The use of glucagon-like peptide 1 receptor agonist (GLP-1 RA) and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA (GIP/GLP-1 RA) classes has increased substantially over the past several years for treating type 2 diabetes and obesity. Increased demand for these pharmacotherapies has resulted in temporary product shortages for both GLP-1 RA and dual GIP/GLP-1 RA medications. These shortages, in part, have led to entities producing and marketing compounded formulations that bypass regulatory measures, raising safety, quality, and efficacy concerns. Even as shortages resolve, compounded GLP-1 RA and GIP/GLP-1 RA products continue to be heavily marketed to people with diabetes and obesity. The purpose of this statement by the American Diabetes Association is to guide health care professionals and people with diabetes and/or obesity in these circumstances of medication unavailability to promote optimal care and medication use safety.
Clinical demand for agents from the glucagon-like peptide-1 receptor agonist (GLP-1 RA) and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA (dual GIP/GLP-1 RA) classes has increased dramatically in recent years (1). These medications are recommended by the American Diabetes Association (ADA) for use in people with type 2 diabetes to 1) mitigate cardiovascular and kidney disease risks in high-risk individuals and 2) achieve and maintain glycemic and weight management goals (2). The U.S. Food and Drug Administration (FDA) approved several incretin-based agents as weight loss therapies, which fueled a demand temporarily exceeding the available supply. Resulting intermittent shortages prompted multiple entities to produce and market compounded formulations of these therapies directly to consumers (3), in some instances bypassing the involvement of the individual’s usual health care team. While compounded medications—medication formulations locally produced and customized to meet individualized clinical needs—play an import role within the health care system, specific concerns have emerged surrounding the recent widespread availability and use of non-FDA-approved incretin-based products. Given concerns about the safety, quality, and effectiveness, the ADA is issuing the following guidance on the use of non-FDA-approved compounded products.
The ADA recommends against using non-FDA-approved compounded GLP-1 and dual GIP/GLP-1 RA products due to safety, quality, and effectiveness concerns and uncertainty about their content. Compounded products are not FDA-approved (4) and do not undergo FDA review for safety, quality, or effectiveness standards (5). As a result, these products may present elevated risks to individuals.
Increased demand for GLP-1 RA and dual GIP/GLP-1 RA therapies resulted in shortages of drug products and/or delivery devices and culminated in the listing of several agents on the FDA shortage list. The FDA allows for compounding copies (i.e., products intended to be an exact duplicate) of FDA-approved products that are listed on the FDA shortage list (only) to facilitate continuity of treatment and uninterrupted access to prescribed pharmacotherapies (6). Human drug compounding is regulated per sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (7). Section 503A applies to human drug compounding by a licensed pharmacist within a state-licensed pharmacy or federal facility or by a licensed physician. Section 503B provides guidance for human drug compounding by outsourcing compounding facilities (7). Compounding under section 503A allows the production of relatively small quantities of compounded products, with 503A compounding facilities largely regulated by state boards of pharmacy. In contrast, 503B facilities are regulated by the FDA and are permitted to manufacture large quantities of compounded products, but only while these products are actively listed on the FDA shortage list (6).
While the FD&C Act allows for compounding of GLP-1 RA and dual GIP/GLP-1 RA therapies by licensed and approved facilities while under shortage (and, specifically, listed on the FDA drug shortage list), several concerns exist regarding the safety, quality, and effectiveness of such non-FDA-approved products (Table 1).
Compounding a copy of an FDA-approved product would ideally follow a U.S. Pharmacopoeia (USP) monograph or other standard to ensure product quality. However, USP monographs for most GLP-1 RA and the dual GIP/GLP-1 RA therapies are currently unavailable to guide standard compounding (8). USP monographs detail quality expectations for a medicine, including its identity, strength, purity, and performance (9). USP monographs also provide product testing recommendations for validation of a product's strength, purity, and performance (9). USP generally begins developing product monographs a few years prior to patent expiration (9); thus, USP monographs are not currently available for products like semaglutide or tirzepatide. Reports by the FDA have noted several ways compounded incretin-based therapies encountered in the marketplace may differ from FDA-approved products. According to the FDA, some compounded products have incorporated additional ingredients (e.g., vitamin B12 or vitamin B6) in the compounded GLP-1 RA formulation. Added ingredients within compounded formulations inherently change the composition of the compounded product relative to its FDA-approved reference product. Because compounded products are not subject to bioequivalence testing, as is required for FDA-approved generic medications, the impact of added ingredients on the pharmacokinetics, pharmacodynamics, efficacy, and safety of the medication is unknown (10). The FDA has also received early reports of compounders using salt forms of semaglutide (e.g., semaglutide sodium or semaglutide acetate) as a substitute for the semaglutide base used in the FDA-approved products (5). Salt forms of a small molecule are not chemically identical to the non-salt form of that molecule, which may similarly result in clinically meaningful differences in the effectiveness and safety of the compounded product compared with the FDA-approved product.
The FDA issued an alert in July 2024 detailing dosing errors associated with compounded semaglutide products (11,12). Several factors were identified as potentially contributing to dosing errors and associated adverse events (Table 2). While FDA-approved products are available only in prefilled pens and single-dose vials that deliver standardized dosing in milligrams, compounded products may be compounded in varying concentrations (even from the same compounder) and dispensed in variable packaging, including multidose vials or prefilled syringes (11,13). The FDA alert details reported administration errors at doses 5- to 20-fold higher than intended. According to the report, many individuals lacked experience with self-injection, were inexperienced with drawing medication from a vial into a syringe, and/or experienced confusion regarding the units of measurement (such as milliliters, milligrams, and/or “units”) listed on product labels, administration instructions, and/or provided syringes (11). Some of the reported cases resulted in adverse events, including gastrointestinal effects, fainting, headache, dehydration, acute pancreatitis, and gallstones—in some instances requiring hospitalization (11,12).
The information in this table is based on information from the FDA (11).
Counterfeit compounded GLP-1 RA and dual GIP/GLP-1 RA products pose significant risks. Determining whether online suppliers of compounded products are reputable or predatory can be difficult for individuals and health care professionals. Even reputable and trusted suppliers and sources may unknowingly market a counterfeit product. A recently published study highlighted important safety and purity concerns related to online distributors of semaglutide products, reporting online vendors that collected payment and did not provide product, issues with product purity and concentrations, and even concerns about product contamination (14). Clinicians have further reported instances of people presenting to the clinic with compounded GLP-1 RA and dual GIP/GLP-1 RA dosage forms not available for the FDA-approved products (e.g., oral and sublingual products) and even compounded incretin therapies not yet approved by the FDA (e.g., retatrutide). The increasing availability of such products poses important concerns about product safety, quality, and effectiveness (15).
Data on the adverse consequences of compounded GLP-1 RA and dual GIP/GLP-1 RA product use are only beginning to emerge. The actual scope of the problem is likely mu
