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.

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.

Eligibility Criteria:
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