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NMR chemical shift perturbation analysis The CSPs were calculated according to the following equation: where H and N indicate the chemical shift changes of the amide proton and nitrogen, respectively, using CcpNMR 2.5 49

Low Risk of Hypoglycemia Unlike other diabetes medications that can cause low blood sugar, GLP-1 injections have a lower risk of hypoglycemia because they increase insulin release in a glucose-dependent manner

Injectable GLP-1 Mechanism: Subcutaneous Injection: When you inject semaglutide or tirzepatide under the skin: Medication forms depot: Creates a small reservoir under the skin Slow absorption: Gradually releases into bloodstream over days Steady drug levels: Maintains consistent therapeutic concentration for one week Nearly complete bioavailability: Almost all medication reaches systemic circulation Predictable dosing: Precise amount of medication absorbed Why This Works So Well: Bypasses digestive system completely No breakdown by stomach acid or enzymes Consistent absorption across patients Once-weekly dosing maintains stable drug levels Can use relatively small doses for maximum effect Oral GLP-1 Mechanism (Rybelsus): Tablet Absorption Process: When you swallow Rybelsus: SNAC creates temporary window: Absorption enhancer raises stomach pH and increases permeability Limited absorption time: 30-minute window before medication moves to small intestine Most medication destroyed: Stomach acid and enzymes break down 99%+ of semaglutide Small amount reaches bloodstream: Less than 1% absorbed Rapid clearance: Daily dosing needed to maintain any therapeutic level Why This Is Challenging: Requires much higher doses (14 mg oral vs 2.4 mg injectable weekly) Strict timing requirements Variable absorption between patients Food, beverages, and other medications interfere with absorption Still less effective despite higher doses Pharmacokinetic Comparison: Absorption Challenges for Oral Peptides: Size Matters: GLP-1 medications are large molecules (peptides with 30-40 amino acids)

Higher chronic cough risk with GLP-1 drugs compared to other diabetes medications Research shows that adults with type 2 diabetes using GLP-1 drugs have a higher chance of developing a chronic cough