Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL)

• ClinicalTrials.gov Identifier: NCT02993614
• Recruitment Status: Completed
• First Posted: December 15, 2016
• Last Update Posted: February 18, 2021
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

CVD-REAL is a multinational, observational cohort study in patients with type 2 diabetes mellitus evaluating the comparative effectiveness of initiating treatment with a sodium-glucose co-transporter-2 (SGLT-2) inhibitor versus another glucose-lowering drug. This study will compare the risk of all-cause mortality and clinically relevant cardiovascular (CV) outcomes respectively in patients who are new users of SGLT-2 inhibitors with those who are new users of other glucose-lowering drugs. CVD-REAL is aiming to collect data from approximately 4 million patients overall, from twelve countries across three major world regions.

Condition or disease
Diabetes Mellitus Type 2

Detailed Description:

Type 2 diabetes mellitus remains a major risk factor for cardiovascular disease with an estimated 425 million adults worldwide having diabetes in 2017, with type 2 diabetes mellitus accounting for about 90% of the cases. Recent evidence indicates that certain glucose-lowering therapies are associated with reduction in cardiovascular outcomes. There is, therefore, an urgent need to improve the understanding of the impact of newer classes of glucose-lowering therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT-2) inhibitors on cardiovascular outcomes in clinical practice.

CVD-REAL is a comparative effectiveness study that aims to compare new users of SGLT-2 inhibitors with new users of other glucose-lowering drugs with regard to the risk of all-cause mortality and clinically relevant CV outcomes (including stroke, myocardial infarction, and hospitalization for heart failure) respectively. The study is based on data from 12 countries across four major world regions.

The study is conducted using data from claims, medical records and national health registries from twelve countries combined in two waves. CVD-REAL 1 includes Germany, Denmark, Norway, Sweden, United Kingdom (UK) and United States of America (USA). CVD-REAL 2 comprises Australia, Canada, Israel, Japan, Singapore and South Korea. The study will collect data from approximately 4 million patients from the time they start treatment with a SGLT-2 inhibitor or another glucose-lowering drug (index date) to the end of the follow-up period.

The Study Population will consist of new users of SGLT-2i and other glucose lowering drugs respectively. These will be compared with all-cause mortality, hospitalization for heart failure, myocardial infarction and stroke during the follow-up period. In addition certain other cardiovascular and renal outcomes will be assessed descriptively in the two groups respectively.

The study period will range from launch of the first SGLT-2i in each of the countries and end at latest available data in each data source.

All-cause mortality and the incidence of cardiovascular events will be compared between new users of SGLT-2 inhibitors and the comparator arm using a hazard ratio (relative risk) and corresponding 95% confidence interval. The analysis will be performed using the Cox proportional hazards model or some other appropriate method.

Matching by propensity scores will be used to balance the potential confounding covariates between the SGLT-2i group and the reference group to ensure that the two groups are as similar as possible at baseline.To achieve sufficient power, a meta-analysis will be applied to integrate the point estimates from each of the individual database analyses and calculate an overall weighted estimate and corresponding 95% CI.

Study Design

• Study Type: Observational
• Actual Enrollment: 99999 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Characteristics and Cardiovascular and Mortality Outcomes in Patients With Type 2 Diabetes Mellitus Initiating Treatment With Sodium-glucose Co-transporter-2 Inhibitors (SGLT-2i) and Other Glucose Lowering Drugs
• Actual Study Start Date: November 30, 2017
• Actual Primary Completion Date: December 17, 2020
• Actual Study Completion Date: December 17, 2020

Groups and Cohorts

Outcome Measures

Primary Outcome Measures :

1. CVD REAL1 Incidence of hospitalization for heart failure. / CVD REAL 2 All-cause mortality [ Time Frame: From index date up to latest available data of first prescription of an SGLT-2i or a new oGLD in each of the countries ranging from Sep 11 (UK) until Apr 15 (IL) until the last date of data collection or outcome ranging from Sep 15 (US) to Nov 17 (SG) ]
   Heart failure events obtained from general practice or hospital records, electronic health records or national health registers; All-cause mortality obtained from linkeage to death national registers

Secondary Outcome Measures :

1. CVD REAL1 All-cause mortality; CVD REAL 2: Hospitalization for heart failure (HHF), stroke, myocardial infarction (MI) and including composite endpoints [ Time Frame: From index date up to latest available data of first prescription of an SGLT-2i or a new oGLD in each of the countries ranging from Sep 11 (UK) until Apr 15 (IL) until the last date of data collection or outcome ranging from Sep 15 (US) to Nov 17 (SG) ]
   Events obtained from general practice or hospital records, electronic health records and national health registers. All cause mortality obtained from linkeage to death national registers

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

New users of SGLT--2i and other glucose lowering drugs respectively

Criteria

Inclusion Criteria:

• New user receiving or dispensed prescription of SGLT-2i medication or other glucose lowering drug, oral as well as injectable, including fixed-dose combination (FDC) products containing these medication groups
• T2DM diagnosis on or prior to the index date
• ≥ 18 years old at index date
• > 1 year data history in the database prior to the index date

Exclusion Criteria:

• Patients with a T1DM diagnosis
• Patients with gestational diabetes within 1 year before index date

Contacts and Locations

Locations

United States, Delaware

Research Site

Wilmington, Delaware, United States, 19850

Australia, D1690r00015

Research Site

Melbourne, D1690r00015, Australia

Canada, D1690r00015

Research Site

Mississauga, D1690r00015, Canada

Denmark

Research Site

Gentofte, D1690r00015, Denmark

Finland

Research Site

Espoo, D1690r00015, Finland

Germany

Research Site

Ulm, D1690r00015, Germany

Israel

Research Site

Raanana, D1690r00015, Israel

Italy

Research Site

Rome, D1690r00015, Italy

Japan

Research Site

Tokyo, D1690r00015, Japan

Korea, Republic of

Research Site

Seoul, D1690r00015, Korea, Republic of

Norway

Research Site

Oslo, D1690r00015, Norway

Portugal

Research Site

Porto, D1690r00015, Portugal

Singapore

Research Site

Singapore, D1690r00015, Singapore

Spain

Research Site

Madrid, D1690r00015, Spain

Sweden

Research Site

Sodertalje, D1690r00015, Sweden

Taiwan

Research Site

Taipei, D1690r00015, Taiwan

United Kingdom

Research Site

Luton, D1690r00015, United Kingdom

Sponsors and Collaborators

AstraZeneca

More Information

Additional Information:

Publication in "Circulation" 

CSP_D1690R00015. 

CSP_amendment_D1690R00015. 

Publication in "JACC" 

Redacted CSR Synopsis 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nicolucci A, Candido R, Cucinotta D, Graziano G, Rocca A, Rossi MC, Tuccinardi F, Manicardi V. Generalizability of Cardiovascular Safety Trials on SGLT2 Inhibitors to the Real World: Implications for Clinical Practice. Adv Ther. 2019 Oct;36(10):2895-2909. doi: 10.1007/s12325-019-01043-z. Epub 2019 Aug 13.

Cavender MA, Norhammar A, Birkeland KI, Jørgensen ME, Wilding JP, Khunti K, Fu AZ, Bodegård J, Blak BT, Wittbrodt E, Thuresson M, Fenici P, Hammar N, Kosiborod M; CVD-REAL Investigators and Study Group. SGLT-2 Inhibitors and Cardiovascular Risk: An Analysis of CVD-REAL. J Am Coll Cardiol. 2018 Jun 5;71(22):2497-2506. doi: 10.1016/j.jacc.2018.01.085.

Kosiborod M, Lam CSP, Kohsaka S, Kim DJ, Karasik A, Shaw J, Tangri N, Goh SY, Thuresson M, Chen H, Surmont F, Hammar N, Fenici P; CVD-REAL Investigators and Study Group. Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study. J Am Coll Cardiol. 2018 Jun 12;71(23):2628-2639. doi: 10.1016/j.jacc.2018.03.009. Epub 2018 Mar 11.

Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, Norhammar A, Birkeland KI, Jørgensen ME, Thuresson M, Arya N, Bodegård J, Hammar N, Fenici P; CVD-REAL Investigators and Study Group*. Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017 Jul 18;136(3):249-259. doi: 10.1161/CIRCULATIONAHA.117.029190. Epub 2017 May 18.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02993614
• Other Study ID Numbers: D1690R00015
• First Posted: December 15, 2016
• Last Update Posted: February 18, 2021
• Last Verified: February 2021

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases