Hypoglycemia and weight gain are well-known adverse effects that can result from insulin and sulfonylureas in patients with type 2 diabetes mellitus (T2DM).1,2 Insulin and sulfonylurea medications can cause additional weight gain in patients who are overweight or obese, which can increase the burden of diabetes therapy with added medications, raise the risk of hypoglycemia complications, and raise atherosclerotic cardiovascular disease risk factors.3 Although increasing the insulin or sulfonylurea dose is an option health care practitioners or pharmacists have, this approach can increase the risk of hypoglycemia, especially in older adults, such as the veteran population, which could lead to complications, such as falls.2
Previous studies focusing on hypoglycemic events in patients with T2DM showed that glucagon-like peptide-1 (GLP-1) agonist monotherapy has a low incidence of a hypoglycemic events. However, when a GLP-1 agonist is combined with insulin or sulfonylureas, patients have an increased chance of a hypoglycemic event.3-8 According to the prescribing information for semaglutide, 1.6% to 3.8% of patients on a GLP-1 agonist monotherapy reported a documented symptomatic hypoglycemic event (blood glucose ≤ 70 mg/dL), based on semaglutide dosing. 9 Patients on combination therapy of a GLP-1 agonist and basal insulin and a GLP-1 agonist and a sulfonylurea reported a documented symptomatic hypoglycemic event ranging from 16.7% to 29.8% and 17.3% to 24.4%, respectively.9 The incidences of hypoglycemia thus dramatically increase with combination therapy of a GLP-1 agonist plus insulin or a sulfonylurea.
When adding a GLP-1 agonist to insulin or a sulfonylurea, clinicians must be mindful of the increased risk of hypoglycemia. Per the warnings and precautions in the prescribing information of GLP-1 agonists, concomitant use with insulin or a sulfonylurea may increase the risk of hypoglycemia, and reducing the dose of insulin or a sulfonylurea may be necessary.9-11 According to the American College of Cardiology guidelines, when starting a GLP-1 agonist, the insulin dose should be decreased by about 20% in patients with a well-controlled hemoglobin A1c (HbA1c).12
This study aimed to determine the percentage of patients who required dose reductions or discontinuations of insulin and sulfonylureas with the addition of a GLP-1 agonist. Understanding necessary dose reductions or discontinuations of these concomitant diabetes agents can assist pharmacists in preventing hypoglycemia and minimizing weight gain.
Methods
This clinical review was a single-center, retrospective chart review of patients prescribed a GLP-1 agonist while on insulin or a sulfonylurea between January 1, 2019, and September 30, 2022, at the Wilkes-Barre Veterans Affairs Medical Center (WBVAMC) in Pennsylvania and managed in a pharmacist-led patient aligned care team (PACT) clinic. It was determined by the US Department of Veterans Affairs Office of Research and Development that an institutional review board or other review committee approval was not needed for this nonresearch Veterans Health Administration quality assurance and improvement project. Patients aged ≥ 18 years were included in this study. Patients were excluded if they were not on insulin or a sulfonylurea when starting a GLP-1 agonist, started a GLP-1 agonist outside of the retrospective chart review dates, or were prescribed a GLP-1 agonist by anyone other than a pharmacist in their PACT clinic. This included if a GLP-1 agonist was prescribed by a primary care physician, endocrinologist, or someone outside the VA system.
The primary study outcomes were to determine the percentage of patients with a dose reduction of insulin or sulfonylurea and discontinuation of insulin or a sulfonylurea at intervals of 0 (baseline), 3, 6, and 12 months. Secondary outcomes included changes in HbA1c and body weight measured at the same intervals of 0 (baseline), 3, 6, and 12 months.
Data were collected using the VA Computerized Patient Record System (CPRS) and stored in a locked spreadsheet. Descriptive statistics were used to analyze the data. Patient data included the number of patients on insulin or a sulfonylurea when initiating a GLP-1 agonist, the percentage of patients started on a certain GLP-1 agonist (dulaglutide, liraglutide, exenatide, and semaglutide), and the percentage of patients with a baseline HbA1c of < 8%, 8% to 10%, and > 10%. The GLP-1 agonist formulary was adjusted during the time of this retrospective chart review. Patients who were not on semaglutide were switched over if they were on another GLP-1 agonist as semaglutide became the preferred GLP-1 agonist.
Patients were considered to have a dose reduction or discontinuation of insulin or a sulfonylurea if the dose or medication they were on decreased or was discontinued permanently within 12 months of starting a GLP-1 agonist. For example, if a patient who was administering 10 units of insulin daily was decreased to 8 but later increased back to 10, this was not counted as a dose reduction. If a patient discontinued insulin or a sulfonylurea and then restarted it within 12 months of initiating a GLP-1 agonist, this was not counted as a discontinuation.