Evaluating Comparative Effectiveness of Empagliflozin in Type 2 Diabetes Population With and Without Chronic Kidney Disease

Comparative Cardiovascular and Renal Effectiveness and Safety of Empagliflozin and Other SGLT2i in Patients With Type 2 Diabetes (T2D) With and Without Baseline Kidney Disease in the United States

The primary purpose of this research study is to determine the cardiovascular and renal effectiveness and safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with Type 2 Diabetes Mellitus (T2DM) with and without established kidney disease.

The secondary purpose of this research study is to determine the cardiovascular and renal effectiveness and safety of any Sodium glucose co-transporter-2 inhibitors (SGLT2i) compared to Glucagon-like Peptide-1 Receptor Agonists (GLP1RA) in patients with T2DM.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Empagliflozin; Drug: Dipeptidyl Peptidate-4 inhibitors

• Study Type: Observational
• Enrollment (Actual): 62197

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27707
      • Duke Clinical Research Institute

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

The analysis will include adults (≥18 years) with type 2 diabetes with or without kidney disease in the US.

Description

Inclusion criteria:

• Patients ≥18 years old
• Having a diagnosis of type 2 diabetes in 12 months before the index date (defined as the date of initiation of empagliflozin or Glucagon-like Peptide-1 Receptor Agonists (GLP1RA) or Dipeptidyl Peptidate-4 inhibitor (DPP4i), based on the cohort evaluated), based on International Classification of Diseases (ICD)-9 and -10 codes and other available data
• Record of prescription for empagliflozin, any Sodium glucose co-transporter-2 inhibitors (SGLT2i), any DPP4 inhibitor, or any GLP1RA use between 1 January 2015 and 31 December 2020, and

• No record of any prescription for the drugs being compared during the 12 months + 30-day grace preceding the index date period, i.e.,

  • For the primary comparison of initiation of empagliflozin versus DPP4i, patients will not have any prescription for empagliflozin/any SGLT2i or DPP4i during the preceding 12 months + 30-day grace period.
  • For the comparison of initiation of SGLT2i versus GLP1RA, patients will not have any prescription for SGLT2i or GLP1RA during the preceding 12 months + 30-day grace period.
  • For the comparison of initiation of empagliflozin versus GLP1RA, patients will not have any prescription for empagliflozin/any SGLT2i or GLP1RA during the preceding 12 months + 30-day grace period.

Exclusion criteria:

• Aged <18 years on the first prescription date of the qualifying prescription,
• Pre-existing diagnosis of type 1 diabetes mellitus (T1DM) during the 12 months before the index date,
• Having a disqualifying diagnosis during the 12 months before the index date, defined as having at least one of the following: estimated glomerular filtration rate (eGFR) <30, dialysis, polycystic kidney disease or a kidney transplant,
• <12 months of available data before the index date, and/or no complete history of drug dispensations/other records of drug use during this period, defined as not having at least 1 ambulatory visit and at least 1 medication prescription during the preceding 12 months, and
• Missing or ambiguous data on serum creatinine in the 12 months prior to the index date or sex

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Empagliflozin initiators; Patient with type 2 diabetes, with or without Chronic Kidney Disease (CKD), who initiated Empagliflozin between January 1, 2016 and December 31, 2020.	Drug: Empagliflozin; Empagliflozin
Dipeptidyl peptidate-4 inhibitor (DPP4i) initiators; Patient with type 2 diabetes, with or without Chronic Kidney Disease (CKD), who initiated dipeptidyl peptidate-4 inhibitor (DPP4i) between January 1, 2016 and December 31, 2020.	Drug: Dipeptidyl Peptidate-4 inhibitors; Dipeptidyl Peptidate-4 inhibitors

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence Rate of the Composite Outcome Including 40% Decline in Estimated Glomerular Filtration Rate (eGFR), Incident End-stage Renal Disease (ESRD) and All-cause Death	40% decline in eGFR: at least 2 measurements during follow-up of at least a 40% decline relative to baseline separated by >= 28 days. the second eGFR measurement is required to be within 2 years from index, at which time, all patients were censored. ESKD: at least 1 kidney transplant or ESKD diagnosis/procedure or at least 2 dialysis diagnoses/procedures separated by >= 28 days or eGFR<15 on 2 measurements separated by >= 28 days. Post-LASSO overlap weighting was used. A LASSO penalized regression model was created with covariates of interest, subgroup variables, and all pairwise interactions. Variables chosen by the LASSO model were refit to a logistic model in order to calculate the PS estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence Rate of the 40% Decline in Estimated Glomerular Filtration Rate (eGFR)	40% decline in eGFR: at least 2 measurements (second measurement must be within 2 years) during follow-up of at least a 40% decline relative to baseline separated by >= 28 days. Post-LASSO (least absolute shrinkage and selection operator) overlap weighting was used. A LASSO penalized regression model was created with the covariates of interest, subgroup variables, and all pairwise covariate-subgroup interactions. Outcome for this model was treatment group (DPP4i as the reference). The variables chosen by the LASSO model were refit to a logistic model in order to calculate the propensity score (PS) estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of End-stage Kidney Disease (ESKD)	ESKD definition: at least 1 kidney transplant or ESKD diagnosis/procedure or at least 2 dialysis diagnoses/procedures separated by >= 28 days or eGFR<15 on 2 measurements separated by >= 28 days. Post-LASSO (least absolute shrinkage and selection operator) overlap weighting was used. A LASSO penalized regression model was created with the covariates of interest, subgroup variables, and all pairwise covariate-subgroup interactions. Outcome for this model was treatment group (DPP4i as the reference). The variables chosen by the LASSO model were refit to a logistic model in order to calculate the propensity score (PS) estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of Dialysis	Incident dialysis, given dialysis in the 12 months preceding index date is a disqualifying diagnosis/procedure. Post-LASSO (least absolute shrinkage and selection operator) overlap weighting was used. A LASSO penalized regression model was created with the covariates of interest, subgroup variables, and all pairwise covariate-subgroup interactions. Outcome for this model was treatment group (DPP4i as the reference). The variables chosen by the LASSO model were refit to a logistic model in order to calculate the propensity score (PS) estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of Kidney Transplant	Kidney transplant: any procedure associated with healthcare encounters, including hospitalizations and specialist outpatient and primary care encounters. Post-LASSO (least absolute shrinkage and selection operator) overlap weighting was used. A LASSO penalized regression model was created with the covariates of interest, subgroup variables, and all pairwise covariate-subgroup interactions. Outcome for this model was treatment group (DPP4i as the reference). The variables chosen by the LASSO model were refit to a logistic model in order to calculate the propensity score (PS) estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of Composite Outcome Including Acute Hospitalization for Heart Failure and All-cause Death	Composite outcome including acute hospitalization for heart failure and All-cause death: Any diagnosis of heart failure associated with hospital admission, including inpatient and emergency department (ED) to inpatient encounters. From death records provided by sites, supplemented with linkage using Datavant Software. Post-LASSO overlap weighting was used. A LASSO penalized regression model was created with covariates of interest, subgroup variables, and all pairwise interactions. Variables chosen by the LASSO model were refit to a logistic model in order to calculate the PS estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of Acute Hospitalization for Heart Failure	Acute hospitalization for heart failure: Any diagnosis of heart failure associated with hospital admission, including inpatient and emergency department (ED) to inpatient encounters. Post-LASSO (least absolute shrinkage and selection operator) overlap weighting was used. A LASSO penalized regression model was created with the covariates of interest, subgroup variables, and all pairwise covariate-subgroup interactions. Outcome for this model was treatment group (DPP4i as the reference). The variables chosen by the LASSO model were refit to a logistic model in order to calculate the propensity score (PS) estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of All-cause Death	All-cause death, from death records provided by sites, supplemented with linkage using Datavant Software. Post-LASSO (least absolute shrinkage and selection operator) overlap weighting was used. a LASSO penalized regression model was created with the covariates of interest, subgroup variables, and all pairwise covariate-subgroup interactions. Outcome for this model was treatment group (DPP4i as the reference). The variables chosen by the LASSO model were refit to a logistic model in order to calculate the propensity score (PS) estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of the Composite Outcome Including MI, Stroke, All-cause Death and Coronary Revascularization Procedure	Composite outcome including MI, Stroke, All-cause death and Coronary revascularization procedure: For MI and stroke, any inpatient diagnosis associated with healthcare encounters, including inpatient and ED to inpatient For all-cause death, death records provided by sites, supplemented with linkage using Datavant Software. Post-LASSO overlap weighting was used. A LASSO penalized regression model was created with covariates of interest, subgroup variables, and all pairwise interactions. Variables chosen by the LASSO model were refit to a logistic model in order to calculate the PS estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of the Composite Outcome Including MI, Stroke, All-cause Death (MACE)	Composite outcome including MI, Stroke, All-cause death: For MI and stroke, any inpatient diagnosis associated with healthcare encounters, including inpatient and ED to inpatient For all-cause death, death records provided by sites, supplemented with linkage using Datavant Software. Post-LASSO overlap weighting was used. A LASSO penalized regression model was created with covariates of interest, subgroup variables, and all pairwise interactions. Variables chosen by the LASSO model were refit to a logistic model in order to calculate the PS estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of Diabetic Ketoacidosis	Any diabetic ketoacidosis diagnosis associated with healthcare encounters in the inpatient setting. Post-LASSO (least absolute shrinkage and selection operator) overlap weighting was used. A LASSO penalized regression model was created with the covariates of interest, subgroup variables, and all pairwise covariate-subgroup interactions. Outcome for this model was treatment group (DPP4i as the reference). The variables chosen by the LASSO model were refit to a logistic model in order to calculate the propensity score (PS) estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of Severe Hypoglycemia	Any severe hypoglycemia diagnosis associated with healthcare encounters in the inpatient or ED setting. Post-LASSO (least absolute shrinkage and selection operator) overlap weighting was used. A LASSO penalized regression model was created with the covariates of interest, subgroup variables, and all pairwise covariate-subgroup interactions. Outcome for this model was treatment group (DPP4i as the reference). The variables chosen by the LASSO model were refit to a logistic model in order to calculate the propensity score (PS) estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of Urinary Tract Cancer	Two or more urinary tract cancer diagnoses associated with healthcare encounters within 2 months. Post-LASSO (least absolute shrinkage and selection operator) overlap weighting was used. A LASSO penalized regression model was created with the covariates of interest, subgroup variables, and all pairwise covariate-subgroup interactions. Outcome for this model was treatment group (DPP4i as the reference). The variables chosen by the LASSO model were refit to a logistic model in order to calculate the propensity score (PS) estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of Severe Urinary Tract Infections (UTI)	Any severe Urinary Tract Infections (UTI) diagnosis associated with healthcare encounters in the inpatient or ED setting for Pyelonephritis or Urosepsis. Post-LASSO (least absolute shrinkage and selection operator) overlap weighting was used. A LASSO penalized regression model was created with the covariates of interest, subgroup variables, and all pairwise covariate-subgroup interactions. Outcome for this model was treatment group (DPP4i as the reference). The variables chosen by the LASSO model were refit to a logistic model in order to calculate the propensity score (PS) estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of Acute Kidney Injury (AKI) That Requires Dialysis	Any Acute kidney injury diagnosis associated with inpatient healthcare encounters for AKI plus at least one inpatient encounter indicating dialysis within 28 days of the AKI encounter. Two or more dialysis encounters separated by 28 days or more was excluded from this definition. Post-LASSO overlap weighting was used. A LASSO penalized regression model was created with covariates of interest, subgroup variables, and all pairwise interactions. Variables chosen by the LASSO model were refit to a logistic model in order to calculate the PS estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.
Incidence Rate of Genital Mycotic Infection	Any genital mycotic infection diagnosis associated with healthcare encounters, including hospitalizations and outpatient encounters, or prescription for fluconazole. Post-LASSO (least absolute shrinkage and selection operator) overlap weighting was used. A LASSO penalized regression model was created with the covariates of interest, subgroup variables, and all pairwise covariate-subgroup interactions. Outcome for this model was treatment group (DPP4i as the reference). The variables chosen by the LASSO model were refit to a logistic model in order to calculate the propensity score (PS) estimates. The overlap weights were then created such that the weights were equal to the PS for participants prescribed the reference treatment (DPP4i) and 1-PS for participants prescribed empagliflozin. Results are presented for the overall cohort and separately for the CKD and non-CKD cohorts.	Starting the day after the index date (date of initiation of empagliflozin or DPP4i) and continuing until the first occurrence of the outcome of interest, or end of study date (date of death, date of study end, 2 years after index date). Up to 2 years.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2022
• Primary Completion (Actual): May 2, 2023
• Study Completion (Actual): May 2, 2023

Study Registration Dates

• First Submitted: July 15, 2022
• First Submitted That Met QC Criteria: July 15, 2022
• First Posted (Actual): July 19, 2022

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: April 25, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Endocrine System Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Kidney Diseases; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 1245-0228

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents. Exceptions might apply, e.g. studies in products where Boehringer Ingelheim is not the license holder; studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; studies conducted in a single center or targeting rare diseases (in case of low number of patients and therefore limitations with anonymization).

For more details refer to: https://www.mystudywindow.com/msw/datatransparency

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No