeat analysis per the protocol amendment, the study period ending date will vary depending on the time of each data extraction and analysis At least 365 days of observation time prior to index At least 1 condition occurrence of 'Type II diabetes' any time before or on index Exactly 0 condition occurrences of 'Type I diabetes' any time before or on index Exclusion Criteria: Participants who had amputations prior to the index date were excluded.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sodium-glucose Co-transporter 2 Inhibitors (SGLT2i) New Users<br>Participants will not receive any intervention as a part of this study. SGLT2i includes canagliflozin, dapagliflozin, empagliflozin as prescribed in clinical practice. Participants will be evaluated in 2 sub-cohorts (with or without high CV risk) and overall. | |
| Canagliflozin New Users<br>Participants will not receive any intervention as a part of this study. This cohort contains new users of canagliflozin as prescribed in clinical practice. Participants will be evaluated in 2 risk) and overall. | |
| Dapagliflozin New Users<br>Participants will not receive any intervention as a part of this study. This cohort contains new users of dapagliflozin as prescribed in clinical practice. Participants will be evaluated in 2 sub-cohorts (with or without high CV risk) and overall. | |
| Empagliflozin New Users<br>Participants will not receive any intervention as a part of this study. This cohort contains new users of empagliflozin as prescribed in clinical practice. Participants will be evaluated in 2 sub-cohorts (with or without high CV risk) and overall. | |
| First-time Non-SGLT2i AHA New Users<br>Participants will not receive any intervention as a part of this study. Non-SGLT2i AHA include dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, thiazolidinediones (TZDs), Sulfonylureas, Insulin, and other AHAs. Participants will be evaluated in 2 sub-cohorts (with or without high CV risk) and overall. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Below-knee Lower Extremity Amputation in Type 2 Diabetes Mellitus (T2DM) Patients Newly Exposed to Sodium-glucose Co-transporter 2 Inhibitors (SGLT2i) Overall and in the Subgroup With High Cardiovascular (CV) Risk | The occurrence of a below-knee lower extremity amputation will be defined by observing an associated procedure code in the outpatient or inpatient medical service claims. | up to 6 years (estimated study duration) | 
| Incidence of Below-Knee Lower Extremity Amputation in T2DM Patients Newly Exposed To non-SGLT2i Aha Overall And In The Subgroup With High CV Risk | The occurrence of a below-knee lower extremity amputation will be defined by observing an associated procedure code in the outpatient or inpatient medical service claims. | up to 6 years (estimated study duration) | 
| Incidence of Below-Knee Lower Extremity Amputation in Canagliflozin New Users Versus non-SGLT2i Aha New Users | Hazard ratio will be estimated using a conditional Cox proportional hazards model based on propensity-matched cohorts. | up to 6 years (estimated study duration) |