Chapter 9 — Quiz
Twenty-two questions.
Multiple choice
1. Tirzepatide activates:
a) GLP-1 only b) GIP and GLP-1 receptors c) GLP-1 and glucagon d) amylin and GLP-1
2. "Unimolecular dual agonist" means:
a) two drugs in one injection b) one molecule activating two receptors c) a drug taken twice daily
d) a molecule with two active sites of identical function
3. Tirzepatide's sequence is based on:
a) GLP-1 b) GIP c) glucagon d) amylin
4. SURMOUNT-1's 15 mg result at 72 weeks was approximately:
a) −10% / −12% b) −21% (treatment-regimen) / −22.5% (efficacy) c) −15% / −24% d) a single −22.5%
5. The efficacy estimand is systematically larger because:
a) it uses a higher dose b) it excludes participants who discontinued, who stopped for reasons
correlated with doing badly c) it runs longer d) it includes more people
6. The treatment-regimen estimand answers:
a) what happens if you take it as prescribed b) what happens if you are prescribed it, counting
everyone c) what happens at the highest dose d) what happens in responders only
7. SURPASS-2 compared tirzepatide against:
a) placebo b) semaglutide 2.4 mg c) semaglutide 1 mg in type 2 diabetes d) insulin
8. Retatrutide targets:
a) GLP-1 and GIP b) GLP-1, GIP, and glucagon receptors c) GLP-1 and amylin d) GIP and glucagon
9. Retatrutide's ~−24% weight result is from:
a) Phase 1 b) Phase 2 c) Phase 3 d) post-marketing data
10. Phase 2 effect sizes compared with subsequent Phase 3 results are:
a) systematically smaller b) systematically larger c) identical d) unrelated
11. CagriSema differs architecturally from tirzepatide in that it is:
a) one molecule, two receptors b) two molecules in one injection c) an oral tablet d) a small
molecule
12. Orforglipron is:
a) a peptide GLP-1 agonist b) an oral small-molecule GLP-1 receptor agonist c) a GIP antagonist
d) an amylin analog
13. "Up to 22.5%" selects for:
a) the highest dose only b) the highest dose, the efficacy estimand, and the non-diabetic population
c) the longest duration d) the placebo arm
14. Tirzepatide was approved for weight management in:
a) 2019 b) 2021 c) 2022 d) 2023
15. As of 2026, tirzepatide's cardiovascular outcomes evidence is:
a) equivalent to semaglutide's b) stronger than semaglutide's c) ongoing, not yet established
d) negative
16. Both GIP agonists and GIP antagonists being pursued for obesity indicates:
a) fraud b) that the mechanism is not understood c) that both must work d) a regulatory error
Short answer
17. Explain the two estimands as two different questions rather than two analyses.
18. State three qualifications on what SURPASS-2 establishes.
19. Give three reasons Phase 2 results systematically exceed Phase 3 results.
20. Explain why one molecule hitting two receptors differs from taking two drugs.
Applying the rating discipline
21. Retatrutide is rated ⚠️ despite a larger headline figure than an approved ✅ drug. Explain, and
state what would move it.
22. Tirzepatide receives ✅ for weight loss and is not rated for cardiovascular outcomes.
Explain why "produces more weight loss" does not justify extending the rating.
Answer key
**1.** b. **2.** b. **3.** b. **4.** b. **5.** b. **6.** b. **7.** c. **8.** b. **9.** b. **10.** b.
**11.** b. **12.** b. **13.** b. **14.** d. **15.** c. **16.** b.
**17.** **Treatment-regimen:** "What happens if a doctor prescribes this?" It counts everyone as
randomized, including those who discontinued, and therefore reflects the real world in which some
people will not tolerate a drug. **Efficacy:** "What happens if you actually take it, as prescribed,
for the full period?" It restricts to those who remained on treatment and reflects the biological
effect more directly. **Both are pre-specified and both are correct.** They differ because they are
answers to different questions, not because one is a better analysis of the same question.
**18.** (1) **Comparator dose** — semaglutide 1 mg was the approved diabetes dose at the time; higher
semaglutide doses exist and were not the comparator. (2) **Indication** — this was a *diabetes* trial,
and extending it to weight management in people without diabetes is a population swap. (3) **Funder**
— manufacturer-sponsored by the maker of the winning drug, which changes the weight of the evidence
and specifically directs attention to whether the comparator was used at an appropriate dose.
**19.** Any three of: **small samples** produce more variable estimates, and the striking ones get
reported; **favorable populations** are often selected in Phase 2; **best-dose selection** — several
doses are studied and the best-performing is quoted; **regression to the mean** — an unusually good
result is more likely to be followed by a less good one; and **shorter duration**, which can flatter
an effect that attenuates.
**20.** Three differences. **One pharmacokinetic profile** — both receptors are engaged in the same
temporal pattern always, rather than two drugs with different half-lives and peaks producing a ratio
that drifts. **A fixed activity ratio** — determined by the molecule's structure and unchangeable
without making a different molecule, whereas two drugs can be dosed independently. **One product** —
one injection, one adherence problem, one cost, rather than two of each. The engineering consequence is
that a dual agonist is a bet on a specific ratio, and getting that ratio right is the design problem.
**21.** **Retatrutide is ⚠️ because its result is a Phase 2 result.** Phase 2 is designed to detect a
*signal*, not to measure an effect: small samples, often favorable populations, best-dose selection,
and regression to the mean all push Phase 2 figures systematically above the Phase 3 results that
follow. A −24% Phase 2 number and a −21% Phase 3 number are not comparable quantities, and ranking them
is the most common error in coverage of this pipeline. **What would move it:** completed, adequately
powered Phase 3 trials in the target population reporting both estimands, plus a cardiovascular
outcomes trial. Either could move it to ✅ — or could reduce the effect substantially.
**22.** Because weight is a **surrogate endpoint** and cardiovascular events are a **hard endpoint**,
and the whole lesson of Chapter 5 §5.6 — and of obesity pharmacology's history in Chapter 8's Case
Study 2 — is that the arrow from surrogate to outcome is a hypothesis rather than a guarantee. Drugs
have repeatedly reduced weight and harmed patients. Semaglutide's cardiovascular ✅ rests on SELECT,
which measured events directly in a defined population over about three years. Tirzepatide's outcomes
program is ongoing as of this writing. **Extending a ✅ from a surrogate to an outcome is precisely
the reasoning error the rating system exists to prevent**, and doing it on the strength of a *larger*
surrogate effect would be worse, not better — because it treats the magnitude of a surrogate change as
though it settled a question the surrogate cannot answer.