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

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.

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