Pharmaceutical Phenomena

Recent studies shed light on the safety and efficacy of diabetes medications

GLP-1 receptor agonists, SGLT2 inhibitors, and DPP4 inhibitors were all scrutinized in new research presented at ENDO 2024. While most of the results were good news for the impact of medications for people with type 2 diabetes, clinicians prescribing these medications should be aware of specific side effects in certain populations as well as obstacles regarding patient access.

Research presented at ENDO 2024 in June shed more light on new or overlooked effects — mostly good — of medications prescribed to combat diabetes, such as GLP-1 receptor agonists, SGLT2 inhibitors, and DPP4 inhibitors. Spoiler alert: the GLP-1 receptor agonists may be emerging as the best in show.

The researchers highlighted here were unanimous in their praise of the meeting, citing the quality of the sessions, the excellent networking opportunities, and the numerous resources the meeting makes available.

GLP-1 Receptor Agonists and SGLT-2 Inhibitors

More good news on the diabetes medications front comes from Alexander Kutz, MD, MPH, MSc, a research fellow in the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, at Brigham and Women’s Hospital and Harvard Medical School in Boston, Mass., and team who aimed to understand the effectiveness of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors in reducing cardiovascular and liver events in patients with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD).

“GLP-1 receptor agonists are contraindicated in patients with a history of pancreatitis … suggesting an increased risk of acute pancreatitis when using these medications. This led to caution in prescribing these drugs to such patients. Therefore, this study aimed to assess the risk of recurrent acute pancreatitis in this population, with the goal of informing safer prescribing practices and ensuring that these patients could also benefit from GLP-1 receptor agonists.” — Mahmoud Nassar, MD, PhD, Department of Medicine fellow, Division of Endocrinology, Diabetes, and Metabolism, Jacobs School of Medicine and Biomedical Sciences University at Buffalo, Buffalo, N.Y.

“This is crucial as MASLD is becoming more prevalent and poses significant health risks, yet has few effective treatment options,” Kutz explains. “The scarcity of therapies highlights the need to explore antidiabetic medications’ potential benefits for MASLD, aiming to expand the therapeutic spectrum and improve patient outcomes.”

Their large cohort design study used data from Medicare and a major U.S. health insurance database from 2013 to 2022 to compare the effectiveness of GLP-1 receptor agonists, SGLT-2 inhibitors, and dipeptidyl peptidase-4 (DPP4) inhibitors among a diverse population of patients with type 2 diabetes and MASLD.

“A weighting approach was employed to balance patient characteristics across study groups, effectively emulating two target trials,” Kutz says. “The data analysis focused on the impact of these medications on cardiovascular and liver-related events, ensuring robust and reliable results that provide valuable insights into the therapeutic potential of these antidiabetic drugs for patients with MALSD.”

They found that those using GLP-1 receptor agonists or SGLT-2 inhibitors had fewer cardiovascular and severe liver events than those using DPP4 inhibitors. Other types of adverse events occurred with similar frequency among the three drug classes, suggesting that the GLP-1 receptor agonists or SGLT-2 inhibitors are overall safe in the setting of MASLD.

Multiple mechanisms are probably at play in why and how GLP-1 receptor agonists and SGLT-2 inhibitors are more effective that DPP4 inhibitors in preventing heart and liver-related events in diabetes and MASLD. “GLP-1 receptor agonists improve glycemic control, reduce inflammation, and have beneficial effects on weight and lipid profiles,” Kutz says. “SGLT-2 inhibitors reduce blood glucose levels by promoting glycosuria, which lowers blood pressure, reduces body weight, and decreases cardiovascular stress. Both drug classes also exhibit direct protective effects on the liver by reducing fat accumulation (induction of lipolysis) and inflammation, which are not observed with DPP4 inhibitors. These combined benefits may explain their superior outcomes in preventing cardiovascular and liver-related events.”

Clinicians should be aware of the significant benefits of GLP-1 receptor agonists and SGLT-2 inhibitors when prescribing diabetes medications. “As the prevalence of MASLD continues to rise, it’s crucial for clinicians to incorporate these drugs into treatment plans for high-risk patients to mitigate long-term health risks and improve overall patient outcomes,” Kutz says. Moreover, a growing body of evidence is revealing other health benefits these drugs confer, providing even more support for including them in a diabetes management toolkit.

“Additionally, it will be interesting to see how effective these drugs will be as compared with the recently approved thyroid b-receptor agonist,” Kutz says.

GLP-1 Receptor Agonists and Pancreatitis Risk

Yet another study by Mahmoud Nassar, MD, PhD, Department of Medicine fellow in the Division of Endocrinology, Diabetes, and Metabolism in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo in Buffalo, N.Y., and team looked at the effects of GLP-1 receptor agonists prescribed for type 2 diabetes and obesity on pancreatitis recurrence, using TriNetX a database comprising information from more than 100,000,000 patients in 15 countries.

“GLP-1 receptor agonists improve glycemic control, reduce inflammation, and have beneficial effects on weight and lipid profiles. SGLT-2 inhibitors reduce blood glucose levels … which lowers blood pressure, reduces body weight, and decreases cardiovascular stress. Both drug classes also exhibit direct protective effects on the liver by reducing fat accumulation … and inflammation, which are not observed with DPP4 inhibitors. These combined benefits may explain their superior outcomes in preventing cardiovascular and liver-related events.” — Alexander Kutz, MD, MPH, MSc, research fellow, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.

“This study was motivated by my interest in research and commitment to using current resources and technologies to improve patient care and support evidence-based medicine,” Nassar says. “TriNetX is an exceptional tool with a vast database of patients, providing an invaluable resource for answering clinical questions.” Specifically, the researchers identified 638,501 individuals with a history of acute pancreatitis and taking either a GLP-1 receptor agonist, an SGLT2 inhibitor, or a DPP4 inhibitor to compare their risk of acute pancreatitis recurrence, having noted that some of these patients were potentially missing out on the benefits of GLP-1 receptor agonists.

“Currently, GLP-1 receptor agonists are contraindicated in patients with a history of pancreatitis due to post-marketing reports suggesting an increased risk of acute pancreatitis when using these medications,” Nassar says. “This led to caution in prescribing these drugs to such patients. Therefore, this study aimed to assess the risk of recurrent acute pancreatitis in this population, with the goal of informing safer prescribing practices and ensuring that these patients could also benefit from GLP-1 receptor agonists.”

The mechanism underlying GLP-1 receptor agonists’ potentially safer profile as compared to SGLT2 and DPP4 inhibitors may stem from their anti-inflammatory properties, especially the reduction of hyperglycemia-induced inflammation, and their benefits in weight loss, explained Nassar. “Collectively, this may contribute to a lower risk of acute pancreatitis recurrence,” he says.

This could be big news for this drug class, potentially leading to expanded use of GLP-1 receptor agonists. Nassar moreover believes that the findings may warrant reassessment of current guidelines and could translate into more personalized treatment approaches.

GLP-1 Receptor Agonists in the Pediatric Population

Amidst all the hype about GLP-1 receptor agonists, Gabriel Castano, MD, of Texas Children’s Hospital Baylor College of Medicine in Houston, Texas, and team shared some less positive findings — not about the medications themselves but rather about access and adherence.

They studied 599 patients with an average age of 15 years who had been prescribed a GLP-1 receptor agonist from 2019 to 2023 for type 2 diabetes and weight management, reviewing insurance approval rates, adherence, dose titration, and side effects. Castano says they undertook this descriptive study because “there are no real-world studies that have looked at children; all that we know is what the clinical trials tell us, and real life is not a clinical trial.”

They found that private insurance denied coverage of 37% of the prescriptions for type 2 diabetes, and Medicaid denied 27%. In patients with obesity only, private insurance denied 64% of prescriptions and Medicaid 70%. The upshot is that, without this insurance coverage, patients may not be able to afford a medication that could improve their health.

“There are no real-world studies that have looked at children; all that we know is what the clinical trials tell us, and real life is not a clinical trial,” regarding a trial that studied almost 600 patients prescribed a GLP-1 receptor agonist for type 2 diabetes and weight management.  — Gabriel Castano, MD, Texas Children’s Hospital Baylor College of Medicine, Houston, Texas

However, Castano says that lack of insurance coverage is not the only barrier for pediatric patients to take GLP-1 receptor agonists because many pediatric patients struggle with medication adherence; others are lost to follow up. On these points, he urges clinicians to have a system in place to be able to track and motivate patients.

Dose titration is another potential barrier when it is not well understood by patients and leads to lower treatment doses and ultimately less overall efficacy, especially because the intended effects of GLP-1 receptor agonists are dose-dependent. “Lastly,” said Castano, “we need to be on the lookout for side effects like pancreatitis, which is an associated risk in type 2 diabetes, as well as some that have not been described, and reported them if observed.” It should be noted that most patients in the study experienced mild to no side effects.”

Horvath is a freelance writer based in Baltimore, Md. She wrote about oral testosterone replacement therapy for men in the October issue.