Chapter 9 — Exercises

Items marked † have worked solutions in Appendix M.

A. Recall

9.1 What is a unimolecular dual agonist? Which two receptors does tirzepatide activate?

9.2 † Name the two tirzepatide development programs and the indication each supports.

9.3 State SURMOUNT-1's two headline figures with the dose, duration, population, and estimand for each.

9.4 What did SURPASS-2 compare, in whom, over how long, and what did it find?

9.5 † What three receptors does retatrutide target, and what phase is its reported weight result from?

9.6 What is orforglipron, and why is it not a peptide?

9.7 What is cagrilintide, and how does CagriSema differ architecturally from tirzepatide?

B. Estimands — the core skill

9.8 † Explain the two estimands in your own words as two different questions, not two analyses.

9.9 Why is the efficacy estimand systematically larger? Explain the selection mechanism.

9.10 What does the size of the gap between the two figures tell you? What is lost when only one is reported?

9.11 † For each situation, say which estimand you would want and why: (a) a patient deciding whether to start; (b) a pharmacologist studying the drug's effect on fat mass; (c) a health system forecasting population-level outcomes; (d) a marketing department.

9.12 A source reports "up to 22.5% weight loss." Identify the three separate selections that "up to" is performing.

C. Comparison discipline

9.13 SURPASS-2 compared tirzepatide against semaglutide 1 mg. State three qualifications on what it establishes.

9.14 † A patient asks "which is better?" Decompose that question into at least five distinct questions and note which have different answers.

9.15 Tirzepatide produces more weight loss; semaglutide has SELECT. Explain why the first does not substitute for the second, using Chapter 5 §5.6.

9.16 In the worked comparison, the last row is "what differs that isn't the molecule." Explain why that row does the most work, and give two examples from the semaglutide/tirzepatide comparison.

D. Phase discipline

9.17 † Explain why Phase 2 effect sizes systematically exceed Phase 3 results. Give at least three contributing causes.

9.18 Retatrutide's ~−24% Phase 2 figure is larger than tirzepatide's ~−21% Phase 3 figure. Explain why treating this as a ranking is an error.

9.19 A press release reports a striking result from a trial whose phase is not stated. What should you assume, and why is that assumption reasonable rather than cynical?

9.20 † Apply the six-question pipeline reading protocol to any real pipeline announcement you can find. Record which questions the announcement answers.

E. Mechanism

9.21 Explain why one molecule hitting two receptors is not equivalent to taking two drugs. Give three distinct differences.

9.22 † (Ch 7) GIP was written off for two sensible reasons and adding it helps anyway. State both reasons and evaluate the four candidate explanations from Chapter 7 §7.5.

9.23 Retatrutide adds glucagon receptor agonism, and glucagon raises blood sugar. State the rationale and identify what would have to be true for it to work.

9.24 Both GIP agonists and GIP antagonists are in development for obesity. Is this evidence that the field is confused, or that it is working properly? Argue a position.

F. "Explain this to a friend"

9.25 † Explain to someone why one trial can honestly report two different weight-loss numbers. Under five sentences, no jargon.

9.26 Your friend says "the new one is better — it does 24% versus 21%." Respond accurately without being pedantic.

9.27 Explain why an oral pill version of these drugs would matter, in a way that covers cost, access, and convenience.

G. Judgment

9.28 Orforglipron is a small molecule, not a peptide. §9.8 calls it "the most consequential pipeline entry in the chapter." Do you agree? What would have to be true for that judgment to be wrong?

9.29 † This chapter rates tirzepatide ✅ for weight and explicitly does not rate it for cardiovascular outcomes, while semaglutide carries a ✅ for both. Someone argues this makes semaglutide "better." Evaluate.

9.30 A dual agonist's receptor activity ratio is fixed by its structure and cannot be tuned. Is that a feature or a limitation? Under what circumstances would you want each?

H. Evidence Dossier extension

9.31 † Run the comparison worksheet on two peptides in your dossier used for the same purpose. Complete every row including the last.

9.32 For your comparison, identify at least one difference that is not about the molecules — duration, population, comparator, endpoint, or funder — and estimate how much of the apparent difference it could account for.

9.33 For every peptide in your dossier, record the phase of the most advanced evidence supporting your rating. Then check whether your ratings are consistent with those phases.