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Importance of GI Events for GLP-1 Receptor Agonists

Study finds fewer T2 patients on exenatide once-weekly reported gastrointestinal adverse events, compared with those on exenatide twice-daily or liraglutide once-daily.

According to findings published in Diabetes, Obesity and Metabolism, patients with type 2 diabetes experienced gastrointestinal events less frequently when treated with a once-weekly dose of the glucagon-like peptide-1 receptor agonist exenatide than a twice-daily dose of exenatide or liraglutide.

“The purpose of the study was to characterize gastrointestinal adverse events (AEs) with different glucagon-like peptide-1 receptor agonists (GLP-1RAs). Gastrointestinal symptoms occur frequently in patients with T2D and represent a substantial cause of morbidity, so it is important to understand the potential effects of medications on these symptoms. GLP-1RAs have been shown to reduce HbA1c and body weight, with low intrinsic risk of hypoglycemia. One potential AE associated with these agents is an increase in gastrointestinal events that is transient in most cases. As such, understanding the specific gastrointestinal AE profile and how it varies across the GLP-1RA class is of interest to patients and physicians, and may be useful in guiding therapy.

Both pooled patient-level data and a single trial were studied in the present analysis, so that data for three separate GLP-1RAs were available. The most common gastrointestinal AEs reported were nausea, vomiting, and diarrhea. Other diagnoses, including dyspepsia and gastroesophageal reflux disease, were also associated with the GLP-1RAs studied, but differed between individual GLP-1RAs and were reported less frequently. The results also suggest that some patients experience both upper and lower gastrointestinal AEs, most commonly nausea followed within 10 days by diarrhea—an observation not previously reported.

Incidences of gastrointestinal AEs differed between the GLP-1RAs investigated. Upper gastrointestinal AEs were less common for exenatide once-weekly, compared with exenatide twice-daily and liraglutide. In contrast, the frequency of lower gastrointestinal AEs was similar across treatment groups, although diarrhea occurred more frequently with liraglutide than with exenatide once-weekly. In head-to-head studies, albiglutide was associated with lower rates of nausea and vomiting compared with liraglutide, while gastrointestinal AE rates were similar for dulaglutide 1.5 mg vs exenatide twice-daily or liraglutide and lower for dulaglutide 0.75 mg vs exenatide twice-daily.

Several studies have suggested a possible relationship between gastrointestinal symptoms and HbA1c in patients with T2D, with symptoms occurring more frequently in patients with poor glycemic control and higher HbA1c levels, possibly because of the impact of long-term poor glycemic control on diabetic complications, such as autonomic neuropathy; however, this association was not observed in the present analyses. Additionally, the presence of gastrointestinal AEs as a whole did not influence changes in HbA1c in response to therapy; however, in the pooled analysis, patients who reported gastrointestinal AEs had significantly greater weight loss than those who did not in both the exenatide once-weekly and exenatide twice-daily groups, although absolute differences in mean weight loss were <1 kg. This is consistent with the outcome of a recent analysis of 12 studies that found that weight loss among exenatide once-weekly-treated patients was greater for those with nausea/vomiting at 24 weeks than those without (−3.1 kg vs −2.2 kg; P < .05).

Although it is commonly perceived that GLP-1RAs cause gastrointestinal AEs by slowing gastric emptying, there is, in general, a weak relationship of symptoms with delayed gastric emptying. Moreover, symptoms occur in the fasted state; therefore, it is likely that centrally mediated effects are important.

Possible reasons for differences in gastrointestinal AEs between GLP-1RAs include differences in drug concentration profiles; the half-life and time to minimal effective and steady-state concentrations are much longer for exenatide once-weekly than for exenatide twice-daily or liraglutide. GLP-1RAs also differ in their ability to cross the blood–brain barrier, with small-molecule GLP-1RAs such as exenatide, liraglutide and lixisenatide being able to enter the brain, whereas larger GLP-1RAs such as albiglutide cannot; it is possible that these differences impact centrally mediated AEs. It was recently established that tachyphylaxis occurs for the effects of exogenous glucagon-like peptide-1 on the slowing of gastric emptying with prolonged exposure. Thus, while short-acting GLP-1RAs such as exenatide twice-daily are likely to have a sustained effect to slow gastric emptying substantially, this effect is likely to be markedly diminished with longer-acting formulations such as exenatide once-weekly or liraglutide. It is unknown whether a similar phenomenon applies to the effects of GLP-1RAs on other gut regions (e.g., the small or large intestine), or for the central effects of these agents.

In conclusion, the present study provides detailed information on the gastrointestinal tolerability of three GLP-1RAs based on patient-level data from the exenatide once-weekly clinical trial program. Gastrointestinal AEs were usually mild and transient and particularly affected the upper gastrointestinal tract, and occurred more frequently with exenatide twice-daily and liraglutide than with exenatide once-weekly. These insights inform physician and patient expectations of potential experiences when initiating GLP-1RA therapy.

Practice Pearls:

  • The most common gastrointestinal AEs reported were nausea, vomiting, and diarrhea.
  • Gastrointestinal events occur less frequently when treated with a once-weekly dose of the glucagon-like peptide-1 receptor agonist exenatide.
  • Albiglutide was associated with lower rates of nausea and vomiting compared with liraglutide.
  • Gastrointestinal AE rates were similar for dulaglutide 1.5 mg vs exenatide twice-daily or liraglutide and lower for dulaglutide 0.75 mg vs exenatide twice-daily.

Reference:

Diabetes, Obesity and Metabolism.