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Benefits and Risks of GLP-1 Receptor Agonists Outlined
Boston, MA—Over the last decade, increased understanding of the pathogenesis of type 2 diabetes has aided the development of new and expanding classes of antihyperglycemic medications such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs).
During a satellite symposium at the ADA meeting, a panel of diabetes experts discussed the suggested roles of GLP-1 RAs in multimodal type 2 diabetes management. They focused on their potential benefits and risks for various types of patients, as well as complicating comorbidities. The symposium was supported by an educational grant from AstraZeneca.
Lawrence Blonde, MD, director, Ochsner Diabetes Clinical Research Unit, said that diabetes is more than just glucose control. Along with lifestyle modifications, comprehensive diabetes management includes patients achieving treatment goals for blood pressure, lipids, and body mass index, as outlined in various clinical practice guidelines.
Dr Blonde reviewed the FDA-approved GLP-1 RAs (Table) and discussed the positioning of GLP-1 RAs in type 2 diabetes algorithms. The ADA recommends the addition of metformin as monotherapy when lifestyle efforts alone have not helped achieve or maintain glycemic goal. If hemoglobin A1c (HbA1c) target is not achieved after approximately 3 months, consider dual therapy with metformin and 6 other treatment options, including GLP-1 RA [Diabetes Care. 2015;38(suppl 1):S41-S48]. For each therapy, look at overall efficacy, hypoglycemia, weight, side effects, and cost, he noted.
Following lifestyle modifications, the AACE/ACE algorithm for glycemic control recommends initiating monotherapy with metformin, GLP-1 RA, a sodium-glucose cotransporter 2 inhibitor, a dipeptidyl peptidase-4 (DPP-4) inhibitor, or an alpha-glucosidase inhibitor for patients with entry HbA1c <7.5%. For patients with an HbA1c ≥7.5%, use dual therapy with metformin plus a second agent, such as GLP-1 RA, SGLT- 2, or DPP-4 inhibitors [Endocr Pract. 2015;21(4):438-447].
“I don’t undertand why GLP-1 RAs are not used much more [in patients]. They are much more attractive than insulin,” said Daniel Einhorn, MD, clinical professor of medicine, University of California, San Diego, who addressed if GLP-1 RAs should be the first injectable agent for those with type 2 diabetes.
He cited a study by Diamant et al [Lancet Diabetes Endrocrinol. 2014;2(6):464-473] that reported the 3-year follow-up of DURATION 3, which compared the GLP-1 RA exenatide once weekly versus insulin glargine. The findings showed that the efficacy of once-weekly exenatide was sustained for 3 years. The researchers concluded that GLP-1 RAs “could be a viable long-term injectable treatment option in patients with type 2 diabetes who have not yet started taking insulin.” Dr Einhorn stressed that an important issue with insulin is hypoglycemia. “Hypoglycemia is not irrelevant. Avoiding it is a major principle of AACE guidelines,” he said, noting that hypoglycemia risk with GLP-1 RAs is higher when used with a sulfonylurea or insulin.
The symposium continued with a presentation of evidence on which agents other than metformin clinicians should use in combination regimens with GLP-1 RAs. One study highlighted by Dr Einhorn assessed initial combination therapy with metformin, pioglitazone, and exenatide in drug-naïve patients recently diagnosed with type 2 diabetes [Diabetes Obes Metab. 2015;17(3):268- 275]. Patients receiving triple therapy experienced significantly greater reduction in HbA1c than those receiving conventional therapy (5.95% versus 6.50%, respectively). Despite lower HbA1c values, the patients receiving triple therapy experienced a 7.5-fold lower rate of hypoglycemia versus the conventional therapy group. Triple therapy compared with conventional therapy was also associated with a mean weightloss of −1.2 kg vs 4.1 kg, respectively. Nausea and vomiting has been associated with GLP-1 RAs, according to Jamie A. Davidson, MD, clinical professor of medicine, University of Texas Southwestern Medical Center. Consider theseapproaches to reduce the risk:
• Educate patients on meal size, eating pace, and dose timing relative to meals
• Use incremental dose titration, particularly with shorter-acting agents
• Prescribe short-term antiemetic therapy for select patients.
Because cases of acute pancreatitis have also been reported, consider treatments other than GLP-1 RAs in patients with such a history.
Postmarketing reports of pancreatitis and pancreatic cancer in patients taking incretin therapy have been a concern of the FDA and European Medicines Agency (EMA). In 2014, both agencies conducted a parallel, independent safety analysis and agreed that “assertions of a causal association are inconsistent with the current data.” The FDA and EMA also stated, “Product information and labeling reflect current understanding of risk.” Both agencies continue to investigate safety signals and data from ongoing trials [N Engl J Med. 2014;370(9):794- 797].—Eileen Koutnik-Fotopoulos
