Acute Liver Injury in Patients on Dapagliflozin

The overall goal of this research study is to estimate the risk of hospitalization for acute
liver injury in patients who are prescribed dapagliflozin compared to patients prescribed
other specific oral antidiabetic drugs. Dapagliflozin and other antidiabetic drugs are used
to treat type 2 diabetes mellitus. Because of the mechanism of action for dapagliflozin and
results from small safety monitoring studies, there is interest in further evaluating the
safety of dapagliflozin in large populations.

The study will be implemented in three administrative health care data sources in two
countries: in the United Kingdom, the Clinical Practice Research Datalink (CPRD); and in the
United States, the Centers for Medicare and Medicaid Services (CMS) Medicare databases and
the HealthCore Integrated Research Database (HIRDSM). Individuals in the databases will be
included in the study if they meet the following age criteria; 18 years and older (CPRD and
HIRD), or 65 years or older (Medicare); and if they did not have type 1 diabetes, are new
users of one of the study drugs and meet the criteria of at least 180 days of electronic data
before their first prescription of the study drug. The study period starts July 1, 2013 in
CPRD, January 1, 2014 in PHARMO and January 9, 2014 in the United States data sources, and
will end at the latest available data at each database at the time of analysis

Inclusion Criteria:

1. receive newly prescribed dapagliflozin (with or without other ADs) or a newly
prescribed AD (with or withoutother ADs) in a class other than SGLT2 inhibitors,
insulin monotherapy, metformin monotherapy, or sulfonylureamonotherapy;

2. do not have evidence of type 1 diabetes;

3. are aged 18 years or older at the index date for CPRDpatients, 18-64 years for HIRDSM
patients, or 65 years or older for Medicare patients; and

4. have been enrolled in the data source for at least 180 days before the first
prescription or dispensing for dapagliflozin or comparator AD.

Exclusion Criteria:

- previous diagnosis of ALI; liver, biliary, or pancreatic disease; hepatobiliary or
pancreatic neoplasm; or congestive heart failure