A Study to Observe the Effectiveness of Empagliflozin, Other SGLT-2 Inhibitors, or DPP-4 Inhibitors in Patients With Type 2 Diabetes

Multi-country Non-interventional Study on the Effectiveness of Empagliflozin in Adult Patients With Type 2 Diabetes in Europe and Asia.

Non-interventional, multi-country cohort study using existing data and including adults (≥18 years) with a diagnosis of Type 2 diabetes mellitus.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Subjects treated with Empagliflozin or any Sodium-glucose cotransporter-2 (SGLT-2) inhibitor; Drug: Subjects treated with Dipeptidyl peptidase-4 (DPP-4) inhibitor

• Study Type: Observational
• Enrollment (Actual): 327624

Contacts and Locations

Study Locations

• Denmark
  • Gentofte, Denmark, 2820
    • Steno Diabetes Center Copenhagen, Department of Clinical Epidemiology
• Finland
  • Helsinki, Finland, 00029
    • Helsinki University Hospital
• Germany
  • Ulm, Germany, 89081
    • University of Ulm, Institute for Epidemiology and medical biometry
• Israel
  • Tel Aviv, Israel, 6812509
    • Maccabi Healthcare Services
• Japan
  • Gifu, Japan, 501-1193
    • Gifu University
• Korea, Republic of
  • Suwon, Korea, Republic of, 16499
    • Ajou University Hospital
• Norway
  • Oslo, Norway, 0424
    • Oslo University Hospital, Department of Clinical Lipidology
  • Oslo, Norway, 0450
    • Oslo University Hospital, Department of Cardiology
• Spain
  • Valencia, Spain, 46010
    • Instituto de Investigacion Sanitaria INCLIVA
• Sweden
  • Lund, Sweden, 223 63
    • TFS Trial Form Support International AB
  • Stockholm, Sweden, 112 21
    • Quantify Research AB
• Taiwan
  • Taipei City, Taiwan, 100
    • Taiwan Society for Pharmacoeconomics and Outcome Research (TaSPOR)
• United Kingdom
  • Leicester, United Kingdom, LE5 4PW
    • Leicester Real World Evidence Unit, Leicester general Hospital

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

This will be a non-interventional, multi-country cohort study using existing data and including adults (≥18 years) with a diagnosis of T2DM. All data will be obtained from electronically recorded longitudinal secondary data sources, separately in each included country. In each country, patients initiating treatment with empagliflozin or any other SGLT-2 inhibitor will be compared with PS-matched patients initiating treatment with any DPP-4inhibitor.

Description

Inclusion Criteria:

• Dispensation or any other record of empagliflozin, any SGLT-2 inhibitor, or any DPP-4 inhibitor use during the study period
• No dispensation or any other record of any other SGLT-2 inhibitor or DPP-4 inhibitor use during the preceding 12 months including at index date
• Having a diagnosis of T2DM before the index date, based on ICD-10 codes or other available data

Exclusion Criteria:

• Aged <18 years on the first dispensation date or date of the first record of empagliflozin, any SGLT-2 inhibitor or any DPP-4 inhibitor use
• Type 1 diabetes mellitus
• Secondary diabetes
• Gestational diabetes
• Having a diagnosis of ESRD during the 12 months before the index date
• <12 months of available data before the index date, and/or no complete history of drug dispensations/other records of the drug use during this period
• Missing or ambiguous data on age or sex

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
New users of SGLT-2i; Patients with type 2 diabetes mellitus (T2DM), who were new users of any sodium-glucose cotransporter-2 inhibitors (SGLT-2i) including empagliflozin.	Drug: Subjects treated with Empagliflozin or any Sodium-glucose cotransporter-2 (SGLT-2) inhibitor; Empagliflozin or any Sodium-glucose cotransporter-2 (SGLT-2) inhibitor
New users of DPP-4i; Patients with type 2 diabetes mellitus (T2DM), who were new users of dipeptidyl peptidase-4 inhibitors (DPP-4i).	Drug: Subjects treated with Dipeptidyl peptidase-4 (DPP-4) inhibitor; Dipeptidyl peptidase-4 (DPP-4) inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Hospitalization for Heart Failure (HHF), Broad + Specific Definition	Number of participants with Hospitalization for Heart Failure (HHF), using broad + specific HHF definition. HHF - broad defined as any diagnosis associated with healthcare encounters, including hospitalizations and specialist outpatient and primary care encounters, or dispensation or any other record of the high-ceiling diuretics (loop diuretics). HHF - specific defined as a primary diagnosis associated with hospital admission. For HHF - broad + specific, HHF-specific definition was used unless only broad definition were available. However, for Japan South Korea and Taiwan, both definitions were available, but broad definition was used.	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i
Number of Participants With Hospitalization for Heart Failure (HHF), Broad Definition	Reported is the number of participants with hospitalization for heart failure (HHF), using broad definition of HHF. HHF - broad is defined as any diagnosis associated with healthcare encounters, including hospitalizations and specialist outpatient and primary care encounters, or dispensation or any other record of the high-ceiling diuretics (loop diuretics).	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i
Number of Participants With Hospitalization for Heart Failure (HHF), Specific Definition	Reported is the number of participants with hospitalization for heart failure, using specific definition for HHF. HHF - specific defined as a primary diagnosis associated with hospital admission.	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i
Number of Participants With All-cause Mortality (ACM)	Number of participants with all-cause mortality (ACM).	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With Composite Outcome, Including Hospitalization for Heart Failure (HHF) and All Cause Mortality (ACM)	Number of participants with composite outcome, including hospitalization for heart failure (HHF) and all cause mortality (ACM).	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With Composite Outcome, Including Myocardial Infraction (MI), Stroke and All Cause Mortality (ACM)	Number of participants with composite outcome, including myocardial infraction (MI), stroke and all cause mortality (ACM).	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With Myocardial Infarction (MI)	Number of participants with myocardial infarction (MI).	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With Stroke	Number of participants with stroke.	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Cardiovascular Mortality (CM)	Number of participants with cardiovascular mortality (CM).	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With Composite Outcome Including Hospitalization for Heart Failure (HHF) and Cardiovascular (CV) Mortality	Number of participants with composite outcome including hospitalization for heart failure (HHF) and cardiovascular (CV) mortality.	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With 3-point Major Adverse Cardiovascular (CV) Events (MACE), Defined as a Composite Outcome Including Myocardial Infarction (MI), Stroke and Cardiovascular (CV) Mortality	Number of participants with 3-point major adverse cardiovascular (CV) events (MACE), defined as a composite outcome including myocardial infarction (MI), stroke and cardiovascular (CV) mortality.	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With Coronary Revascularization Procedure	Number of participants with coronary revascularization procedure.	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With End-stage Renal Disease (ESRD)	Number of participants with end-stage renal disease (ESRD).	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With Estimated Glomerular Filtration Rate (eGFR) Decline	Number of participants with estimated glomerular filtration rate (eGFR) decline.	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With Progression From Normoalbuminuria to Micro- or Macroalbuminuria	Number of participants with progression from normoalbuminuria to micro- or macroalbuminuria.	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With Composite Outcome Including eGFR Decline and Progression to Micro- or Macroalbuminuria	Number of participants with composite outcome including Estimated glomerular filtration rate (eGFR) decline and progression to micro- or macroalbuminuria.	From index date until end of follow-up, up to 67 months for matched cohort of empagliflozin/DPP-4i. Up to 86 months for matched cohort of SGLT-2i/DPP-4i.
Number of Participants With Bone Fracture	Number of participants with bone fracture. Data for this endpoint was only collected and analyzed for the matched cohort of empagliflozin/DPP-4i.	From index date until end of follow-up, up to 67 months.
Number of Participants With Diabetic Ketoacidosis	Number of participants with diabetic ketoacidosis. Data for this endpoint was only collected and analyzed for the matched cohort of empagliflozin/DPP-4i	From index date until end of follow-up, up to 67 months.
Number of Participants With Severe Hypoglycemia	Number of participants with severe hypoglycemia. Data for this endpoint was only collected and analyzed for the matched cohort of empagliflozin/DPP-4i.	From index date until end of follow-up, up to 67 months.
Number of Participants With Lower-limb Amputation	Number of participants with lower-limb amputation. Data for this endpoint was only collected and analyzed for the matched cohort of empagliflozin/DPP-4i.	From index date until end of follow-up, up to 67 months.
Number of Participants With Acute Kidney Injury Requiring Dialysis	Number of participants with acute kidney injury requiring dialysis. Data for this endpoint was only collected and analyzed for the matched cohort of empagliflozin/DPP-4i.	From index date until end of follow-up, up to 67 months.
Healthcare Resource Utilization (HCRU): Number of Any Medical Visit	HCRU data were collected from seven of the 11 participating countries including Finland, Japan, South Korea, Norway, Spain, Sweden, and Taiwan. Outcomes captured as HCRU include emergency room visits, first inpatient stay, all-cause hospital admissions and outpatient healthcare visits. HCRU outcomes were investigated for the matched cohort of empagliflozin/DPP-4 only. Due to possibly huge differences in healthcare systems and local practices, HCRU outcomes were presented descriptively by country as per prespecified analysis plan. For arms with 0 patients analyzed, no data was collected for the specific outcome in this country.	From index date until end of follow-up, up to 67 months.
Healthcare Resource Utilization (HCRU): Number of Any Prescription	HCRU data were collected from seven of the 11 participating countries including Finland, Japan, South Korea, Norway, Spain, Sweden, and Taiwan. Outcomes captured as HCRU include pharmacy dispensations/prescriptions of different antidiabetic drugs, different drugs and prescriptions. HCRU outcomes were investigated for the matched cohort of empagliflozin/DPP-4 only. Due to possibly huge differences in healthcare systems and local practices, HCRU outcomes were presented descriptively by country as per prespecified analysis plan. For arms with 0 patients analyzed, no data was collected for the specific outcome in this country.	From index date until end of follow-up, up to 67 months.
Total Healthcare Costs - Finland, Norway, Sweden	Total healthcare cost include costs for emergency room visits, first inpatient stay, all-cause hospital admissions, outpatient healthcare visits and pharmacy dispensations/prescriptions of different antidiabetic drugs, different drugs and prescriptions. Total healthcare costs for Finland, Norway and Sweden are reported in Euro per year. Due to possible huge differences in healthcare systems, cost of care outcomes are presented by country as prespecified in the analysis plan.	From index date until end of follow-up, up to 67 months.
Total Healthcare Cost - Japan	Total healthcare costs include costs for emergency room visits, first inpatient stay, all-cause hospital admissions, outpatient healthcare visits and pharmacy dispensations/prescriptions of different antidiabetic drugs, different drugs and prescriptions. Total healthcare cost for Japan are reported in Japanese Yen (JPY) per year. Due to possible huge differences in healthcare systems, cost of care outcomes are presented by country as prespecified in the analysis plan.	From index date until end of follow-up, up to 67 months.
Total Healthcare Cost - South Korea	Total healthcare costs include costs for emergency room visits, first inpatient stay, all-cause hospital admissions, outpatient healthcare visits and pharmacy dispensations/prescriptions of different antidiabetic drugs, different drugs and prescriptions. Total healthcare costs for South Korea are reported in 1000 Korean Won (KRW) per year. Due to possible huge differences in healthcare systems, cost of care outcomes are presented by country as prespecified in the analysis plan.	From index date until end of follow-up, up to 67 months.
Total Healthcare Cost - Taiwan	Total healthcare costs include costs for emergency room visits, first inpatient stay, all-cause hospital admissions, outpatient healthcare visits and pharmacy dispensations/prescriptions of different antidiabetic drugs, different drugs and prescriptions. Total healthcare cost for Taiwan are reported in United States Dollar (USD) per year. Due to possible huge differences in healthcare systems, cost of care outcomes are presented by country as prespecified in the analysis plan.	From index date until end of follow-up, up to 67 months.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Investigators: Study Chair: Kimberly G Brodovicz, (203) 448-1937, kimberly.brodovicz@boehringer-ingelheim.com

Publications and helpful links

General Publications

• Nystrom T, Toresson Grip E, Gunnarsson J, Casajust P, Karlsdotter K, Skogsberg J, Ustyugova A; EMPRISE Study Group. Empagliflozin reduces cardiorenal events, healthcare resource use and mortality in Sweden compared to dipeptidyl peptidase-4 inhibitors: Real world evidence from the Nordic EMPRISE study. Diabetes Obes Metab. 2023 Jan;25(1):261-271. doi: 10.1111/dom.14870. Epub 2022 Oct 10.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2019
• Primary Completion (Actual): December 10, 2021
• Study Completion (Actual): December 10, 2021

Study Registration Dates

• First Submitted: January 24, 2019
• First Submitted That Met QC Criteria: January 24, 2019
• First Posted (Actual): January 25, 2019

Study Record Updates

• Last Update Posted (Actual): September 23, 2024
• Last Update Submitted That Met QC Criteria: May 28, 2024
• Last Verified: May 1, 2024

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; Enzyme Inhibitors; Protease Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin; Dipeptidyl-Peptidase IV Inhibitors
• Other Study ID Numbers: 1245-0195

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