Safety of Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors Among Patients with Type 2 Diabetes

NCT04017221 | Completed

• 1 other identifier: Q18-09/10/11
• Study Type: observational
• Target: 1,249,636
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to compare the risk of serious adverse 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. More specifically, the investigators will assess the risk of severe urinary tract infection (urosepsis), diabetic ketoacidosis and lower extremity amputation. The investigators hypothesize that the use of SGLT2 inhibitors will be associated with an increased risk of serious adverse events in comparison with the use of DPP-4 inhibitors. The investigators will carry out separate population-based cohort studies using health care databases in seven Canadian provinces and the United Kingdom. Separate study cohorts will be created for each of the three safety outcomes. The study cohorts 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 an adverse event. The results from the separate sites will be combined by meta-analysis to provide an overall assessment of the risk of serious adverse events in users of SGLT2 inhibitors in comparison to users of DPP-4 inhibitors.

Conditions

Diabetes Mellitus, Type 2; Urosepsis; Diabetic Ketoacidosis; Lower Extremity Amputation

Keywords

Sodium-glucose cotransporter 2 inhibitors; Diabetes mellitus, type 2; Urosepsis; Diabetic ketoacidosis; Lower extremity amputation

Outcome Measures

Primary Outcomes (3)

• Incidence rate of urosepsis

  Urosepsis will be defined as a hospitalization with a diagnosis of acute pyelonephritis or urinary tract infection with a corresponding code for sepsis, using the following ICD-10-CA codes: * Acute pyelonephritis (ICD-10-CA: N10) or urinary tract infection (ICD-10-CA: N30.0, N39.0) in combination with; * Sepsis (ICD-10-CA: A41.x, R56.2, R57.2).

  Patients will be followed from the date of study cohort entry until hospitalization for urosepsis, death, end of health care coverage, or for up to 64 months, whichever occurs first.

• Incidence rate of diabetic ketoacidosis (DKA)

  DKA will be defined as a hospitalization with a primary diagnosis of DKA or visit to the emergency department (in sites where this data is available) using the following ICD-10-CA codes: E11.10, E11.12, E13.10, E13.12.

  Patients will be followed from the date of study cohort entry until hospitalization for DKA, death, end of health care coverage, or for up to 64 months, whichever occurs first.

• Incidence rate of lower extremity amputation

  Lower extremity amputation will be defined by procedure codes recorded in the hospital discharge abstract or the physician claims using the following CCI (Canadian Classification of Health Interventions) codes: 1VC93, 1VG93, 1VQ93, 1WA93, 1WE93, 1WI93, 1WJ93, 1WK93, 1WL93, 1WM93, 1WN93.

  Patients will be followed from the date of study cohort entry until occurrence of a lower extremity amputation, death, end of health care coverage, or for up to 64 months, whichever occurs first.

Secondary Outcomes (1)

• Incidence rate of Fournier's gangrene

  Patients will be followed from the date of study cohort entry until occurrence of Fournier's gangrene, death, end of health care coverage, or for up to 64 months, whichever occurs first.

Study Arms (3)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Current use of a SGLT2 inhibitor alone or in combination with other antidiabetic drugs, excluding DPP-4 inhibitors and insulin.

Drug: Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors

Current use of a DPP-4 inhibitor alone or in combination with other antidiabetic drugs, excluding SGLT2 inhibitors and insulin.

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

Other treatment combinations

Current use of other antidiabetic drugs, current use of insulin (alone or combination with other antidiabetic drugs), and non-current use of antidiabetic drugs.

Drug: Other treatment combinations

Interventions

Sodium-glucose cotransporter 2 (SGLT2) inhibitors DRUG

Current exposure to SGLT2 will be defined as a prescription for a SGLT2 inhibitor (canagliflozin, dapagliflozin, empagliflozin) alone or in combination with other antidiabetic drugs, excluding DPP-4 inhibitors and insulin.

Also known as: ATC A10BK

Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors DRUG

Current 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 other antidiabetic drugs, excluding SGLT2 inhibitors and insulin.

Also known as: ATC A10BH

Dipeptidyl peptidase-4 (DPP-4) inhibitors

Other treatment combinations DRUG

Current exposure to other treatment combinations will be defined as a prescription of other antidiabetic drugs (metformin, sulfonylureas, thiazolidinediones, GLP-1 receptor agonists, alpha-glucosidase inhibitors, meglitinides, insulin, or combinations of these drugs), current use of insulin (alone or combination with other antidiabetic drugs), and non-current use of antidiabetic drugs.

Also known as: ATC A10A and A10B (excluding A10BH and A10BK)

Other treatment combinations

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 including all new users of SGLT2 inhibitors or DPP-4 inhibitors between January 1, 2013 and June 30, 2018 will be created for each safety outcome. Specific exclusion criteria will be applied for each study cohort. Study cohort entry date will be defined by the dispensation date (or prescription for CPRD) of the newly prescribed SGLT2 or DPP-4 inhibitor.

You may qualify if:

• Patients who newly initiated a SGLT2 inhibitor or DPP-4 inhibitor between January 1, 2013 and June 30, 2018 (or latest date of data availability at each site)

You may not qualify if:

• Patients aged less than 18 years at cohort entry date (\<66 years in Ontario)
• Patients with less than 365 days of health care coverage prior to cohort entry
• Patients with a hospitalization for urinary tract infection or acute pyelonephritis in the 30 days prior to cohort entry (for urosepsis study cohort only)
• Patients with spinal cord injuries affecting the bladder (for urosepsis study cohort only)
• Patients with long-term urinary catheter use (for urosepsis study cohort only)
• Patients with a hospitalization for DKA in the year prior to cohort entry (for DKA study cohort only)
• Patients with a history of lower extremity amputation at any time prior to cohort entry (for lower extremity amputation study cohort only)

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 (3)

• Fisher A, Fralick M, Filion KB, Dell'Aniello S, Douros A, Tremblay E, Shah BR, Ronksley PE, Alessi-Severini S, Hu N, Bugden SC, Ernst P, Lix LM; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Sodium-glucose co-transporter-2 inhibitors and the risk of urosepsis: A multi-site, prevalent new-user cohort study. Diabetes Obes Metab. 2020 Sep;22(9):1648-1658. doi: 10.1111/dom.14082. Epub 2020 Jun 4.

  PMID: 32383792 BACKGROUND

• Yu OHY, Dell'Aniello S, Shah BR, Brunetti VC, Daigle JM, Fralick M, Douros A, Hu N, Alessi-Severini S, Fisher A, Bugden SC, Ronksley PE, Filion KB, Ernst P, Lix LM; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Below-Knee Amputation: A Multicenter Observational Study. Diabetes Care. 2020 Oct;43(10):2444-2452. doi: 10.2337/dc20-0267. Epub 2020 Aug 5.

  PMID: 32759360 BACKGROUND

• Douros A, Lix LM, Fralick M, Dell'Aniello S, Shah BR, Ronksley PE, Tremblay E, Hu N, Alessi-Severini S, Fisher A, Bugden SC, Ernst P, Filion KB; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis : A Multicenter Cohort Study. Ann Intern Med. 2020 Sep 15;173(6):417-425. doi: 10.7326/M20-0289. Epub 2020 Jul 28.

  PMID: 32716707 BACKGROUND

Related Links

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

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Diabetic Ketoacidosis

Interventions

Sodium-Glucose Transporter 2

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Ketosis; Acidosis; Acid-Base Imbalance; Diabetes Complications

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: July 3, 2019
• First Posted: July 12, 2019
• Study Start: October 1, 2018
• Primary Completion: December 1, 2019
• Study Completion: December 1, 2019
• Last Updated: September 19, 2024

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)