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