Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors

Type 2 diabetes mellitus remains a major risk factor for cardiovascular disease with an
estimated 425 million adults worldwide having diabetes in 2017, with type 2 diabetes mellitus
accounting for about 90% of the cases. Recent evidence indicates that certain
glucose-lowering therapies are associated with reduction in cardiovascular outcomes. There
is, therefore, an urgent need to improve the understanding of the impact of newer classes of
glucose-lowering therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like
peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT-2) inhibitors
on cardiovascular outcomes in clinical practice.

CVD-REAL is a comparative effectiveness study that aims to compare new users of SGLT-2
inhibitors with new users of other glucose-lowering drugs with regard to the risk of
all-cause mortality and clinically relevant CV outcomes (including stroke, myocardial
infarction, and hospitalization for heart failure) respectively. The study is based on data
from 12 countries across four major world regions.

The study is conducted using data from claims, medical records and national health registries
from twelve countries combined in two waves. CVD-REAL 1 includes Germany, Denmark, Norway,
Sweden, United Kingdom (UK) and United States of America (USA). CVD-REAL 2 comprises
Australia, Canada, Israel, Japan, Singapore and South Korea. The study will collect data from
approximately 4 million patients from the time they start treatment with a SGLT-2 inhibitor
or another glucose-lowering drug (index date) to the end of the follow-up period.

The Study Population will consist of new users of SGLT-2i and other glucose lowering drugs
respectively. These will be compared with all-cause mortality, hospitalization for heart
failure, myocardial infarction and stroke during the follow-up period. In addition certain
other cardiovascular and renal outcomes will be assessed descriptively in the two groups
respectively.

The study period will range from launch of the first SGLT-2i in each of the countries and end
at latest available data in each data source.

All-cause mortality and the incidence of cardiovascular events will be compared between new
users of SGLT-2 inhibitors and the comparator arm using a hazard ratio (relative risk) and
corresponding 95% confidence interval. The analysis will be performed using the Cox
proportional hazards model or some other appropriate method.

Matching by propensity scores will be used to balance the potential confounding covariates
between the SGLT-2i group and the reference group to ensure that the two groups are as
similar as possible at baseline.To achieve sufficient power, a meta-analysis will be applied
to integrate the point estimates from each of the individual database analyses and calculate
an overall weighted estimate and corresponding 95% CI.

Inclusion Criteria:

- New user receiving or dispensed prescription of SGLT-2i medication or other glucose
lowering drug, oral as well as injectable, including fixed-dose combination (FDC)
products containing these medication groups

- T2DM diagnosis on or prior to the index date

- ≥ 18 years old at index date

- > 1 year data history in the database prior to the index date

Exclusion Criteria:

- Patients with a T1DM diagnosis

- Patients with gestational diabetes within 1 year before index date