Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors and Risk of Cardiovascular Events

NCT03939624 | Completed

• 1 other identifier: Q18-06
• Study Type: observational
• Target: 419,734
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to compare the risk of cardiovascular events associated with the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in comparison with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with type 2 diabetes. The investigators will carry out separate population-based cohort studies using health care databases in seven Canadian provinces and the United Kingdom. The study cohort will be defined by the initiation of a SGLT2 inhibitor or a DPP-4 inhibitor after SGLT2 inhibitors entered the market. Patients will be followed up until the occurrence of a cardiovascular event. The results from the separate sites will be combined by meta-analysis to provide an overall assessment of the risk of cardiovascular events in users of SGLT2 inhibitors. The investigators hypothesize that the use of SGLT2 inhibitors will be associated with a decreased risk of cardiovascular events in comparison with the use of DPP-4 inhibitors.

Conditions

Type2 Diabetes; Myocardial Infarction; Ischemic Stroke; Cardiovascular Death; Heart Failure; All-Cause Mortality

Keywords

Sodium-Glucose Cotransporter 2 Inhibitors; Type 2 Diabetes; Myocardial Infarction; Ischemic Stroke; Cardiovascular Death

Outcome Measures

Primary Outcomes (3)

• Myocardial infarction

  Patients hospitalized for myocardial infarction recorded as the most responsible diagnosis or present on admission in the hospitalization record with the following ICD-10-CA codes: I21.x.

  Patients will be followed from the date of study cohort entry until hospitalization for myocardial infarction, treatment discontinuation, death, end of healthcare coverage, or for up to 64 months, whichever occurs first.

• Ischemic stroke

  Patients hospitalized for ischemic stroke recorded as the most responsible diagnosis or present on admission in the hospitalization record with the following ICD-10-CA codes: I63.x, I64.x.

  Patients will be followed from the date of study cohort entry until hospitalization for ischemic stroke, treatment discontinuation, death, end of healthcare coverage, or for up to 64 months, whichever occurs first.

• Cardiovascular death

  Cardiovascular death will be defined using the following algorithm: * In-hospital death with a cardiovascular diagnosis (ICD-10-CA: I00.x-I77.x (except I46.9)) recorded as the most responsible diagnosis or present on admission; or * Out-of-hospital death (including death in the emergency department) without: * Documentation of cancer (ICD-9-CM: 140-172, 174-209; ICD-10-CA: C00-C43, C45-C97) in hospital, emergency department or physician claims data in the prior year; or * Documentation of trauma (ICD-9-CM: 800-999, E000-E999; ICD-10-CA: S00-T98, V01-Y98) in hospital, emergency department or physician claims data in the preceding month. In a sensitivity analysis, the algorithm will be validated in the sites with access to vital statistics data with cause of death.

  Patients will be followed from the date of study cohort entry until death, treatment discontinuation, end of healthcare coverage, or for up to 64 months, whichever occurs first.

Secondary Outcomes (2)

• All-cause mortality

  Patients will be followed from the date of study cohort entry until death, treatment discontinuation, end of healthcare coverage, or for up to 64 months, whichever occurs first.

• Heart failure

  Patients will be followed from the date of study cohort entry until hospitalization for heart failure, treatment discontinuation, death, end of healthcare coverage, or for up to 64 months, whichever occurs first.

Study Arms (2)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Patients who received a SGLT2 inhibitor alone (canagliflozin, dapagliflozin, empagliflozin) or in combination with non-DPP4 inhibitor drugs at cohort entry date.

Drug: Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors

Patients who received a DPP-4 inhibitor (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin) alone or in combination with non-SGLT2 inhibitor drugs at cohort entry date.

Drug: Dipeptidyl peptidase-4 (DPP-4) inhibitors

Interventions

Sodium-glucose cotransporter 2 (SGLT2) inhibitors DRUG

Exposure to SGLT2 will be defined as a prescription for a SGLT2 inhibitor alone (canagliflozin, dapagliflozin, empagliflozin) or in combination with non-DPP4 inhibitor drugs at cohort entry date.

Also known as: ATC A10BK, A10BD15, A10BD16, A10BD19, A10BD20, A10BD21, A10BD23, A10BD24, A10BD25

Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors DRUG

Exposure to DPP-4 will be defined as a prescription for a DPP-4 inhibitor (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin) alone or in combination with non-SGLT2 inhibitor drugs at cohort entry date.

Also known as: ATC A10BH, A10BD07, A10BD08, A10BD09, A10BD10, A10BD11, A10BD12, A10BD13, A10BD18, A10BD19, A10BD20, A10BD21, A10BD22, A10BD24, A10BD25

Dipeptidyl peptidase-4 (DPP-4) inhibitors

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

In each jurisdiction, the investigators will assemble a source population that includes all patients who received an antidiabetic medication between January 1, 2006 and June 30, 2018. From this source population, a study cohort will be formed including all patients who received a prescription for a SGLT2 inhibitor or DPP-4 inhibitor on or after the date of the first dispensation of a SGLT2 inhibitor in each jurisdiction and on or before June 30, 2018. Study cohort entry date will be defined by the SGLT2 dispensation date or the corresponding dispensation date for a DPP-4 inhibitor in the matched exposure set.

You may qualify if:

• Patients who received a prescription for a SGLT2 inhibitor or DPP-4 inhibitor on or after the date of the first dispensation of a SGLT2 inhibitor at each site and on or before June 30, 2018 (or latest date of data availability at each site)

You may not qualify if:

• Patients who received both a first prescription for a SGLT2 inhibitor and a DPP-4 inhibitor on the same date
• Patients with missing sex
• Patients aged less than 18 years at cohort entry date (\<19 years in Alberta and \<66 years in Ontario)
• Patients with less than 365 days of healthcare coverage prior to cohort entry date
• Patients with date inconsistencies or no follow-up

Sponsors & Collaborators

• Canadian Network for Observational Drug Effect Studies, CNODES: lead
• Drug Safety and Effectiveness Network, Canada: collaborator
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (1)

Lady Davis Institute for Medical Research, Jewish General Hospital

Montreal, Quebec, H3T1E2, Canada

Location

Related Publications (4)

• Brunetti VC, St-Jean A, Dell'Aniello S, Fisher A, Yu OHY, Bugden SC, Daigle JM, Hu N, Alessi-Severini S, Shah BR, Ronksley PE, Lix LM, Ernst P, Filion KB; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Characteristics of new users of recent antidiabetic drugs in Canada and the United Kingdom. BMC Endocr Disord. 2022 Sep 29;22(1):241. doi: 10.1186/s12902-022-01140-1.

  PMID: 36175881 BACKGROUND

• Suissa S, Moodie EE, Dell'Aniello S. Prevalent new-user cohort designs for comparative drug effect studies by time-conditional propensity scores. Pharmacoepidemiol Drug Saf. 2017 Apr;26(4):459-468. doi: 10.1002/pds.4107. Epub 2016 Sep 9.

  PMID: 27610604 BACKGROUND

• Filion KB, Lix LM, Yu OH, Dell'Aniello S, Douros A, Shah BR, St-Jean A, Fisher A, Tremblay E, Bugden SC, Alessi-Severini S, Ronksley PE, Hu N, Dormuth CR, Ernst P, Suissa S; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Sodium glucose cotransporter 2 inhibitors and risk of major adverse cardiovascular events: multi-database retrospective cohort study. BMJ. 2020 Sep 23;370:m3342. doi: 10.1136/bmj.m3342.

  PMID: 32967856 BACKGROUND

• Lix LM, Sobhan S, St-Jean A, Daigle JM, Fisher A, Yu OHY, Dell'Aniello S, Hu N, Bugden SC, Shah BR, Ronksley PE, Alessi-Severini S, Douros A, Ernst P, Filion KB. Validity of an algorithm to identify cardiovascular deaths from administrative health records: a multi-database population-based cohort study. BMC Health Serv Res. 2021 Jul 31;21(1):758. doi: 10.1186/s12913-021-06762-0.

  PMID: 34332563 BACKGROUND

Related Links

• This is the website describing the general functions of the organization, other CNODES projects, and investigator profiles.

MeSH Terms

Conditions

Myocardial Infarction; Ischemic Stroke; Heart Failure; Diabetes Mellitus, Type 2

Interventions

Sodium-Glucose Transporter 2

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Sodium-Glucose Transport Proteins; Symporters; Ion Pumps; Membrane Transport Proteins; Carrier Proteins; Proteins; Amino Acids, Peptides, and Proteins; Monosaccharide Transport Proteins; Solute Carrier Proteins; Membrane Proteins

Study Officials

• Pierre Ernst, MD, MSc, FRCPC

  Lady Davis Institute for Medical Research, Jewish General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 3, 2019
• First Posted: May 7, 2019
• Study Start: October 1, 2018
• Primary Completion: October 1, 2019
• Study Completion: October 1, 2019
• Last Updated: September 19, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)