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They can reduce levels of inflammatory biomarkers, such as C-reactive protein and inflammatory cytokines (eg, tumor necrosis factor-alpha and interleukin-6).100,101 This positively impacts various pathophysiological conditions, including type 2 diabetes, obesity, and non-alcoholic fatty liver disease.100102 In addition, inflammatory cytokines are reportedly involved in CYP gene expression, with the reduced cytokine levels-mediated by GLP-1 RA administration may alter CYP gene expression, potentially leading to changes in the pharmacokinetics of co-administered drugs (Figure 3).213 Finally, cardiovascular outcome trials have demonstrated that GLP-1 RAs offer beneficial effects on kidney function in type 2 diabetes and decrease the risk of major adverse kidney events in patients with type 2 diabetes and acute kidney disease.99,214 These renoprotective effects are expected to be driven by both direct and indirect mechanisms including reducing albuminuria, reducing inflammation, natriuresis and diuresis induction, and antioxidative effects.215 Moreover, GLP-1 RA treatment reportedly increased renal plasma flow and GFR in rats, leading to natriuresis and diuresis.216 It is known that changes in GFR can affect the elimination of many drugs including narrow therapeutic index drugs (aminoglycosides, lithium, digoxin), diuretics, and nonsteroidal anti-inflammatory drugs.217221 Therefore, pharmacokinetic changes in drugs mediated by increased GFR and renal plasma flow following GLP-1 RA administration may occur, and the impact of its mechanism of action need to be investigated in the future

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The prediction model results further highlight the extent of the change in actual prescriptions supplied at the time of the shortages, with the decrease in semaglutide prescriptions likely to be more than the fall seen in actual semaglutide prescription numbers in the months following the TGA semaglutide shortage announcement

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Quick look at the key results According to clinical trial investigators, orforglipron: Led to significant weight reduction across all dosing groups Showed greater effects at the highest dose levels Helped lower blood sugar in people with diabetes Supported modest improvements in blood pressure Demonstrated mainly mild to moderate side effects The trial results suggest that the once-daily pill performs competitively with early GLP-1 injection studies

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