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FDA-APPROVED INDICATIONS Obesity or overweight with cormobidities Tirzepatide (Zepbound) is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with one of the following: BMI 30 BMI 27 in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease) Obstructive sleep apnea Moderate to severe obstructive sleep apnea (OSA) in adults with obesity WEIGHT LOSS The effects of tirzepatide on weight loss in overweight adults were evaluated in the trials below RCT SURMOUNT-1 trial - Tirzepatide vs Placebo for Weight Loss in Obese Patients Without Diabetes, NEJM (2022) [PubMed abstract] The SURMOUNT-1 trial enrolled 2539 adults with a BMI 30 or a BMI 27 and at least one weight-related complication Main inclusion criteria Age 18 years History of unsuccessful dieting BMI 30 or 27 and 1 or more of the following: Hypertension Dyslipidemia OSA CVD Main exclusion criteria Diabetes Previous bariatric surgery Other weight loss drug within 90 days Baseline characteristics Average age 45 years Female sex - 68% Average body weight - 231 lbs (105 kg) Average BMI - 38 Randomized treatment groups Group 1 (630 patients): Tirzepatide 5 mg once weekly Group 2 (636 patients): Tirzepatide 10 mg once weekly Group 3 (630 patients): Tirzepatide 15 mg once weekly Group 4 (643 patients): Placebo once weekly Tirzepatide was initiated at a dose of 2.5 mg once weekly (or matching placebo) and was increased by 2.5 mg every 4 weeks during the dose-escalation period to reach a maintenance dose of up to 15 mg once weekly by week 20 The coprimary end points were the percentage change in body weight from baseline to week 72 and a weight reduction of 5% or more at week 72 Primary outcome: Results In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight

Transport There are few measurements of overall transport rates of the metabolites between the compartments of the model