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. 2024 Jul 27;40(5):223–229. doi: 10.1177/87551225241266773

Utilization of Glucagon-Like Peptide-1 Receptor Agonist and Dipeptidyl Peptidase-4 Inhibitors at the Veterans Health Administration

Aditya Krishnan 1, Sowmya K Suryanarayanan 2, Ishak A Mansi 3,4,✉
PMCID: PMC11462932  PMID: 39391328

Abstract

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) are incretin-based therapies commonly used in the management of type 2 diabetes. Public interest in GLP-1RA soared after discovering their ability to lower body weight in patients without diabetes. Objective: To examine recent trends in usage of GLP-1RA and DPP-4i in the Veterans Health Administration (VHA). Methods: We extracted GLP-1RA and DPP-4i use from the national VHA Corporate Data Workhouse (CDW) between fiscal years (FYs) 2011 to 2021, which encompass medication class, name, dosage, date of filled prescription, and patients’ characteristics. Results: A total of 3 037 006 prescriptions for DPP-4i and 2 183 294 prescriptions for GLP-1RA were filled during FY 2011 to 2021. More patients were prescribed DPP-4i (273 002 subjects) compared with GLP-1RA (157 209 subjects) from FY 2011 to 2021. Overall, 10.7% used DPP-4i for 90 days or less in comparison to 9.1% in GLP-1RA (P < 0.001). The proportion of patients prescribed DPP-4i who were 75 years of age or older was relatively stable over the years 2011 to 2021 (mean proportion = 19%). However, the proportion of patients who were 75 years of age or older prescribed GLP-1RA increased from 4.2% in 2011 to 16.9% in 2021. Conclusions: Incretin-based therapies have become a well-established class of drugs within the VHA. Even though DPP-4i usage in older adults has remained stable over the past 10 years, prescriptions for GLP-1RA in older adults have increased multifold over the last few years, which might be attributed to recent trial evidence showing benefit in cardiovascular outcomes and weight reduction.

Keywords: glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitors, Veterans Health Administration, type 2 diabetes

Introduction

Incretin hormone-based therapies, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i), became increasingly popular over the last decade. Incretins are hormones produced by the gastrointestinal system that has been shown to increase insulin levels in response to glucose. The 2 main incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), both of which contribute to approximately two thirds of postprandial insulin release after a meal. 1 The GLP-1 is secreted by L cells in the ileum, colon, and rectum, whereas the GIP is released from K-cells found predominately in the duodenum and proximal gut. Their actions are manifold including stimulation of insulin secretion in a glucose-dependent manner, suppression of glucagon, reduction in appetite, deceleration of gastric emptying, stimulation of beta-cell neogenesis, growth, and differentiation, and in vitro inhibition of beta-cell apoptosis. 2 The GLP-1 and GIP are rapidly inactivated in vivo by dipeptidyl peptidase-4 (DPP-4) enzyme.

In patients with type 2 diabetes, impaired secretion of incretin hormones has been shown and can be multifactorial.1,2 Incretin-based therapies aim to augment incretin effects. The DPP-4i medications inhibit DPP-4 enzyme; hence, they increase endogenous levels of GLP-1 and GIP. The GLP-1RA medications are recombinant peptide-based derivatives of human GLP-1 and are shown to withstand breakdown by DPP-4 enzyme for longer duration; hence, they act as receptor agonist.3,4 Both these agents are recommended for use in diabetes; however GLP-1RAs have gained popularity in clinical use due to their efficacy as weight loss treatment in people who can tolerate them. 5

There are numerous factors to consider when selecting a glucose-lowering medication for type 2 diabetes. These factors include medications’ mechanisms of action, efficacy in lowering hemoglobin A1C, differential effects on fasting and postprandial plasma glucose, effects on pancreatic β-cell function, tolerability, risk of hypoglycemia, adverse events profile, effects on body weight, patients’ preferences, ease of use, and cost.

Incretin mimetics have more favorable pharmacokinetic profiles to slow gastric emptying and suppress glucagon secretion, and thereby regulate postprandial glucose in circulation. 6 The GLP-1RA medications, particularly the longer-acting ones, lower blood glucose to a greater extent (typically lower hemoglobin A1C by 0.8%-1.5%) 7 and promote more weight loss than DPP-4i, which are weight neutral.8,9 The GLP-1RA medications also suppresse appetite, increase satiety, and slow gastric emptying leading to weight loss. 10 Cardiovascular and kidney benefits were demonstrated with improvement in microalbuminuria, blood pressure (BP), and other markers when compared with other agents.9,11 Data from several studies have shown that use of GLP-1RA was associated with 2 to 6 mm Hg reduction in systolic BP; such an effect has been suggested as a mediator of cardiovascular event reduction. 12 In addition, GLP-1RA may have beneficial effects on B-cell growth and protection. 13

The DPP-4i medications (commonly known as Gliptins), through preserving endogenous incretin hormones, are effective anti-diabetes agents through increasing insulin secretion to glucose, reducing glucagon, and lowering glucose levels.3,4 The DPP-4i medications have the modest improvement on glucose control (typically reduce hemoglobin A1C by 0.5%-0.8%) 7 and low risk of hypoglycemia even in renal failure patients but have not shown weight reduction. 5 The DPP-4i medications also have cardiovascular and renal benefits.14,15 The DPP-4i medications have the advantage of oral administration and better gastrointestinal tolerability profile than GLP-1RA medications, which are mainly injectable, with exception of oral semaglutide. 16

The recent paradigm shift in type 2 diabetes management to focus on favorable cardiometabolic and renal effects of glucose-lowering medications has brought incretin-based therapies to the forefront. The DPP-4i and GLP-1RA not only improve glycemic control but also they were noted to reduce BP and improve beta-cell function.17,18 The GLP-1RA medications also have increased cardiovascular protective effects with respect to improving lipid profile and systolic BP. Studies comparing DPP-4i to GLP-1RA have shown superiority of GLP-1RA in reducing hyperglycemia, inducing weight loss, and offering cardiovascular benefits, which prompted some researchers to recommend switching DPP-4i users to GLP-1RA.5,19-23

Current American Diabetes Association (ADA) guidelines regarding pharmacologic therapy of type 2 diabetes recommended use of metformin as first-line therapy, followed by (or in combination to) GLP-1RA. 24 In addition, the guidelines recommended that GLP-1RA or sodium-glucose cotransporter 2 inhibitor (SGLT-2i) medications to be started in patients with established atherosclerotic cardiovascular disease or indicators of high cardiovascular risk, established kidney disease, or heart failure, as part of the glucose-lowering regimen independent of hemoglobin A1C level. 24 The guidelines also recommended that in adults with type 2 diabetes, GLP-1RA is preferred to insulin when possible. The American College of Physicians (ACP) also recently updated their guidelines on newer pharmacologic treatments for type 2 diabetes to recommend adding an SGLT-2i or GLP-1RA to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control (strong recommendation; high-certainty evidence) to reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke. 25 The ACP recommended against adding a DPP-4i to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control, because these agents have not been shown to reduce morbidity and all-cause mortality (strong recommendation; high-certainty evidence). 25 However, despite of the increasing recommendations by scientific societies, the actual percentage of patients receiving them for cardiovascular outcomes in diabetes has been low. 7

Yet, the utilization of GLP-1RA was influenced by factors other than their favorable cardiometabolic profile. Public interest with GLP-1RA soared after discovering their ability to lower body weight in patients without diabetes, fueled by direct-to-consumer advertisements. 26 Studies have shown that public online searches for GLP-1RA have increased by 295% from 2016 to 2021. 27 Such increase in online searches was associated with strong correlation with their prescription rate (correlation coefficients range = 0.86-0.99). 27 However, the use of incretin-based therapies was fraught by their gastrointestinal adverse events such as nausea and vomiting, which frequently resulted in discontinuation of therapy. 28

Given these contrasting factors, this study aims to examine the utilization of these agents in the Veterans Health Administration (VHA) system, where prescribing these medications is relatively governed by formulary availability and prescribing policy. We hypothesized that utilization of GLP-1RA will exceed DPP-4i and that the rate of discontinuing GLP-1RA within 90 days of prescribing will be higher than DPP-4i.

Methods

This study used pharmacy data from the national VA Corporate Data Warehouse (CDW) accessible in the VA Informatics and Computing Infrastructure (VINCI). 29 The CDW catalogs its data according to published protocols. 30 Pharmacy data in CDW contain details of medications prescribed and filled for veterans from any VA pharmacy including patients’ personal information, name of medications, dosage, form, instructions, amount dispensed, days’ supply, date and time of medication release, and financial information. We queried the pharmacy files for prescription of GLP-1RA and DPP-4i medications that were filled during the period from fiscal year (FY) 2011 to 2021 (October 1, 2011, to September 30, 2021) and were available at VA formulary using both trade and chemical names (GLP-1RA: exenatide, liraglutide, semaglutide, albiglutide, and dulaglutide, lixisenatide, tirzepatide [trade names: adlyxin, bydureon, byetta, degludec, mounjaro, ozempic, rybelsus, saxenda, soliqua, tanzeum, trulicity, victoza, wegovy, xultophy]; DPP-4i: alogliptin, alogliptin/pioglitazone, alogliptin/metformin, dapagliflozin-saxagliptin, linagliptin, linagliptin/metformin, metformin/saxagliptin, metformin/sitagliptin, saxagliptin, saxagliptin-metformin, simvastatin/sitagliptin, sitagliptin, sitagliptin-metformin [trade names: glyxambi, janumet, januvia, jentadueto, juvisync, kazano, kombiglyze, linaglipt, nesina, onglyza, qtern, steglujan, tradjenta, trijardy]). We verified the date of the first prescription of each medication class by looking backward to FY2006. The Orlando VA institutional review board approved the study and waived participants’ informed consent as only preexisting deidentified data were analyzed. Data analysis and management were performed using STATA, version 17 (Stata Corp LLC, College Station) and Microsoft Excel.

Results

A total of 3 037 006 prescriptions of DPP-4i and 2 183 294 prescriptions for GLP-1RA were filled during FY 2011 to 2021. The total number of prescriptions for DPP-4i increased from 34 272 in FY 2011 to 603 235 prescriptions in FY 2021. The total number of prescriptions for GLP-1RA increased from 8096 prescriptions in FY 2011 to 721 458 in FY 2021 (Figure 1). The most commonly prescribed DPP-4i were alogliptin (45%), saxagliptin (39.3%), sitagliptin (11.1%), and linagliptin (4.3%). The most commonly prescribed GLP-1RA were semaglutide (32.9%), liraglutide (32.0%), dulaglutide (25.8%), and exenatide (6.6%).

Figure 1.

Figure 1.

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Number of prescriptions filled for GLP-1RA and DPP-4i for VA patients from 2011 to 2021.

The number of subjects newly initiated on DPP-4i increased from 3430 in FY 2011 to 45 301 subjects in FY 2021. The number of subjects newly initiated on GLP-1RA increased from 747 subjects in FY2011 to 44 641 in FY 2021. Overall, more subjects were newly prescribed DPP-4i (273 002 subjects) compared with GLP-1RA (157 209 subjects) throughout FY 2011 to 2021 (Figure 2).

Figure 2.

Figure 2.

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Number of patients initiated on GLP-1RA and DPP-4i prescriptions at the VA from 2011 to 2021.

The DPP-4i medications were prescribed for a mean total duration of 780 days (standard deviation [SD] = 715); median: 569 (interquartile = 208, 1146 days). The GLP-1RA medications were prescribed for a mean total duration of 669 days (SD = 628), median: 496 (interquartile: 166, 993 days). The proportion of patients who were taking GLP-1RA or DPP-4i for 90 days or less is depicted in Figure 3. Overall, 10.7% used DPP-4i for 90 days or less in comparison to 9.1% in GLP-1RA (P < 0.001).

Figure 3.

Figure 3.

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Proportions of patients at the VA using GLP-1RA (panel a) or DPP-4i (panel b) for 90 days or more vs less than 90 days from 2011 to 2020.

The proportions of patients who were 75 years of age or older at the time they were first prescribed GLP-1RA or DPP-4i are depicted in Figure 4. The proportion of patients prescribed DPP-4i who were 75 years of age or older was relatively stable over FY 2011 to 2021 (mean proportion = 19%). However, the proportion of patients prescribed GLP-1RA increased from 4.2% in FY 2011 to 16.9% in FY 2021. Table 1 depicts the characteristics of our study population.

Figure 4.

Figure 4.

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Proportion of patients at the VA who were ≥75 years of age vs <75 years of age and who were prescribed GLP-1RA (panel a) or DPP-4i (panel b) during the years from 2011 to 2021.

Table 1.

Characteristics of Veterans Initiated on GLP-1 Receptor Agonist or DPP-4 Inhibitors.

Baseline characteristics DPP-4i (N = 273 002) GLP-1RA (N=157 209) Total
Age in years at medication initiation:
 Mean (standard deviation) 66 (11) 65 (11) 66 (11)
 Median (interquartile) 68 (60-73) 66 (58-72) 68 (59-73)
Gender:
 Men: N (%) 257 875 (94.5%) 144 972 (92.2) 402 847 (93.6%)
 Women: N (%) 15 127 (5.5%) 12 237 (7.8%) 27 364 (6.4%)
Race:
 Whites: N (%) 192 142 (70.4%) 116 173 (73.9%) 308 315 (71.7%)
 Blacks: N (%) 50 927 (18.7%) 25 616 (16.3%) 76 543 (17.8%)
 Others: N (%) 10 606 (3.9%) 5236 (3.3%) 15 842 (3.7%)
 Unknown or missing: N (%) 19 327 (7.0%) 10 184 (6.5%) 29 511 (6.8)
Ethnicity:
 Hispanic or Latino: N (%) 18 787 (6.9%) 10 273 (6.5%) 29 060 (6.7%)
 Not Hispanic or Latino: N (%) 241 109 (88.3%) 140 353 (89.3%) 381 462 (88.7%)
 Unknown or missing: N (%) 13 106 (4.8%) 6583 (4.2%) 19 689 (4.6%)
Open in a new tab

DPP-4i: dipeptidyl peptidase-4 inhibitor; GLP-1RA: glucagon-like peptide-1 receptor agonist.

Discussion

This study found that between 2011 and 2021, the use of incretin-based therapies has exponentially increased at the VA with more patients prescribed DPP-4i medications as compared with GLP-1RA medications. However, the number of patients newly prescribed GLP-1RA was nearing those prescribed DPP-4i in FY 2021. It appears that proportions of patients who discontinued their medications within 90 days were about 10%, which is comparable to reported rates in some clinical trials. 23 Whereas the proportions of subjects 75 years or older who were prescribed and filled prescriptions for DPP-4i remained stable during the study period, this proportion was very low for GLP-1RA at FY2011 (4.2%) but increased multifold in FY 2021 (16.9%). This increased use of GLP-1RA in older adults may reflect the increasing familiarity of these medications among providers and the increasing acceptance by patients with the availability of once-weekly injections. The results of this study inform clinical providers, patients, and administrators about the growing utilizations of this important and increasingly popular class of medications. The GLP-1RA prescriptions in VA lagged DPP-4i prescriptions for several reasons including that GLP-1RA prescriptions at the VA, until recently, required prior authorization from a pharmacy or endocrine consultation, whereas DPP-4i prescriptions did not require such authorization. In addition, the fact that DPP-4i agents are oral medications and not injectables and may have a better gastrointestinal profile made it more acceptable to patients. No off-label use of GLP-1RA at the VA is allowed. In 2022, criteria for GLP-1RA use in the VA limited it to patients with type 2 diabetes and atherosclerotic cardiovascular disease or chronic kidney disease. For patients without atherosclerotic cardiovascular disease or chronic kidney disease, criteria for use were inadequate glycemic control on 2 or more oral medications, one of which should be metformin (unless unable to use), or inadequate glycemic control on basal insulin plus 1 or more oral medications. 31

The gastrointestinal side effects of these medications could explain why many patients end up discontinuing the medications despite their benefits. In a retrospective cohort study from the United Kingdom, the overall proportion of patients who discontinued therapy was 45.2% after 12 months and 64.7% after 24 months. 23 The mean duration of use of DPP-4i in our study was 780 days (2.1 years), and the mean duration of GLP-1RA use was 669 days (1.8 years). There is paucity of data about the use of GLP-1RA in older population. It is presumed that these medications may be as effective and tolerated in older population as younger population. Our data show the increasing utilization of GLP-1RA in subjects older than 75 years of age.

Studies that examined the use of GLP-1RA in non-VA setting have also reported a multifold increase in their use. Using a national prescription database that captures more than 70% of all prescription activity in the United States, a study reported that GLP-1RA prescription increased by 221.0% (95% confidence interval = 212.1%-229.9%) between 2016 and 2021. 27 Of interest, the same study reported that public online search for these medications also increased by 295.2% (95% confidence interval = 257.7%-332.6%) during the same time period. 27 Our study shows that the use of GLP-1RA at the VA increased during the same time period from 61 122 prescriptions in 2026 to 721 458 prescriptions in 2021 (more than 1000% increase).

This study is the first study, to our knowledge, to examine the utilization of GLP-1RA and DPP-4i medications in the VA. Some of the limitation of our study is that it is limited to veterans who used the VA system to fill their prescriptions and cannot account for those who received care outside the VA system. In addition, GLP-1RA are now approved at the VA for weight loss in veterans participating in a lifestyle change program (that includes diet, physical activity, and behavioral counseling) but are not meeting their weight loss goal. Hence, our data that stopped at 2021 may not reflect this newer utilization.

Conclusions and Relevance

Overall, our study found that more patients at the VA are being prescribed DPP-4i medications compared with GLP-1 RA. However, more patients are being prescribed GLP-1RA in more recent years, including older adults with reasonable retention rate for medication use. This study informs clinical providers, patients, and administrators about the growing utilizations of this important and increasingly popular class of medications.

Footnotes

Data Availability Statement: Data are stored in the VA Informatics and Computing Infrastructure (VINCI), the operational platform for health services research at the Veterans Healthcare Administration (VHA). The VINCI acts as a data steward for VHA Data Systems. The data in VINCI cannot be copied, transferred, or printed. Access to data by other researchers is possible following VINCI protocols, as described on the VINCI Central website: http://vaww.vinci.med.va.gov/VinciCentral.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: No funding was provided by this work. Resources of the Orlando VA Medical Center were used to conduct the study.

Disclaimer: The views expressed herein are those of the authors and do not reflect the official policy or position of the VA Administration, US Government, or any of its affiliated entities. Some of the authors are employees of the US government. This work was prepared as part of their official duties, and as such, there is no copyright to be transferred.

Ethics Approval and Informed Consent: The Orlando VA institutional review board approved the study and waived participants’ informed consent as only pre-existing deidentified data were analyzed.

ORCID iD: Ishak A. Mansi Inline graphic https://orcid.org/0000-0001-6122-3716

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