GLP-1RAs Don’t Work Better Than Oral Agents to Enable Insulin Discontinuation in T2D

VA Study Finds Them More Likely to Just Decrease Insulin Need

NEW HAVEN, CT — With all of the hype surrounding glucagon-like peptide-1 receptor agonists (GLP-1RAs) for Type 2 diabetes, some proponents have questioned whether patients using the drugs could eventually discontinue their use of insulin for glucose control.

While there has been evidence that Type 2 diabetes patients who add to basal insulin can decrease their insulin requirements, the jury was still out on whether prescribing GLP-1RAs in that situation can actually allow insulin discontinuation.

A recent VA study provided the most definitive verdict to date. Researchers from the Yale School of Medicine in New Haven, CT, and the VA Connecticut Healthcare System in West Haven and colleagues sought to compare rates of insulin discontinuation among patients with Type 2 diabetes (T2D) receiving basal insulin who initiated treatment with a GLP-1RA, sodium–glucose cotransporter-2 inhibitor (SGLT-2i), or dipeptidyl peptidase-4 inhibitor (DPP-4i) between 2020 and 2022.

The target trial emulation used data from the VHA electronic health record (EHR) data. Included in the study were veterans with T2D receiving basal insulin.

For the article published in Annals of Internal Medicine, Insulin discontinuation was defined as the first gap in insulin prescription fills of 12 months or more over 3 years of follow-up.¹

The researchers divided the veterans into 8,869 matched sets of GLP-1RA (76.6% semaglutide, 15.2% dulaglutide, 7.9% liraglutide, and 0.3% exenatide), SGLT-2i (99.7% empagliflozin) and DPP-4i (95.9% alogliptin) initiators. Of the participants, 63% were 65 years or older, 93% were male, 70% were white, and 48% had a hemoglobin A1c (HbA1c) level of 9% or more.

Over 3 years of follow-up, the study team reports that 1,480 (16.7%) GLP-1RA initiators compared with 1,585 (17.9%) SGLT-2i initiators and 1,517 (17.1%) DPP-4i initiators discontinued insulin therapy in the intention-to-treat analysis (risk ratio, 0.93 [95% CI, 0.86 to 1.01] and 0.98 [CI, 0.87 to 1.09] for the GLP-1RA arm compared with the SGLT-2i and DPP-4i arms, respectively).

“Results were not substantively different in a modified per protocol analysis. None of the subgroups showed a comparative advantage of GLP-1RAs with respect to insulin discontinuation over SGLT-2is or DPP-4is,” the study pointed out.

The authors concluded, “Among veterans with T2D receiving basal insulin therapy, addition of GLP-1RA did not increase the chances of stopping insulin therapy compared with SGLT-2i or DPP-4i therapy.”

The results were not all that surprising, however. In 2024, Washington University School of Medicine-led researchers wrote in Diabetes Therapy why they thought insulin would remain a critically important treatment for Type 2 diabetes, not just Type 1.²

They discussed “an acceleration in the development of new classes of diabetes medications for individuals with Type 2 diabetes and obesity, such as, for example, glucagon-like peptide-1 receptor agonists (GLP-1 RAs). These formulations have been shown to confer significant benefits in achieving good glycemic control with reduced hypoglycemia risk, weight loss, and cardiorenal protection. Therefore, it is reasonable to question whether there is still a role for insulin therapy in the management of type 2 diabetes.”

The study continued, “However, there are clear limitations inherent to GLP-1 RA therapy, including high rates of suboptimal adherence and treatment discontinuation due to high cost and side effects, which diminish long-term efficacy, and supply issues. In addition, newer formulations have shown improvements in convenience and tolerability, and have been shown to be even more effective when used in conjunction with basal insulin. In this narrative review, we discuss current evidence that supports GLP-1 RA use in combination with insulin therapy and the potential pitfalls of reliance on GLP-1 RAs as a substitute for insulin therapy.”

Those authors pointed out that patients might require insulin therapy even earlier, if they cannot afford the cost or tolerate the side effects and/or the lack of efficacy of GLP-1 RA medications. That is especially the case, it noted, because recent real-world studies have reported relatively high rates of poor adherence and discontinuation of GLP-1 RA therapy over time

The researchers further explained, “Discontinuation of therapy can be life-threatening in insulin-treated patients with T2D when insulin dosages are significantly reduced or discontinued. In its 2019 guidance, the European Medicines Agency (EMA) warned that the occurrence of diabetic ketoacidosis reported in a consistent number of cases could be attributed to the abrupt dose reduction or discontinuation of insulin while initiating the GLP-1 RA therapy.”

Another issue, according to that review, is that GLP-1 RAs are dependent upon beta-cell function and insulin availability. That means that basal insulin and, over time, prandial insulin often must be added because of the progressive nature of T2D. A 2016 study in Diabetes Care concluded, “Clinical markers of low beta cell function are associated with reduced glycemic response to GLP-1R agonist therapy. C-peptide and islet autoantibodies represent potential biomarkers for the stratification of GLP-1R agonist therapy in insulin treated diabetes.”

The study observed a “significantly reduced glycemic response to GLP-1 RA therapy in individuals with severe insulin deficiency, leading to the conclusion that C-peptide levels and islet autoantibodies—both indicators of low beta-cell function—are potential biomarkers for determining the appropriateness of GLP-1 RA therapy in insulin-treated individuals.”³ 

On the other hand, all of the studies tout the benefit of combined GLP-1 RA/basal insulin therapy. A recent review in JAMA noted that the combination “provides effective glycemic management and cardiorenal protection, with reduced hypoglycemia risk. Combined therapy with GLP-1 RA and basal insulin leverages the complementary effects of each medication. GLP-1 RA act upon postprandial glucose by stimulating insulin secretion, increasing satiety, slowing gastric emptying, and reducing the glucagon-release responses, whereas basal insulin addresses elevated fasting glucose by primarily suppressing hepatic glucose production.”

Led by researchers from Johns Hopkins University Medical School and colleagues, the JAMA article advises that the risk of hypoglycemia is highest in patients taking insulin or secretagogues such as sulfonylureas or meglitinides who are 75 years or older or have cognitive impairment, CKD, or insulin deficiency.

 

1. Lipska KJ, Zawack K, Yan L, Mutalik P, Li J, Gulanski B, Ioannou GN, Aslan M. Comparative Effectiveness of Glucagon-like Peptide-1 Receptor Agonists Versus Oral Agents for Insulin Discontinuation in Type 2 Diabetes : A Target Trial Emulation. Ann Intern Med. 2026 Jul 14. doi: 10.7326/ANNALS-25-05216. Epub ahead of print. PMID: 42441965.
2. McGill JB, Hirsch IB, Parkin CG, Aleppo G, Levy CJ, Gavin JR 3rd. The Current and Future Role of Insulin Therapy in the Management of Type 2 Diabetes: A Narrative Review. Diabetes Ther. 2024 May;15(5):1085-1098. doi: 10.1007/s13300-024-01569-8. Epub 2024 Apr 4. PMID: 38573469; PMCID: PMC11043311.
3. Jones AG, McDonald TJ, Shields BM, Hill AV, Hyde CJ, Knight BA, Hattersley AT; PRIBA Study Group. Markers of β-Cell Failure Predict Poor Glycemic Response to GLP-1 Receptor Agonist Therapy in Type 2 Diabetes. Diabetes Care. 2016 Feb;39(2):250-7. doi: 10.2337/dc15-0258. Epub 2015 Aug 4. PMID: 26242184; PMCID: PMC4894547.
4. Kalyani RR, Neumiller JJ, Maruthur NM, Wexler DJ. Diagnosis and Treatment of Type 2 Diabetes in Adults: A Review. JAMA. 2025;334(11):984–1002. doi:10.1001/jama.2025.5956