Type2 DiabetesNCT03939624
Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors and Risk of Cardiovascular Events
An observational study of Type2 Diabetes and Myocardial Infarction, run by Canadian Network for Observational Drug Effect Studies, CNODES at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Type2 Diabetes, Myocardial Infarction, Ischemic Stroke
- What is being tested?
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors and Dipeptidyl peptidase-4 (DPP-4) inhibitors
- How many people
- 419,734 participants
- Where
- 1 siteCanada
- Study dates
- 1 Oct 2018to 1 Oct 2019
- Phase
- Observational
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
Who may be able to join
- 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)
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Canada1 site
Lady Davis Institute for Medical Research, Jewish General Hospital
Montreal, Quebec, H3T1E2
About this study
Official title: Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors and the Risk of Cardiovascular Events Among Patients With Type 2 Diabetes: a Multicenter Cohort Study
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.
Read the detailed description
The objective of this study is to compare the risk of major adverse cardiac events (MACE) 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.
A common-protocol approach will be used to conduct retrospective cohort studies using administrative health care data from seven Canadian provinces (Alberta, British Columbia, Manitoba, Nova Scotia, Ontario, Quebec, and Saskatchewan) and the United Kingdom (UK) Clinical Practice Research Datalink (CPRD). Briefly, the Canadian databases include population-level data on physician billing, diagnoses and procedures from hospital discharge abstracts, and dispensations for prescription drugs. The data in Ontario will be restricted to patients aged 65 years old and older. The CPRD is a clinical database that is representative of the UK population and contains the records for patients seen at over 680 general practitioner practices in the UK; these data will be linked to the Hospital Episode Statistics (HES) database, which contains in-hospital diagnosis and procedure data.
The investigators will use a prevalent new-user cohort design (Suissa et al., 2017). In each jurisdiction, the investigators will assemble a source population that includes all patients who received an antidiabetic medication (metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, alpha-glucosidase inhibitors, meglitinides, insulin, or combinations of these drugs) between January 1, 2006 and June 30, 2018 (or the latest date of data availability at each site). From this source population, a study cohort including all patients who received a prescription for a SGLT2 inhibitor or DPP-4 inhibitor on or after the date of the first dispensing (or prescription in CPRD) of a SGLT2 inhibitor in each jurisdiction and on or before June 30, 2018 (or latest date of data availability at each site) will be created. 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. Patients will be followed until the occurrence of an event (defined below), death, end of healthcare coverage (plus 30 days), or end of the study period, whichever occurs first. Patients will be eligible to enter the cohort twice, a first time with a DPP-4 prescription and a second time with a SGLT2 prescription.
Exposure will be defined as a prescription for a SGLT2 inhibitor or a DPP-4 inhibitor on the date of cohort entry. DPP-4 inhibitors will serve as the reference category as both classes are second- to third-line therapy, and DPP-4 inhibitors have no known association with the outcome. Analyses will be conducted using an as-treated approach. Patients will be followed until drug discontinuation or the initiation of the other study drug. The primary outcome will be MACE, defined as a composite endpoint of myocardial infarction, ischemic stroke, or cardiovascular death. Secondary outcomes will include the individual endpoints of MACE, all-cause mortality, and hospitalization for heart failure.
Using a prevalent new-user design with time-based exposure sets, each user of a SGLT2 inhibitor will be matched to a DPP-4 inhibitor user on the number of prior antidiabetic medication classes and on time-conditional propensity score. Cox proportional hazards models will be used to estimate site-specific adjusted hazards ratios (HR) and corresponding 95% confidential intervals (CI) for each outcome of interest among patients exposed to a SGLT2 inhibitor in comparison to those exposed to a DPP-4 inhibitor. As secondary analyses, the MACE and heart failure outcomes will be stratified by age (≥70 and <70 years), sex, prior insulin use, and SGLT2 molecule. The MACE composite outcome will be stratified by history of cardiovascular disease, and the heart failure outcome by history of heart failure. Sensitivity analyses will be performed to assess the robustness of study results and address some of the study limitations. Meta-analyses of the site-specific results will be performed using random effects models.
- Conditions
- Type2 Diabetes, Myocardial Infarction, Ischemic Stroke, Cardiovascular Death, Heart Failure, All-Cause Mortality
- Being tested
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors, Dipeptidyl peptidase-4 (DPP-4) inhibitors
- Keywords
- Sodium-Glucose Cotransporter 2 Inhibitors, Type 2 Diabetes, Myocardial Infarction, Ischemic Stroke, Cardiovascular Death
- Medical subject headings
- Myocardial Infarction, Ischemic Stroke, Heart Failure, Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sodium-glucose cotransporter 2 (SGLT2) inhibitorsDrug
Also called ATC A10BK, A10BD15, A10BD16, A10BD19, A10BD20, A10BD21, A10BD23, A10BD24, A10BD25
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.
Dipeptidyl peptidase-4 (DPP-4) inhibitorsDrug
Also called ATC A10BH, A10BD07, A10BD08, A10BD09, A10BD10, A10BD11, A10BD12, A10BD13, A10BD18, A10BD19, A10BD20, A10BD21, A10BD22, A10BD24, A10BD25
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Dipeptidyl peptidase-4 (DPP-4) inhibitors |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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 hospitalized for heart failure recorded as the most responsible diagnosis in the hospitalization record with the following ICD-10-CA codes: I11.0, I13.0, I13.2, I50.x.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 May 2019
- Study start1 Oct 2018
- Primary completion1 Oct 2019
- Study completion1 Oct 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Type2 DiabetesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 419,734 participants (actual)
Sponsor and investigators
- Lead sponsor
- Canadian Network for Observational Drug Effect Studies, CNODES
- Sponsor type
- University, hospital or other
- Collaborators
- Drug Safety and Effectiveness Network, Canada, Canadian Institutes of Health Research (CIHR)
- Responsible party
- Sponsor
- Investigators
- Pierre Ernst, MD, MSc, FRCPC, Principal investigator, Lady Davis Institute for Medical Research, Jewish General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03939624
- Sponsor's protocol ID
- Q18-06
- Status last verified
- Jan 2024
- First submitted
- 3 May 2019
- Last updated
- 19 Sep 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 27610604Brunetti 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.
PubMed 36175881Filion 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.
PubMed 32967856Lix 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.
PubMed 34332563