What to know about using non-insulin agents in type 1 diabetes
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Susan Weiner, MS, RDN, CDN, CDCES, FADCES, talks with Joshua J. Neumiller, PharmD, CDCES, FADCES, FASCP, about nuances of using SGLT2 inhibitors and GLP-1 receptor agonists in type 1 diabetes, and a therapy for delaying type 1 diabetes onset.
Weiner: People with type 2 diabetes can benefit greatly from using SGLT2 inhibitors and GLP-1 receptor agonists, alone or in addition to insulin. Can people with type 1 diabetes benefit from these agents?
Neumiller: Both SGLT2 inhibitors and GLP-1 receptor agonists have been studied in people with type 1 diabetes as add-on to background insulin therapy to improve glycemia, provide insulin-sparing effects, and aid with weight loss.
Studies with SGLT2 inhibitors in people with type 1 diabetes have reported modest reductions in HbA1c (0.2% to 0.4%), modest weight loss (2-3 kg) and the ability to reduce background bolus and basal insulin doses by approximately 10%. Similarly, studies of GLP-1 receptor agonists as add-on to background insulin demonstrated modest reductions in HbA1c (0.2% to 0.4%), an ability to down-titrate background insulin doses, and average weight loss of about 5 kg.
It is worth noting that the largest studies of GLP-1 receptor agonists in people with type 1 diabetes were performed with liraglutide (Victoza, Novo Nordisk), so greater HbA1c reductions and weight loss would be likely with use of higher potency agents, such as semaglutide (Ozempic and Rybelsus, Novo Nordisk) and tirzepatide (Mounjaro, Eli Lilly).
While early studies of SGLT2 inhibitors and GLP-1 receptor agonists in type 1 diabetes have primarily focused on glycemic, weight and safety outcomes, there is renewed interest in use of these agents for people with type 1 diabetes for potential cardiovascular and kidney benefits.
Weiner: The FDA hasn’t approved any of these agents for use in type 1 diabetes, yet some prescribers use them off-label. What are the risks to people with type 1 diabetes of using these drugs?
Neumiller: There are some important risks that clinicians and people with type 1 diabetes should understand when using an SGLT2 inhibitor or GLP-1 receptor agonist off-label. In the case of SGLT2 inhibitors, an important safety consideration is risk for development of diabetic ketoacidosis. SGLT2 inhibitor-associated DKA can uniquely present as euglycemic DKA, where the individual does not present with severe hyperglycemia as is typically expected with DKA. Risk for DKA with SGLT2 inhibitor use is a key reason this class of medications has not yet been approved for use in type 1 diabetes in the United States. Other important safety considerations with SGLT2 inhibitors include risk for hypoglycemia when used as add-on to background insulin and risk for genital mycotic infections.
In the case of GLP-1 receptor agonists, people with type 1 diabetes can experience many of the same adverse events that are seen among people with type 2 diabetes, such as gastrointestinal effects and injection site reactions. The addition of GLP-1 receptor agonists to background insulin can also place people with type 1 diabetes at risk for hypoglycemia, thus necessitating careful insulin down-titration as informed by the person’s current HbA1c and glycemic patterns.
Weiner: Can you provide some tips or insights into safely using SGLT2 inhibitors and GLP-1 receptor agonists in type 1 diabetes?
Neumiller: For SGLT2 inhibitors, it is important to educate people with type 1 diabetes about situations and factors that can increase their risk for experiencing DKA, such as acute illness, engaging in strenuous exercise, excessive alcohol intake, missing insulin doses, dramatic decreases in carbohydrate intake and insulin pump failure.
Ketone testing is recommended with any symptoms suggestive of DKA, even in the absence of severe hyperglycemia. Several treatment protocols have been suggested for people with type 1 diabetes using SGLT2 inhibitors when they test positive for ketones. STICH is one such protocol: STop the SGLT2 inhibitor, Inject bolus insulin, Consume 30 g carbohydrates and Hydrate. It is recommended that people continue rechecking ketones every 3 to 4 hours and seek emergency medical care if the ketosis does not resolve or if overt DKA symptoms — such as abdominal pain, nausea, vomiting, dyspnea — occur.
For both SGLT2 inhibitors and GLP-1 receptor agonists, considering down-titration of the background insulin regimen is important to avoid hypoglycemia. While SGLT2 inhibitors and GLP-1 receptor agonists carry a low hypoglycemia risk when used as monotherapy in type 2 diabetes, their additive glucose-lowering effects can precipitate hypoglycemia when used in combination with insulin. Individualized adjustment of the background insulin regimen is recommended based on a person’s glycemic profile, patterns and clinical response.
Weiner: Teplizumab-mzwv (Tzield, Sanofi) was approved last year to delay onset of type 1 diabetes in certain people. What can you tell us about its use?
Neumiller: Teplizumab is the first FDA-approved agent to delay the onset of type 1 diabetes in at-risk individuals. Specifically, teplizumab is an anti-CD3 antibody that interferes in the autoimmune destruction of pancreatic beta cells to help delay type 1 diabetes.
The medication is specifically indicated for use by people 8 years and older with stage 2 type 1 diabetes. Stage 2 type 1 diabetes is characterized by abnormal glucose (impaired fasting glucose and/or impaired glucose tolerance) and the presence of at least two positive pancreatic islet autoantibodies. In a key clinical trial supporting the approval of teplizumab, participants taking the medication had a median time to a diagnosis of type 1 diabetes of 48 months compared to a median 24 months in those randomized to placebo. Teplizumab is administered by intravenous infusion daily for 14 days. Each daily treatment is infused over a minimum of 30 minutes. People receiving the infusion can experience infusion-related side effects, so the manufacturer recommends premedication (for at least the first five infusions) with an NSAID or acetaminophen, an antihistamine, and/or an antiemetic. Because teplizumab is an immunosuppressive agent, it should not be used in people with active infections and it is recommended that people receive all age-appropriate vaccinations prior to starting treatment.
References:
- Garg SK, et al. Diabetes Technol Ther. 2018;doi:10.1089/dia.2018.0246.
- Herold K, et al. N Engl J Med. 2020;doi:10.1056/NEJMx190033.
- Holt RIG, et al. Diabetologia. 2021;doi:10.1007/s00125-021-05568-3.
- Tzield [package insert]. Red Bank, NJ: Provention Bio; 2022. Available at: products.sanofi.us/tzield/tzield.pdf.
For more information:
Joshua J. Neumiller, PharmD, CDCES, FADCES, FASCP, is the Allen I. White Distinguished Professor in the department of pharmacotherapy in the College of Pharmacy and Pharmaceutical Sciences at Washington State University. He can be reached at jneumiller@wsu.edu; X (Twitter): @JoshuaNeumiller.
Susan Weiner, MS, RDN, CDN, CDCES, FADCES, is co-author of The Complete Diabetes Organizer and Diabetes: 365 Tips for Living Well. She is the owner of Susan Weiner Nutrition PLLC and is the Endocrine Today Diabetes in Real Life column editor. She can be reached at susan@susanweinernutrition.com; X (Twitter): @susangweiner.
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