# Comparative Effectiveness and Safety of Newer and Older Antihyperglycemic Medications

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2021 · —

## Abstract

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 differ...

## Key facts

- **NIH application ID:** 10165946
- **Project number:** 1I01HX003252-01A1
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** Ziyad Al-Aly
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165946

## Citation

> US National Institutes of Health, RePORTER application 10165946, Comparative Effectiveness and Safety of Newer and Older Antihyperglycemic Medications (1I01HX003252-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10165946. Licensed CC0.

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