| Eligibility |
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.
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