Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP1) receptor agonists as first-line treatments for type 2 diabetes would improve outcomes but their costs would need to decrease by at least 70% to make these agents cost-effective, according to study findings published in Annals of Internal Medicine.

Neda Laiteerapong, MD, MS, FACP, lead author of the study, hopes the findings will “motivate the medical community to be more aware of the tradeoffs between costs and benefits for these drugs and consider advocating for lower prices for these drugs when they become generic.” Dr Laiteerapong is associate professor in the Section of General Internal Medicine and associate director for clinical outcomes at the Center for Chronic Disease Research and Policy (CDRP) at the University of Chicago Department of Medicine.

These agents are currently recommended as second-line therapy for patients with diabetes without atherosclerotic cardiovascular disease (ASCVD) and as first-line therapy for those with ASCVD, heart failure, or chronic kidney disease, according to the 2020 American Diabetes Association and European Association for the Study of Diabetes guidelines. The effectiveness of SGLT2 inhibitors and GLP1 receptors is not being debated; rather, the high cost of these agents has added a caveat to the ADA/EASD guidelines recommending against their use if “cost is a major issue.” Since the release of these newer agents, the cost of treating type 2 diabetes has risen to $327 billion annually, up from $174 billion in 2007.

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To further investigate cost-effectiveness, Dr Laiteerapong and colleagues created an individual patient-level model to simulate the lifetime incidence, prevalence, mortality, and costs associated with having type 2 diabetes. The model used 2013 to 2016 National Health and Nutrition Examination Survey (NHANES) data from a nationally representative sample of patients with diabetes eligible to start first-line therapy using participants who self-reported diabetes or had a hemoglobin A1c of more than 6.5%.

They created several treatment outcomes including first-line use of metformin and second-line use of SGLT2 inhibitors or GLP1 agonists, first-line use of SGLT2 inhibitors, and first-line use of GLP1 agonists. The study was funded by the American Diabetes Association and grants from the National Institute on Aging.

Key Findings

First-line use of SGLT2 inhibitors and GLP1 receptor agonists was associated with lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke compared with metformin (Table). As a result, projected life expectancy was expected to improve by 3.0 months with SGLT2 inhibitors and 3.4 months with GLP1 receptor agonists as first-line therapies compared with metformin.

Table. Type 2 Diabetes Macrovascular Complication Rates by First-Line Therapy

First-Line TherapyHeart FailureIschemic Heart DiseaseMyocardial InfarctionStroke
GLP1 receptor agonist13.1%17.2%25.5%16.2%
SGLT2 inhibitor13.2%17.3%26.0%16.3%
Data extracted from Choi et al.

However, neither SGLT2 inhibitors or GLP1 receptor agonists fell below the willingness-to-pay threshold of $150,000 per quality-adjusted life-year (QALY), the predetermined criteria for being cost-effective. Comparing oral medications with injections on quality of life did not significantly affect the findings. To be cost-effective first-line agents, the modeling showed that a price reduction of 70% for SGLT2 inhibitors and 90% for oral GLP1 receptor agonists would be needed based on a willingness-to-pay threshold of under $150,000 per QALY. That equates to annual costs for SGLT2 inhibitors of $1,800 per year ($5 per day) and for oral GLP1 receptors of $2,100 per year ($6 per day).

“I was surprised that the drugs could become cost-effective after significant lowering of their prices,” Dr Laiteerapong said in an interview. “Price competition in the generic market for these drugs would do wonders to increase their access.”

Although generic formulations for these agents seem to be a promising solution, the authors noted that it may take decades for even the generic formulations to become cost-effective. Case in point, “a generic GLP1 receptor agonist became available in 2017, but its costs remain high,” they noted. With 1 of the 2 patents for the SGLT2 inhibitor dapagliflozin ending in October 2020, a generic formulation may become available, the authors added.

The findings are limited by the known limitations of the diabetes-related complication and mortality modules from the United Kingdom Prospective Diabetes Study (UKPDS) such as the overestimation of macrovascular complications that may artificially increase cost and disutilities associated with these complications. The incomplete demographic and heart failure history in NHANES along with the limited sample of participants included in this analysis also limited the findings.

Some [or one] study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Choi JG, Winn AN, Skandari MR, et al. First-line therapy for type 2 diabetes with sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: a cost-effectiveness study. Ann Intern Med. Published online October 4, 2022. doi:10.7326/M21-2941