medwireNews: A comprehensive network meta-analysis has validated the efficacy of 15 glucagon-like peptide (GLP)-1 receptor agonists for the treatment of type 2 diabetes, but also highlighted the risk for gastrointestinal adverse events (AEs).
Jin-Yi Wan (Beijing University of Chinese Medicine, China) and co-authors report in The BMJ that tirzepatide, a combined insulinotropic polypetide receptor and GLP-1 receptor agonist, was the most effective agent for glycemic control relative to placebo, while CagriSema, the combination agent of the GLP-1 receptor agonist semaglutide and the amylin analog cagrilintide, performed best for weight loss.
The analysis included data from 76 randomized controlled trials involving 39,246 adults with type 2 diabetes. At baseline, participants had a mean age of 57 years, a mean diabetes duration of 8.5 years, mean BMI of 31.7 kg/m2, and a mean glycated hemoglobin (HbA1c) level of 8.1% (65 mmol/mol). Just over half (54%) of participants were men. Treatment duration varied from 12 to 78 weeks.
The researchers found that all 15 GLP-1 receptor agonists included in the study significantly reduced HbA1c concentration versus placebo. The greatest reduction occurred with tirzepatide, which was associated with a mean HbA1c difference of 2.10%. This was followed by mazdutide (2.09%), CagriSema (1.80%), orforglipron (1.49%), semaglutide (1.40%), retatrutide (1.32%), dulaglutide (1.09%), liraglutide (1.04%), polyethylene glycol (PEG)-loxenatide (1.04%), albiglutide (1.01%), PEGylated exenatide (0.97%), ITCA 650 pump delivery of exenatide (0.91%), exenatide (0.81%), efpeglenatide (0.74%), and lixisenatide (0.61%).
Tirzepatide also induced the greatest reduction in fasting plasma glucose (FPG) relative to placebo, at a significant mean difference of 3.12 mmol/L (56.28 mg/dL), followed by CagriSema (2.79 mmol/mol; 50.33 mg/dL), orforglipron (2.09 mmol/mol; 37.73 mg/dL), and semaglutide (1.99 mmol/mol; 35.92 mg/dL), all with significant reductions. Treatment with the remaining 11 GLP-1 receptor agonists also resulted in significantly lower FPG levels versus placebo, apart from ITCA 650, for which there was no data available.
The highest mean weight loss versus placebo occurred with CagriSema, at a significant 14.03 kg, followed by tirzepatide (8.47 kg), retatrutide (7.87 kg), orforglipron (4.88 kg), and semaglutide (3.13 kg). No other treatments significantly reduced weight, however.
Semaglutide was the only GLP-1 receptor agonist that significantly reduced the concentration of low-density lipoprotein (0.16 mmol/L) and total cholesterol (0.48 mmol/L) relative to placebo, while PEG-loxenatide was the only treatment that significantly increased high density lipoprotein concentrations (0.16 mmol/L). For triglycerides, significant reductions versus placebo were only observed with ITCA 650 (1.59 mmol/L) and tirzepatide (0.89 mmol/L).
When Wan et al. evaluated AE rates with GLP-1 receptor agonist drugs, “the results implied safety concerns.” Patients given lixisenatide, semaglutide, exenatide, tirzepatide, or liraglutide were all significantly more likely to discontinue treatment due to AEs than those given placebo, at odds ratios of 2.86, 2.61, 2.39, 2.30, and 2.15, respectively. Gastrointestinal events such as diarrhea, nausea, and vomiting were the most reported AEs.
The researchers found that the risk for such events heightened with increasing dose, which they say “raised a warning for high dose administration of GLP-1 [receptor agonist] drugs.”
Wan and team conclude that “GLP-1 [receptor agonists] can be used to reach the desired short term outcome in diabetes management: effective glucose lowering without weight gain.”
However, they stress that their analysis highlights “the risks of gastrointestinal adverse events induced by GLP-1 [receptor agonists], and safety concern is especially warranted for high dose administration.
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