Please select the eligibility criteria that correspond to the clinical trial below.
Title: Replication of the CARMELINA Diabetes Trial in Healthcare Claims
Brief Summary: Investigators are building an empirical evidence base for real world data through large-scale replication of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.


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

Inclusion Criteria:

* Patients with a diagnosis of T2DM (ICD-9 Dx code of 250.x0 or 250.x2; ICD-10 Dx code of E11.x) in the 6 months prior to drug initiation
* Metformin, pioglitazone, or a sulfonylurea (monotherapy or any dual combination) for each day in the prior 3 months
* Any insulin use for each day in the prior 3 months
* 2 outpatient visits
* Patient is ≥50 years of age
* History of a major clinical manifestation of coronary artery disease (i.e., MI, surgical or percutaneous \[balloon and/or stent\] coronary revascularization procedure
* Ischemic cerebrovascular disease, including:

  * History of ischemic stroke. Strokes not known to be hemorrhagic will be allowed as part of this criterion;
  * Occlusion and stenosis of carotid artery without mention of cerebral infarction as History of carotid arterial disease as documented by ≥50% stenosis documented by carotid ultrasound, magnetic resonance imaging (MRI), or angiography, with or without symptoms of neurologic deficit
  * Peripheral arterial stenting or surgical revascularization, Lower extremity amputation, and Ankle brachial pressue index \<0.9 as: Atherosclerotic peripheral arterial disease, as documented by objective evidence such as amputation due to vascular disease, current symptoms of intermittent claudication confirmed by an anklebrachial pressure index or toe brachial pressure index less than 0.9, or history of surgical or percutaneous revascularization procedure.
* Encounter for contraceptive management and oral contraceptives as Female patients agree to use an effective method of contraception or must not otherwise be at risk of becoming pregnant.

Exclusion Criteria:

* Patient has a history of type 1 diabetes mellitus or a history of ketoacidosis.
* Patient has a history of ≥2 episodes of severe hypoglycemia during the 12 months prior to enrollment. Severe hypoglycemia (hypoglycemia requiring assistance) refers to instances in which the patient was sufficiently disoriented or incapacitated as to require help from another individual or from medical personnel (whether or not this assistance was actually provided).
* Patient has taken an approved or investigational DPP-4 inhibitor agent (eg, sitagliptin, alogliptin, saxagliptin, or vildagliptin), GLP-1 analogues (eg, exenatide, exenatide LAR, or liraglutide), or a thiazolidinedione other than pioglitazone within the past 3 months.
* Patient has cirrhosis of the liver, as assessed by medical history.
* Pregnancy or planned pregnancy during the trial period.
* Exclude patients with a combined comorbidity score \>95th percentile as Patient has medical history that indicates a life expectancy of b2 years or might limit the individual's ability to take trial treatments for the duration of the study.
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: Please see: https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions.

Eligible cohort entry dates:

Market availability of empagliflozin in the U.S. started on August 1, 2014.

* For Marketscan and Medicare: Aug 1, 2014-Dec 31, 2017 (end of data availability).
* For Optum: Aug 1, 2014-Mar 31, 2019 (end of data availability).

Inclusion Criteria:

All of the following criteria needed to be met:

* Subjects with T2DM on a diet and exercise regimen who are drug-naïve (no anti-diabetes therapy for ≥12 weeks prior to randomization) or treated with any anti-diabetes therapy (except pioglitazone in Japan)

  * Drug-naive patients were required to have HbA1c ≥7.0% (≥53 mmol/mol) and ≤9.0% (≤75 mmol/mol) at screening
  * Pre-treated patients were required to have HbA1c ≥7.0% (≥53 mmol/mol) and ≤10.0 (≤86 mmol/mol) at screening

    * Background anti-diabetes therapy had to be unchanged for ≥12 weeks prior to randomization
    * If background anti-diabetes therapy included insulin, insulin dose had to be unchanged by \>10% from the dose at randomization in the previous 12 weeks
* Age ≥18 years (≥20 years in Japan and ≤65 years in India)
* Body mass index ≤45 kg/m2 at screening
* High risk of a cardiovascular event defined as ≥1 of the following:

  * Confirmed history of myocardial infarction (\>2 months prior to informed consent)
  * Evidence of multivessel coronary artery disease (CAD), in ≥2 major coronary arteries or in the left main coronary artery, irrespective of revascularization status, i.e. one of the following:

    * Presence of a significant stenosis (imaging evidence of ≥50% narrowing of the luminal diameter measured during a coronary angiography or a multi-sliced computed tomography \[CT\] angiography)
    * Revascularization (percutaneous transluminal coronary angioplasty \[PTCA\] with or without stent, or coronary artery bypass grafting \[CAGB\]) ≥2 months prior to consent
    * Combination of revascularization in one major coronary artery ≥2 months prior to consent (PCTA with or without stent, or CABG), and the presence of significant stenosis in another major coronary artery (imaging evidence of ≥50% narrowing of the luminal diameter measured during a coronary angiography or a multi-sliced CT angiography)
  * Evidence of a single vessel CAD with the presence of significant stenosis i.e. imaging evidence of ≥50% narrowing of the luminal diameter of one major coronary artery in patients not subsequently successfully revascularized (measured during a coronary angiography or a multi-sliced CT angiography) and one or both of the following:

    -- A positive non-invasive stress test, confirmed by one of the following:
    * Positive exercise tolerance test in subjects without a complete left bundle branch block, Wolff-Parkinson-White syndrome, or paced ventricular rhythm
    * Positive stress echocardiography showing regional systolic wall motion abnormalities
    * Positive scintigraphic test showing stress-induced ischemia, i.e. development of transient perfusion defects during myocardial perfusion imaging
  * Patient discharged from hospital with a documented diagnosis of unstable angina within 12 months of consent
  * Last episode of unstable angina \>2 months prior informed consent with confirmed evidence of single- or multi-vessel CAD as defined above
  * History of ischemic or haemorrhagic stroke (\>2 months prior to informed consent)
  * Presence of peripheral artery disease (symptomatic or asymptomatic ) documented by one of the following:

    * Previous limb angioplasty, stenting, or bypass surgery
    * Previous limb or foot amputation due to circulatory insufficiency; or angiographic evidence of significant (\>50%) peripheral artery stenosis in at least one limb
    * Evidence from a non-invasive measurement of significant (\>50% or as reported as hemodynamically significant) peripheral artery stenosis in at least one limb
    * Ankle brachial index of \<0.9 in at least one limb
  * Signed and dated written informed consent prior to screening in accordance with Good Clinical Practice and local legislation

Exclusion Criteria:

* Uncontrolled hyperglycemia with glucose \>240 mg/dL (\>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day)
* Indication of liver disease, defined by serum levels of alanine amininotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal (ULN) during screening or run-in phase
* Planned cardiac surgery or angioplasty within 3 months
* Estimated glomerular filtration rate \<30 ml/min/1.73m2 (according to the Modification of Diet in Renal Disease equation) at screening or during run-in phase
* Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
* Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells e.g. malaria, babesiosis, hemolytic anemia)
* Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
* Contraindications to background therapy according to the local label
* Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at time of screening leading to unstable body weight (e.g. surgery, aggressive diet regimen, etc.)
* Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent
* Any uncontrolled endocrine disorder except T2DM
* Pre-menopausal women (last menstruation ≤1 year prior to informed consent) who were nursing, pregnant, or of child-bearing potential and were not practicing an acceptable method of birth control, or did not plan to continue using this method throughout the study, or did not agree to submit to periodic pregnancy testing during the trial

  - Acceptable methods of birth control include tubal ligation, transdermal patch, intrauterine devices/systems, oral, implantable or injectable contraceptives, sexual abstinence, double barrier method, vasectomy of partner
* Alcohol or drug abuse within 3 months of informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance with study procedures or study drug intake
* Intake of an investigational drug in another trial within 30 days prior to intake of study medication in this trial or participating in another trial involving an investigational drug and/or follow-up
* Any clinical condition that would jeopardize patient safety while participating in this clinical trial (in Canada, this included current genito-urinal infection or genito-urinal infection within 2 weeks prior to informed consent)
* Acute coronary syndrome, stroke, or transient ischemic attack within 2 months prior to informed consent
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 dapagliflozin in the U.S. started on January 8, 2014.

* For Marketscan and Medicare: Jan 8, 2014-Dec 31, 2017 (end of data availability).
* For Optum: Jan 8, 2014-Mar 31, 2019 (end of data availability).

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures (including run-in)
2. Female or male aged ≥ 40 years
3. Diagnosed with T2DM
4. High Risk for CV event defined as having either established CV disease and/or multiple risk factors:

   - Established CV Disease (See Appendix E for details) OR No known cardiovascular disease AND at least two cardiovascular risk factors in addition to

   T2DM, defined as:
   * Age \> 55 years in men and \> 60 in women AND presence of at least 1 of the following additional risk factors (see Appendix E for details)
   * Dyslipidemia
   * Hypertension
   * Tobacco use
5. WOCBP must take precautions to avoid pregnancy throughout the study and for 4 weeks after intake of the last dose.

   * WOCBP must have a negative urine pregnancy test. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal.
   * WOCBP must be willing to use a medically accepted method of contraception that is considered reliable in the judgment of the Investigator. For inclusion in the optional genetic research, patients must fulfill the criterion specified in

Exclusion Criteria:

Patients should not meet any exclusion criteria at the time of randomization. If at the time of enrollment, it is known that the patient will not meet criteria after a successful run-in period he/she should not be entered into run in.

1. Use of the following excluded medications:

   * Current or recent (within 24 months) treatment with pioglitazone and/or use of pioglitazone for 2 years or more at any time
   * Current or recent (within 12 months) treatment with rosiglitazone
   * Previous treatment with any SGLT2 inhibitor
   * Any patient currently receiving chronic (\>30 consecutive days) treatment with an oral steroid at a dose equivalent to oral prednisolone ≥10 mg (e.g., betamethasone ≥1.2 mg, dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg) per day
2. Acute cardiovascular event \[e.g., acute coronary syndrome (ACS), transient ischemic attack (TIA), stroke, any revascularization, decompensated HF, sustained tachycardia \<8 weeks prior to randomization. Patients with acute cardiovascular events can be enrolled in the run-in period as long as randomization does not occur within 8 weeks of the event.
3. Systolic BP \>180 or diastolic BP \>100 mmHg at randomization
4. Diagnosis of Type 1 diabetes mellitus, MODY, or secondary diabetes mellitus
5. History of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time
6. History of any other malignancy within 5 years (with the exception of successfully treated non-melanoma skin cancers)
7. Chronic cystitis and/or recurrent urinary tract infections (3 or more in the last year)
8. Any conditions that, in the opinion of the Investigator, may render the patient unable to complete the study including but not limited to cardiovascular (NYHA class IV CHF, recurrent ventricular arrhythmias) or non-cardiovascular disease (e.g., active malignancy with the exception of basal cell carcinoma, cirrhosis, chronic lung disease, severe autoimmune disease) and/or a likely fatal outcome within 5 years
9. Pregnant or breast-feeding patients
10. Involvement in the planning and/or conduct of the study or other dapagliflozin studies (applies to AZ, BMS, Hadassah and Thrombolysis in Myocardial Infarction \[TIMI\] or representative staff and/or staff at the study site)
11. Previous randomization in the present study
12. Active participation in another clinical study with IP and/or investigational device
13. Individuals at risk for poor protocol or medication compliance during run-in period (reasonable compliance defined as 80 - 120%, unless a reason for non-compliance is judged acceptable by the Investigator). If for any reason, the Investigator believes that the patient will not tolerate or be compliant with IP or study procedures, the patient should not be randomized and considered a run-in failure. Patients will be excluded during run-in and should not be randomized if the following are observed from laboratory or observation during enrollment and run-in assessments:
14. HbA1c ≥12% or HbA1c\<6.5%
15. AST or ALT \>3x ULN or Total bilirubin \>2.5 x ULN
16. CrCl \< 60 ml/min (based on the Cockroft-Gault equation)
17. Hematuria (confirmed by microscopy at Visit 1) with no explanation as judged by the Investigator up to randomization. If bladder cancer is identified, patients are not eligible to participate.
18. Any reason the Investigator believes the patient is not likely to be compliant with the study medication and protocol.

Answer: B