A Study Using Medical Records of Danish People With Type 2 Diabetes Comparing Empagliflozin and Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RA) in the Occurrence of Serious Cardiovascular Outcomes

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Cardiovascular Outcomes, and Mortality in Danish Patients With Type 2 Diabetes Who Initiate Empagliflozin Versus Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RA): A Danish Nationwide Comparative Effectiveness Study [EMPLACEtm]

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03993132
• Other study ID #: 1245-0194
• Status: Completed
• Start date: October 1, 2018
• Est. completion date: June 16, 2022

Study information

• Verified date: June 2023
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The primary research question is to evaluate whether, among patients with type 2 diabetes mellitus (T2D), initiation of empagliflozin changes the adjusted incidence of outcomes compared with initiation of Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RA).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26774
• Est. completion date: June 16, 2022
• Est. primary completion date: June 16, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

The empagliflozin-exposed population must also meet the following criteria:

• Have at least one prescription for empagliflozin or fixed-dose combination of empagliflozin with another drug, with or without treatment with another glucose-lowering drug

• Have no prescription/dispensing of SGLT2 inhibitors (including empagliflozin) alone or in fixed-dose combination prior to the index date

• Have no prescription/dispensing of a GLP-1 receptor agonist alone or in fixed dose combination prior to the index date

The population exposed to GLP1-RA must meet the following criteria:

• Have at least one prescription for GLP1-RA or a fixed-dose combination of GLP1-RA with another drug, with or without treatment with another glucose-lowering drug.

• Have no prescription/dispensing of a GLP-1 receptor agonist alone or in fixed dose combination prior to the index date

• Have no prescription/dispensing of SGLT2 inhibitors (including empagliflozin) alone or in fixed-dose combination prior to the index date

Exclusion Criteria:

-Patients with type 1 diabetes T1D before the index date will not be included in the study.

Exclusion criteria by outcome of interest: Different exclusion criteria will be applied to generate sets of cohorts for the analysis of the different outcomes of interest.

In one main analysis, we will assess co-primary and secondary outcomes among all patients, regardless of a history of previous outcome events being present or not. In other words, we will allow a previous history of CVD events. We will adjust for the history of these events in the regression model rather than excluding patients with previous events (e.g. assess outcome rates of myocardial infarction in empagliflozine and liraglutide initiators while adjusting for previous history of myocardial infarction, unstable angina, or coronary revascularization).

In another main analysis of outcomes, we will exclude patients who had a specific outcome previously.

For example in the analysis of the primary heart failure outcome (heart failure admission or loop-diuretics), patients will not be included if a diagnosis of heart failure is recorded any time before or at the index date, or if a prescription for loop-diuretics has been filled within 12 months before or at the index date. For the secondary outcome of acute hospital admission with heart failure, we will include also patients with previous prescription for loop-diuretics, but exclude those with previous heart failure admission.

For analysis of stroke, patients will not be included if a diagnosis of stroke is recorded any time before or at the index date.

For analysis of myocardial infarction, unstable angina, or coronary revascularization, patients will not be included if any of these 3 major atherosclerotic cardiovascular events are recorded any time before or at the index date.

In additional analyses, other criteria will apply (To be discussed, RWT). Thus, an additional analysis will include also patients with previous outcome events, and adjust for the history of these events in the regression model rather than excluding them (e.g. assess outcome rates of myocardial infarction in empagliflozine and liraglutide initiators while adjusting for previous history of myocardial infarction, unstable angina, or coronary revascularization).

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• Empagliflozin
new users (initiators) of Empagliflozin
• Liraglutide
initiators of Liraglutide

Locations

Country	Name	City	State
Denmark	Department of Clinical Epidemiology - Aarhus Unversiteteshospital	Aarhus

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence Rate of Expanded Major Adverse Cardiovascular Event (MACE) Composite Outcome - OT Analysis	Composite outcome includes: All-cause death, acute admission with non-fatal (within 30 days) stroke, with non-fatal (within 30 days) myocardial infarction (MI), admission with unstable angina, coronary revascularization, or acute admission with non-fatal heart failure (HF).; The results from on-treatment (OT) analysis are reported. For the OT analyses, treatment duration was based on the estimated number of days covered by each filled prescription, calculated as the number of drug packages times the numerical volume of a package. A grace period of 30 days were added.; In the OT analysis, participants were censored from further follow-up at either treatment cessation, initiation of an alternative drug in the study drug class and initiation of a drug from the comparator study drug class.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Primary	Incidence Rate of Expanded Major Adverse Cardiovascular Event (MACE) Composite Outcome - ITT Analysis	Composite outcome includes: All-cause death, acute admission with non-fatal (within 30 days) stroke, with non-fatal (within 30 days) myocardial infarction (MI), admission with unstable angina, coronary revascularization, or acute admission with non-fatal heart failure (HF).; The results from intention-to-treat (ITT) analysis are reported. For the ITT analyses, participants were defined as exposed from the start of treatment throughout follow-up, analogous to an ITT design in a interventional trial. Follow-up was not censored if glucose-lowering drugs other than the index drugs were prescribed in addition to empagliflozin or GLP-1RA after the index date.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of Heart Failure (HF) Hospitalization or All-cause Death - OT Analysis	The incidence rate of heart failure (HF) hospitalization or all-cause death based on on-treatment (OT) analysis is reported.; For the OT analyses, treatment duration was based on the estimated number of days covered by each filled prescription, calculated as the number of drug packages times the numerical volume of a package. A grace period of 30 days were added.; In the OT analysis, participants were censored from further follow-up at either treatment cessation, initiation of an alternative drug in the study drug class and initiation of a drug from the comparator study drug class.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of Heart Failure (HF) Hospitalization or All-cause Death - ITT Analysis	The incidence rate of heart failure (HF) hospitalization or all-cause death based on Intention-to-treat (ITT) analysis is reported. For the ITT analyses, participants are defined as exposed from the start of treatment throughout follow-up, analogous to an ITT design in a interventional trial. Follow-up was not censored if glucose-lowering drugs other than the index drugs were prescribed in addition to empagliflozin or GLP-1RA after the index date.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of First Hospitalized Heart Failure (HHF) or Initiation of Community Prescription Drug Therapy With Loop Diuretics - OT Analysis	The incidence rate of first hospitalized Heart Failure (HHF) or initiation of community prescription drug therapy with loop diuretics based on on-treatment (OT) analysis is reported.; For the OT analyses, treatment duration was based on the estimated number of days covered by each filled prescription, calculated as the number of drug packages times the numerical volume of a package. A grace period of 30 days were added.; In the OT analysis, participants were censored from further follow-up at either treatment cessation, initiation of an alternative drug in the study drug class and initiation of a drug from the comparator study drug class.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of First Hospitalized Heart Failure (HHF) or Initiation of Community Prescription Drug Therapy With Loop Diuretics - ITT Analysis	The incidence rate of first hospitalized Heart Failure (HHF) or initiation of community prescription drug therapy with loop diuretics based on intention-to-treat (ITT) analysis was reported. For the ITT analyses, participants are defined as exposed from the start of treatment throughout follow-up, analogous to an ITT design in a interventional trial. Follow-up was not censored if glucose-lowering drugs other than the index drugs were prescribed in addition to empagliflozin or GLP-1RA after the index date.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of All-cause Hospitalization or Death - OT Analysis	Incidence rate of all-cause hospitalization or death, based on on-treatment (OT) analysis is reported.; For the OT analyses, treatment duration was based on the estimated number of days covered by each filled prescription, calculated as the number of drug packages times the numerical volume of a package. A grace period of 30 days were added. In the OT analysis, participants were censored from further follow-up at either treatment cessation, initiation of an alternative drug in the study drug class and initiation of a drug from the comparator study drug class.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of All-cause Hospitalization or Death - ITT Analysis	Incidence rate of all-cause hospitalization or death, based on intent-to-treat (ITT) analysis.; For the ITT analyses, participants were defined as exposed from the start of treatment throughout follow-up, analogous to an ITT design in a interventional trial. Follow-up was not censored if glucose-lowering drugs other than the index drugs were prescribed in addition to empagliflozin or GLP-1RA after the index date.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of All Cause Hospitalization - OT Analysis	Incidence rate of all cause hospitalization, based on on-treatment (OT) analysis is reported.; For the OT analyses, treatment duration was based on the estimated number of days covered by each filled prescription, calculated as the number of drug packages times the numerical volume of a package. A grace period of 30 days were added. In the OT analysis, participants were censored from further follow-up at either treatment cessation, initiation of an alternative drug in the study drug class and initiation of a drug from the comparator study drug class.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of All Cause Hospitalization - ITT Analysis	Incidence rate of all cause hospitalization, based on intent-to-treat (ITT) analysis.; For the ITT analyses, participants were defined as exposed from the start of treatment throughout follow-up, analogous to an ITT design in a interventional trial. Follow-up was not censored if glucose-lowering drugs other than the index drugs were prescribed in addition to empagliflozin or GLP-1RA after the index date.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of All-cause Death - OT Analysis	Incidence rate of all-cause death, based on on-treatment (OT) analysis is reported.; For the OT analyses, treatment duration was based on the estimated number of days covered by each filled prescription, calculated as the number of drug packages times the numerical volume of a package. A grace period of 30 days were added.; In the OT analysis, participants were censored from further follow-up at either treatment cessation, initiation of an alternative drug in the study drug class and initiation of a drug from the comparator study drug class.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of All-cause Death - ITT Analysis	Incidence rate of all-cause death, based on intent-to-treat (ITT) analysis. For the ITT analyses, participants were defined as exposed from the start of treatment throughout follow-up, analogous to an ITT design in a interventional trial. Follow-up was not censored if glucose-lowering drugs other than the index drugs were prescribed in addition to empagliflozin or GLP-1RA after the index date.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of Hospitalization for Heart Failure (HF) - OT Analysis	Incidence rate of hospitalization for heart failure (HF), based on on-treatment (OT) analysis is reported.; For the OT analyses, treatment duration was based on the estimated number of days covered by each filled prescription, calculated as the number of drug packages times the numerical volume of a package. A grace period of 30 days were added.; In the OT analysis, participants were censored from further follow-up at either treatment cessation, initiation of an alternative drug in the study drug class and initiation of a drug from the comparator study drug class.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary	Incidence Rate of Hospitalization for Heart Failure (HF) - ITT Analysis	Incidence rate of hospitalization for heart failure (HF), based on intent-to-treat (ITT) analysis.; For the ITT analyses, participants were defined as exposed from the start of treatment throughout follow-up, analogous to an ITT design in a interventional trial. Follow-up was not censored if glucose-lowering drugs other than the index drugs were prescribed in addition to empagliflozin or GLP-1RA after the index date.	From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.

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