Please select the eligibility criteria that correspond to the clinical trial below.
Title: Prediction of Findings From the Ongoing CAROLINA Trial Using Healthcare Database Analyses
Brief Summary: 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.


Options:
A: Please see: https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions.

Eligible cohort entry dates: 4/1/2013-12/31/2016 (market availability of sitagliptin in the U.S. started on 10/17/2006). For Optum, 4/1/2013-9/30/2017.

Inclusion Criteria:

* Man or woman with a diagnosis of type 2 diabetes with glycated hemoglobin level ≥7.0% to≤10.5% at screening and be either

  1. not currently on antihyperglycemic agent (AHA) therapy or
  2. on AHA monotherapy or combination therapy with any approved class of agents: e.g., sulfonylurea, metformin, peroxisome proliferator-activated receptor gamma (PPARγ) agonist, alpha-glucosidase inhibitor, glucagon-like peptide-1 (GLP-1) analogue, dipeptidyl peptidase-4 (DPP-4) inhibitor, or insulin.
* Age ≥30 years with documented symptomatic atherosclerotic cardiovascular disease
* Age ≥50 years with 2 or more of the following risk factors determined at the screening visit

Exclusion Criteria:

* History of diabetic ketoacidosis, type 1 diabetes, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy.
* History of one or more severe hypoglycemic episode within 6 months before screening
* Ongoing, inadequately controlled thyroid disorder.
* Renal disease that required treatment with immunosuppressive therapy or a history of dialysis or renal transplant.
* MI, unstable angina, revascularization procedure, or cerebrovascular accident within 3 months before screening, or a planned revascularization procedure, or history of New York Heart Association (NYHA) Class IV cardiac disease.
* Findings on 12-lead electrocardiogram (ECG) that would require urgent diagnostic evaluation or intervention
* History of hepatitis B surface antigen or hepatitis C antibody positive
* Any history of or planned bariatric surgery.
* History of malignancy within 5 years before screening
* History of human immunodeficiency virus (HIV) antibody positive.
* Subject has a current clinically important hematological disorder (e.g., symptomatic anemia, proliferative bone marrow disorder, thrombocytopenia).
* Major surgery (i.e., requiring general anesthesia) within 3 months of the screening visit or any surgery planned during the subject's expected participation in the study
* Current use of other sodium glucose co-transporter 2 (SGLT2) inhibitor.
* Current use of a corticosteroid medication or immunosuppressive agent, or likely to require treatment with a corticosteroid medication
B: Please see: https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions.

Eligible cohort entry dates Market availability of linagliptin in the U.S. started on May 2, 2011. For Marketscan and Medicare: May 2, 2011-Dec 31, 2016 (end of data availability).

For Optum: May 2, 2011-Sep 30, 2017 (end of data availability).

Inclusion Criteria:

1. Documented diagnosis of T2DM before visit 1 (screening).
2. Male or female patients who are drug-naïve or pre-treated with any antidiabetic background therapy, excluding treatment with GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors if ≥ 7 consecutive days.
3. Stable antidiabetic background medication (unchanged daily dose) for at least 8 weeks prior to randomization. If insulin is part of the background therapy, the average daily insulin dose should not have been changed by more than 10% within the 8 weeks prior to randomization compared with the daily insulin dose at randomization.
4. HbA1c of ≥ 6.5% and ≤ 10.0% at visit 1 (screening).
5. Age ≥ 18 years at visit 1 (screening). For Japan only: Age ≥ 20 years at Visit 1.
6. Body Mass Index (BMI) 45 kg/m2 at visit 1 (screening).
7. Signed and dated written informed consent by date of visit 1 (screening) in accordance with GCP and local legislation prior to any study related procedure.
8. High risk of CV events (I and/or II):

Albuminuria (UACR ≥ 30 mg/g creatinine or ≥ 30 µg/min \[microgram albumin per minute\] or ≥ 30 mg/24 h \[milligram albumin per 24 hours\] in two out of three unrelated spot urine or timed samples in the last 24 months prior to randomization)\*

AND previous macrovascular disease, defined as either one or more:

Confirmed history of MI (\> 2 months prior to Visit 1)

Advanced coronary artery disease, defined by any one of the following:

* ≥ 50% narrowing of the luminal diameter in 2 or more major coronary arteries by coronary angiography, MRI angiography or CT angiography; Definition of major coronary arteries: LAD (Left Anterior Descending). CX (Circumflex) or RCA (right coronary artery)
* Left main stem coronary artery with ≥ 50% narrowing of the luminal diameter by coronary angiography, MRI angiography or CT angiography;
* Prior percutaneous or surgical revascularization of 2 major coronary arteries at least 2 months prior to Visit 1 (screening);
* The combination of prior percutaneous or surgical revascularization of 1 major coronary artery at least 2 months prior to visit 1 (screening), and ≥ 50% narrowing of the luminal diameter by coronary angiography, MRI angiography or CT angiography of at least 1 additional major coronary artery.

  10) High-risk single-vessel coronary artery disease, defined as the presence of 50% narrowing of the luminal diameter of one major coronary artery by coronary angiography, MRI angiography or CT angiography in patients not revascularised:

AND at least one of the following:

* A positive non invasive stress test, confirmed by either:
* a positive ECG exercise tolerance test in patients without left bundle branch block, Wolff-Parkinson-White syndrome, left ventricular hypertrophy with repolarization abnormality, or paced ventricular rhythm, atrial fibrillation in case of abnormal ST-T segments;
* a positive stress echocardiogram showing induced regional systolic wall motion abnormalities;
* a positive nuclear myocardial perfusion imaging stress test showing stress- induced reversible perfusion abnormality;
* a positive cardiac stress perfusion MRI showing a stress induced perfusion defect;
* Patient discharged from hospital with a documented diagnosis of unstable angina pectoris between 2 and 12 months prior to visit 1 (screening).

  10) History of ischemic or haemorrhagic stroke (\>3 months prior to visit 1) 11) Presence of carotid artery disease (symptomatic or not) documented by either:
* imaging techniques with at least one lesion estimated to be ≥50% narrowing of the luminal diameter;
* prior percutaneous or surgical carotid revascularization. 12) Presence of peripheral artery disease documented by either:
* previous limb angioplasty, stenting or bypass surgery;
* previous limb or foot amputation due to macrocirculatory insufficiency;
* angiographic evidence of peripheral artery stenosis 50% narrowing of the luminal diameter in at least one limb (definition of peripheral artery: common iliac artery, internal iliac artery, external iliac artery, femoral artery, popliteal artery).

  13) Evidence of impaired renal function with predefined UACR, with or without CV co- morbidities, defined as follows (and/or criteria):
  * Impaired renal function (as defined by MDRD formula) with an eGFR: 15- \<45 mL/min/1.73 m2 at visit 1 (screening) with any UACR.
  * Impaired renal function (as defined by MDRD formula) with an eGFR ≥ 45-75 mL/min/1.73 m2 at visit 1 (screening) with an UACR \> 200 mg/g creatinine or \> 200 µg/min (microgram albumin per minute) or \> 200 mg/24 h \[milligram albumin per 24 hours\] demonstrated in two out of three unrelated spot urine or timed samples in the last 24 months prior to randomization.

Exclusion Criteria:

1. Type 1 diabetes mellitus.
2. Treatment (≥ 7 consecutive days) with GLP-1 receptor agonists, other DPP-4 inhibitors or SGLT-2 inhibitors prior to informed consent. Note: This also includes clinical trials where these antidiabetic drugs have been provided to the patient.
3. Active liver disease or impaired hepatic function, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase (AP) ≥3 x upper limit of normal (ULN) as determined at Visit 1.
4. eGFR \<15 ml/min/1.73 m2 (severe renal impairment or ESRD, MDRD formula), as determined during screening at Visit 1 and/or the need for maintenance dialysis.
5. Any previous (or planned within next 12 months) bariatric surgery (open or laparoscopic) or intervention (gastric sleeve).
6. Pre-planned coronary artery re-vascularisation (PCI, CABG) or any previous PCI and/or CABG ≤ 2 months prior informed consent"
7. Known hypersensitivity or allergy to the investigational products or its excipients.
8. Any previous or current alcohol or drug abuse that would interfere with trial participation in the opinion of the investigator.
9. Participation in another trial with an investigational drug ongoing or within 2 months prior to visit 1 (screening)\*.
10. Pre-menopausal women (last menstruation 1 year prior to informed consent) who:

    * are nursing or pregnant,
    * or are of child-bearing potential and are not practicing an acceptable method of birth control (acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if allowed by local authorities), double barrier method and vasectomised partner) or do not plan to continue using acceptable method of birth control throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial.
11. Patients considered unreliable by the investigator concerning the requirements for follow- up during the study and/or compliance with study drug administration, have a life expectancy less than 5 years for non-CV causes, or have cancer other than non-melanoma skin cancer within last 3 years, or has any other condition than mentioned which in the opinion of the investigator, would not allow safe participation in the study."
12. Acute coronary syndrome (ACS), diagnosed ≤ 2 months prior to visit 1 (screening).
13. Stroke or TIA ≤ 3 months prior to visit 1 (screening).
C: 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
D: Please see: https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions.

Eligible cohort entry dates Market availability of liraglutide in the U.S. started on January 20, 2010. For Marketscan and Medicare: January 20, 2010-Dec 31, 2016 (end of data availability).

For Optum: January 20, 2010-Sep 30, 2017 (end of data availability).

Inclusion Criteria:

* Men or women with type 2 diabetes
* Either of the following:

  * Prior cardiovascular disease cohort: Age ≥ 50 years at screening, AND at least one of the following:

    * Prior MI
    * Prior stroke or TIA
    * Prior coronary, carotid or peripheral arterial revascularization
  * \>50% stenosis of coronary, carotid, or lower extremity arteries coded by Peripheral vascular disease
  * Chronic heart failure NYHA class II-III
  * CKD stage 3-6 as Chronic renal failure:
* No Prior cardiovascular disease group: Age ≥ 60 years at screening, AND at least one of the following:

  * Microalbuminuria or proteinuria
  * Hypertension and left ventricular hypertrophy by ECG or imaging
  * Ankle-brachial index \<0.9

Exclusion Criteria:

* Type 1 diabetes
* Use of a GLP-1 receptor agonist (exenatide, liraglutide or other) or pramlintide or any (dipeptidyl peptidase 4 (DPP-4) inhibitor within the 3 months prior to screening
* Use of long-term insulin in 90 days prior
* Diabetic ketoacidosis in 3 months prior to index date as Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (e.g., diabetic ketoacidosis) in the previous 3 months
* Inpatient (hospitalization) code for MI, stroke, revascularization, PTCA, CABG IN PRIOR 14 DAYS as An acute coronary or cerebrovascular event in the previous 14 days
* inpatient Heart failure (CHF) as Chronic heart failure NYHA class IV
* ESRD codes as Current continuous renal replacement therapy
* Liver disease as "End stage liver disease, defined as the presence of acute or chronic liver disease and recent history of one or more of the following: ascites, encephalopathy, variceal bleeding, bilirubin ≥ 2.0 mg/dL, albumin level ≤ 3.5 g/dL, prothrombin time ≥ 4 seconds prolonged, international normalised ratio (INR) ≥1.7 or prior liver transplant"
* Organ transplant codes as A prior solid organ transplant or awaiting solid organ transplant
* History of malignant neoplasm in previous 5 years 140.xx-208.xx (except 173.xx, non-melanoma skin cancer)
* Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (FMTC)
* Personal history of non-familial medullary thyroid carcinoma
* Drug abuse or dependence as Known use of non prescribed narcotics or illicit drugs
* Encounter for contraceptive management, Oral contraceptives, and pregnancy as "Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods (adequate contraceptive measures as required by local law or practice)"

Answer: C