Clinical trial NCT03993132: 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
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]
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2019-06-20
Enrollment: 26774
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The source population for our study consists of individuals with type 2 diabetes, who are defined in our study as individuals who live in Denmark and who have never used oral antihyperglycemic drugs or insulin.

Brief 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).


Eligibility criteria: 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).

Primary outcomes:
measure: Incidence Rate of Expanded Major Adverse Cardiovascular Event (MACE) Composite Outcome - OT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of Expanded Major Adverse Cardiovascular Event (MACE) Composite Outcome - ITT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Secondary outcomes:
measure: Incidence Rate of Heart Failure (HF) Hospitalization or All-cause Death - OT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of Heart Failure (HF) Hospitalization or All-cause Death - ITT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of First Hospitalized Heart Failure (HHF) or Initiation of Community Prescription Drug Therapy With Loop Diuretics - OT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of First Hospitalized Heart Failure (HHF) or Initiation of Community Prescription Drug Therapy With Loop Diuretics - ITT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of All-cause Hospitalization or Death - OT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of All-cause Hospitalization or Death - ITT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of All Cause Hospitalization - OT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of All Cause Hospitalization - ITT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of All-cause Death - OT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of All-cause Death - ITT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of Hospitalization for Heart Failure (HF) - OT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
measure: Incidence Rate of Hospitalization for Heart Failure (HF) - ITT Analysis
timeFrame: From first initiation of empagliflozin or liraglutide until end of follow-up, up to 6 years.
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Department of Clinical Epidemiology - Aarhus Unversiteteshospital
Study officials:
References:
citation: Thomsen RW, Christensen LWB, Kahlert J, Knudsen JS, Ustyugova A, Sandgaard S, Holmgaard P, Ehlers LH, Sorensen HT. Healthcare Resource Utilization and Costs for Empagliflozin Versus Glucagon-Like Peptide-1 Receptor Agonists in Routine Clinical Care in Denmark. Diabetes Ther. 2022 Dec;13(11-12):1891-1906. doi: 10.1007/s13300-022-01323-y. Epub 2022 Oct 31.