Incretin-based Drugs and the Risk of Heart Failure

NCT02456428 | Completed

• 1 other identifier: Q13-06C
• Study Type: observational
• Target: 1,499,650
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine whether incretin-based drugs (used to treat type 2 diabetes) taken either alone or in combination with other anti-diabetic drugs are associated with an increased risk of heart failure (HF) compared to other combinations of oral hypoglycemic agents (OHA). The investigators will carry out separate population based cohort studies using administrative health databases in six jurisdictions in Canada, the US and the UK. Cohorts will be defined by the initiation of a new anti-diabetic drug when incretin-based drugs entered the market, with follow-up until hospitalization for HF. Analyses will be done separately for groups of patients with and without prior HF. The results from the separate sites will be combined to provide an overall assessment of the risk of HF in users of incretin-based drugs and by class of incretin-based drugs.

Conditions

Type 2 Diabetes Mellitus

Keywords

Incretins; Antidiabetic Agents; Heart Failure

Outcome Measures

Primary Outcomes (1)

• Hospitalization for incident heart failure

  Patients hospitalized for incident heart failure (HF) recorded in either the discharge abstract or hospitalization record with the following ICD codes: ICD-9 code: 428.x ICD-10 code: I50.x For patients who had no history of prior HF, cases were identified by the presence of a HF diagnosis in any position (most responsible, primary, or secondary), while for patients with a history of established HF, the event definition was restricted to those with a HF diagnosis as the primary or most responsible reason for hospitalization.

  Patients were followed from the date of study cohort entry until hospitalization for incident heart failure, censoring, or for up to 87 months.

Study Arms (5)

Treated with incretins

Current use of incretin-based drugs ((DPP-4 inhibitors \[sitagliptin, vildagliptin, and saxagliptin\] or GLP-1 analogs \[exenatide, liraglutide\]) alone or in combination with other anti-diabetic drugs (if the prescription overlaps with the index or event day with a 30-day grace period).

Drug: DPP-4 inhibitors; Drug: GLP-1 analogs

Treated with insulin

Current use of insulins between base cohort entry and the index or event day (alone or in combination with other anti-diabetic drugs) and no current use of incretin-based drugs.

Drug: Insulins

Treated with ≥2 oral hypoglycemic agents

Current use of 2 or more non-insulin anti-diabetic medications (biguanides, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, meglitinides) (if the prescriptions overlap with the index or event day with a 30-day grace period), and no current use of incretin-based drugs or insulins.

Drug: Biguanides; Drug: Sulfonylureas; Drug: Thiazolidinediones; Drug: Alpha-glucosidase inhibitors; Drug: Meglitinides

Treated with single oral agent

Current use of any single non-insulin anti-diabetic medications (biguanides, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, meglitinides) (if the prescription overlaps with the index or event day with a 30-day grace period) and no current use of more than 2 OHAs, incretin-based drugs, or insulins.

Drug: Biguanides; Drug: Sulfonylureas; Drug: Thiazolidinediones; Drug: Alpha-glucosidase inhibitors; Drug: Meglitinides

Not currently exposed group

All patients not currently exposed to: incretin-based drugs, insulins, ≥2 OHAs, or a single OHA.

Interventions

DPP-4 inhibitors DRUG

Current exposure to DPP-4 inhibitors (ATC A10BH, A10BD07-A10BD13) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.

Also known as: incretin-based drugs, sitagliptin, vildagliptin, saxagliptin

Treated with incretins

GLP-1 analogs DRUG

Current exposure to GLP-1 analogs (ATC A10BX04, A10BX07) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.

Also known as: incretin-based drugs, exenatide, liraglutide

Treated with incretins

Insulins DRUG

Current exposure to insulin (ATC A10A) will be defined as any use of insulin between base cohort entry and the index day.

Also known as: insulins and analogues for injection, fast-acting, insulins and analogues for injection, intermediate-acting, insulins and analogues for injection, long-acting, insulins and analogues for inhalation

Treated with insulin

Biguanides DRUG

Current exposure to biguanides (ATC A10BA) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.

Also known as: oral hypoglycemic agent, phenformin, metformin, buformin

Treated with single oral agent; Treated with ≥2 oral hypoglycemic agents

Sulfonylureas DRUG

Current exposure to sulfonylureas (ATC A10BB or A10BC) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.

Also known as: oral hypoglycemic agent, glibenclamide, chlorpropamide, tolbutamide, glibornuride, tolazamide, carbutamide, glipizide, gliquidone, gliclazide, metahexamide, glisoxepide, glimepiride, acetohexamide, glymidine

Treated with single oral agent; Treated with ≥2 oral hypoglycemic agents

Thiazolidinediones DRUG

Current exposure to thiazolidinediones (ATC A10BG) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.

Also known as: oral hypoglycemic agent, troglitazone, rosiglitazone, pioglitazone

Treated with single oral agent; Treated with ≥2 oral hypoglycemic agents

Alpha-glucosidase inhibitors DRUG

Current exposure to alpha-glucosidase inhibitors (ATC A10BF) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.

Also known as: oral hypoglycemic agent, acarbose, miglitol, voglibose

Treated with single oral agent; Treated with ≥2 oral hypoglycemic agents

Meglitinides DRUG

Current exposure to meglitinides (ATC A10BX02, A10BX03) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index (event)day.

Also known as: oral hypoglycemic agent, repaglinide, nateglinide

Treated with single oral agent; Treated with ≥2 oral hypoglycemic agents

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, a base cohort will be assembled including all patients with a first-ever prescription for a non-insulin anti-diabetic drug. Base cohort entry is defined as the date of prescription or dispensation of a first-ever non-insulin anti-diabetic drug. From this base cohort, a study cohort will be formed consisting of all patients who initiated a new anti-diabetic drug class during the year in which incretin-based drugs entered the market in each jurisdiction or any time thereafter. Study cohort entry is defined by the prescription date of the newly-prescribed drug class. Two separate cohorts will be created based on the presence or absence of a history of HF prior to and including study cohort entry.

You may qualify if:

• Patients with a first-ever prescription for a non-insulin anti-diabetic drug, including biguanides, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, GLP-1 analogs, alpha-glucosidase inhibitors, meglitinides, or combinations of these drugs from the earliest availability of data at each site to the last date of availability of data.
• Patients with at least 1 year of history in the database.
• Patients at least 18 years of age.

You may not qualify if:

• Patients who died or left the cohort before the year the first incretin-based drug entered the market.
• Patients who never added-on or switched to a new anti-diabetic drug after incretin-based drugs entered the market up until June 30, 2014.
• Patients diagnosed with HIV or initiating HAART therapy before and at study cohort entry.

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 (1)

• Filion KB, Azoulay L, Platt RW, Dahl M, Dormuth CR, Clemens KK, Hu N, Paterson JM, Targownik L, Turin TC, Udell JA, Ernst P; CNODES Investigators. A Multicenter Observational Study of Incretin-based Drugs and Heart Failure. N Engl J Med. 2016 Mar 24;374(12):1145-54. doi: 10.1056/NEJMoa1506115.

  PMID: 27007958 RESULT

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Heart Failure

Interventions

Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate; Vildagliptin; saxagliptin; Glucagon-Like Peptide-1 Receptor Agonists; Exenatide; Liraglutide; Insulins; Injections; Inhalation; Biguanides; Hypoglycemic Agents; Phenformin; Metformin; Buformin; Sulfonylurea Compounds; Glyburide; Chlorpropamide; Tolbutamide; glibornuride; Tolazamide; Carbutamide; Glipizide; gliquidone; Gliclazide; metahexamide; glisoxepide; glimepiride; Acetohexamide; glymidine; Thiazolidinediones; Troglitazone; Rosiglitazone; Pioglitazone; Glycoside Hydrolase Inhibitors; Acarbose; miglitol; voglibose; meglitinide; repaglinide; Nateglinide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Physiological Effects of Drugs; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Nitriles; Organic Chemicals; Pyrrolidines; Peptides; Amino Acids, Peptides, and Proteins; Venoms; Complex Mixtures; Toxins, Biological; Biological Factors; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pancreatic Hormones; Peptide Hormones; Drug Administration Routes; Drug Therapy; Therapeutics; Respiratory Mechanics; Respiration; Respiratory Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena; Guanidines; Amidines; Urea; Amides; Sulfones; Sulfur Compounds; Benzenesulfonamides; Sulfonamides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Thiazoles; Chromans; Benzopyrans; Pyrans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Trisaccharides; Oligosaccharides; Polysaccharides; Carbohydrates; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids

Study Officials

• Pierre Ernst, MD, MSc

  Lady Davis Institute for Medical Research, Jewish General Hospital - McGill University

  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 21, 2015
• First Posted: May 28, 2015
• Study Start: March 1, 2014
• Primary Completion: May 1, 2015
• Study Completion: May 1, 2015
• Last Updated: April 19, 2016

Record last verified: 2016-04

Locations

CA (1)