Comparative Effectiveness and Safety of Newer and Older Antihyperglycemic Medications

Background: People diagnosed with diabetes are initially advised on lifestyle changes and started on
metformin, but often require the addition of 2nd line antihyperglycemic medications. The choice of 2nd line
antihyperglycemic therapy is complex because the multiple available drugs, distributed across several drug
classes, have different benefits and risks. Newer 2nd line antihyperglycemics (sodium-glucose co-transporter-2
inhibitor (SGLT2i), and glucagon-like peptide-1 receptor agonist (GLP1)) have been shown to reduce risk of
cardiovascular events compared to placebo in individuals at high risk of cardiovascular disease. Evidence also
suggests that these newer agents may reduce risk of kidney disease in people with relatively preserved kidney
function. Whether the newer agents offer benefits in cardiovascular and kidney outcomes compared to older
(less costly) 2nd line agents including dipeptidyl peptidase-4 inhibitors (DPP4) and sulfonylureas, and whether
these benefits extend to individuals with intermediate or low cardiovascular risk and people with reduced
kidney function is not known.
Significance/Impact: Results will provide real-world evidence to guide the selection of antihyperglycemic
agents by cardiovascular risk status, kidney function category, and will provide evidence on the risk of adverse
events. The proposal falls under several Health Services Research priorities including Primary Care
Practice (diabetes is highly prevalent in veterans) and Health Care Informatics (using big data to advance
care of veterans); and Office of Research & Development priorities as our approach will highlight VA data
as a national resource and the results will have direct and substantial real-world impact in informing care.
Innovation: The proposal will leverage the power of the VA’s large-scale electronic health records and recent
methodologic innovations in causal inference and pharmacoepidemiology — specifically in the use of real-
world observational data to emulate a target randomized trial — to provide much needed evidence of the
comparative effectiveness and safety of newer vs. older antihyperglycemic agents.
Specific Aims: To use observational healthcare data from the Department of Veterans Affairs to emulate four-
arm randomized trials of the comparative effectiveness of incident use of newer (SGLT2i, GLP1) and older
(DPP4, sulfonylureas) 2nd line antihyperglycemics—among metformin users—on cardiovascular
outcomes (aim 1), kidney outcomes (aim 2), and evaluate the risk of adverse events associated with these
drug classes (aim 3).
Methodologies: For each specific aim we will define a target randomized trial protocol, including eligibility
criteria, treatment assignment, treatment initiation, treatment strategy follow-up, outcome assessment, and
analytic plan. We then will use electronic medical record data from the VA to construct aim-specific cohorts to
emulate the specifications of the target trial for the related aim, estimating the differences in risk of
cardiovascular disease, kidney disease, and adverse events between the studied antihyperglycemics.
Randomization will be emulated by inverse probability of treatment weighting based on predefined variables
and a high dimensional variable selection algorithm. Intention-to-treat effects will be estimated using discrete
time survival analyses, and adjusted intention-to-treat-effects will be estimated after accounting for loss to
follow-up. Per-protocol effects (of a specified treatment strategy) will be estimated after accounting for non-
adherence to assigned treatment strategies. Differences in risk of outcomes between the second-line
antihyperglycemics will be reported as hazard ratios and adjusted incidence rates.
Implementation/Next Steps: The results from this proposal will inform clinical practice guidelines for the
treatment of diabetes. Future studies will leverage advances in machine learning to create unique
individualized precision care plans for each person with diabetes.

Grant Number: 5I01HX003252-05
NIH Institute/Center: VA
Principal Investigator: Ziyad Al-Aly