Prediction of Findings From the Ongoing CAROLINA Trial Using Healthcare Database Analyses

This cohort study was initiated to predict the findings of CAROLINA trial in a real world setting using electronic claims data from insurance databases with results anticipated prior to the completion of CAROLINA.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus

Detailed Description

The CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) is an ongoing randomized controlled trial (RCT) designed to assess whether linagliptin is non-inferior, and if so, superior compared with glimepiride 1-4 mg once daily with respect to cardiovascular (CV) events in adults with relatively early Type 2 Diabetes at increased risk of CV events and with less than optimized glycaemic control. Given that medications of both classes are currently advocated as second-line therapy after metformin, and since sulfonylureas have been associated with concerns regarding their CV safety, while dipeptidyl peptidase-4 inhibitors have been suggested to exhibit CV benefits in preclinical and mechanistic trials, the results of this trial will provide answers to several clinically relevant questions and have a significant impact on clinical practice.

This cohort study was initiated to predict the findings of CAROLINA trial in a real world setting using electronic claims data from insurance databases with results anticipated prior to the completion of CAROLINA. Trial eligibility criteria were adapted in claims data to generate a comparable study cohort (of linagliptin and glimepiride initiators) to that of the trial population. Using 1:1 propensity score-matching was used to control for >120 baseline characteristics. Patients were followed up for a composite cardiovascular outcome adapted from the primary end-point of the CAROLINA trial.

• Study Type: Observational
• Enrollment (Actual): 48262

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02120
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients 40 - 85 years of age with early Type 2 Diabetes mellitus, increased cardiovascular risk or established complications

Description

Inclusion Criteria:

• Patients with Type 2 diabetes who were new users of Linagliptin or new users of Glimepiride and:

  - Had no more than 3 anti-diabetic drugs including index drug

• AND at elevated risk of cardiovascular (CV) events according to specific criteria:

  • Previous vascular disease
  • Evidence of vascular-related end-organ damage
  • Age ⩾ 70 years

  • ⩾ 2 CV risk factors:

    • Treated hypertension
    • Smoking
    • Using any lipid lowering treatment
• Age ≥ 40 and ≤ 85 years at treatment initiation

Exclusion Criteria:

• Patients with Type 1 Diabetes Mellitus
• Previous exposure to dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, thiazolidinediones (TZDs), insulin or sodium glucose co-transporter-2 (SGLT-2s).
• Exclude anti-diabetic background therapy if initiated in 2 months prior
• Morbid obesity or treatment with anti-obesity drugs 3 months prior to treatment initiation
• Severe hyperglycemia
• Active liver disease or impaired hepatic function
• Any previous bariatric surgery
• Coronary artery re-vascularisation ≤ 6 weeks prior to treatment initiation
• Prior hospitalization for congestive heart failure
• Acute or chronic metabolic acidosis
• Hereditary galactose intolerance
• Alcohol or drug abuse within the 3 months prior to treatment initiation
• Use of oral corticosteroids
• Pregnant women
• Patients with cancer
• Acute coronary syndrome ≤ 6 weeks prior to treatment initiation
• Stroke or Transient ischemic attack ≤ 3 months prior to treatment initiation

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Linagliptin; Patients who initiate Linagliptin with no use in the prior 180 days
Glimepiride; Patients who initiate Glimepiride with no use in the prior 180 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Cardiovascular (CV) Outcome	Composite CV Outcome includes Myocardial infarction, Stroke, hospitalization for unstable angina and Death	From treatment initiation to end of follow-up, up to 53 months

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Elisabetta Patorno, MD DrPH, Brigham and Women's Hospital, Harvard Medical School

Publications and helpful links

General Publications

• Franklin JM, Patorno E, Desai RJ, Glynn RJ, Martin D, Quinto K, Pawar A, Bessette LG, Lee H, Garry EM, Gautam N, Schneeweiss S. Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies: First Results From the RCT DUPLICATE Initiative. Circulation. 2021 Mar 9;143(10):1002-1013. doi: 10.1161/CIRCULATIONAHA.120.051718. Epub 2020 Dec 17.
• Patorno E, Schneeweiss S, Gopalakrishnan C, Martin D, Franklin JM. Using Real-World Data to Predict Findings of an Ongoing Phase IV Cardiovascular Outcome Trial: Cardiovascular Safety of Linagliptin Versus Glimepiride. Diabetes Care. 2019 Dec;42(12):2204-2210. doi: 10.2337/dc19-0069. Epub 2019 Jun 25.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2011
• Primary Completion (Actual): June 1, 2019
• Study Completion (Actual): June 1, 2019

Study Registration Dates

• First Submitted: August 24, 2018
• First Submitted That Met QC Criteria: August 24, 2018
• First Posted (Actual): August 27, 2018

Study Record Updates

• Last Update Posted (Actual): September 25, 2020
• Last Update Submitted That Met QC Criteria: September 23, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Stroke; Type 2 diabetes mellitus; Myocardial Infarction; Glimepiride; Linagliptin; Cardiovascular Death; Hospitalization for Unstable Angina
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: 2013P002157

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No