Chapter 8 — Exercises
Items marked † have worked solutions in Appendix M.
A. Recall
8.1 Name semaglutide's three modifications, their positions, and what each accomplishes.
8.2 † Name the four trial programs and state what each established.
8.3 What is A1C, and why is it described as a surrogate?
8.4 State the STEP 1 and STEP 2 weight results with their populations attached.
8.5 † State the SELECT result in relative terms, in absolute terms, and with its population and duration.
8.6 What does the boxed warning describe, and in what species was the finding made?
8.7 Which brand names correspond to which formulation and indication?
B. Populations and trials
8.8 † STEP 1 and STEP 2 used the same drug, dose, and duration and produced different results. State the difference, give at least two contributing explanations, and say what error quoting one for the other produces.
8.9 SUSTAIN 6 was designed to rule out cardiovascular harm and found benefit. Why are cardiovascular outcome trials required for new diabetes drugs, and why does finding benefit in a safety trial matter more than finding it in an efficacy trial would?
8.10 Both STEP arms received intensive lifestyle support. Explain the two opposite ways this affects interpretation, and state what the trial result actually describes.
8.11 † SELECT moved semaglutide from a drug that improves a risk factor to one that reduces events. Explain why that distinction matters, using Chapter 5 §5.6.
8.12 The trials were nominally double-blind, but gastrointestinal effects allow participants to guess assignment. Explain the specific problem this creates, and which endpoints it most and least affects.
C. Adverse effects
8.13 † Write the accurate version of the thyroid warning — neither alarmist nor dismissive — in under 100 words, suitable for saying to a patient.
8.14 The pancreatitis signal was raised early and not confirmed at the feared magnitude. Is that a success of pharmacovigilance, a failure of the initial alarm, or neither?
8.15 Aspiration under anesthesia emerged from post-marketing experience rather than from Phase III. Explain why Phase III could not have detected it, using Chapter 5 §5.4.
8.16 † Explain why the gastrointestinal effects are described as "the mechanism overshooting" rather than as an unrelated side effect, and what follows from that for how a patient should think about them.
D. Muscle and body composition
8.17 Lean mass is lost during weight loss on these drugs. Explain why this is not specific to the drug class, and identify the population in which it is most concerning.
8.18 † "Lean mass is a surrogate." State what it is a surrogate for, and explain why trials finding improved physical function complicate the simple concern.
8.19 Design a study that would establish whether lean mass loss on GLP-1 therapy produces meaningful functional decline in older adults. What is your population, endpoint, comparator, and duration?
E. Discontinuation
8.20 † Explain why weight returns on discontinuation, using the override-versus-replace rule.
8.21 "This is chronic therapy, not a course of treatment." Explain what changes as a consequence — for the decision to start, for cost, and for how the drug should be described.
8.22 §8.9 argues that expecting permanent change after stopping is an expectation applied to no other chronic therapy. Evaluate this argument. Is the comparison to antihypertensives fair?
8.23 † A person stops the drug because they cannot afford it, and regains weight. Is that a treatment failure? Whose? Argue carefully.
F. "Explain this to a friend"
8.24 † Your friend says "Ozempic makes you lose 15% of your body weight." State what you would ask and then what you would say.
8.25 Explain to someone why the drug has a black box warning for thyroid cancer and why that is not a reason for most people to panic — without being dismissive.
8.26 Explain why the weight comes back, in a way that does not sound like the drug failed.
G. Judgment
8.27 This chapter says taking a drug seriously "in both directions" is harder than it sounds. Identify the two narratives it is resisting and say which you find more tempting.
8.28 † SELECT does not establish benefit in primary prevention. Someone argues that the benefit "obviously" extends to lower-risk people. Evaluate the argument using Chapter 5, and state what would settle it.
8.29 The chapter gives semaglutide three ✅ ratings and declines to rate primary prevention. Explain why declining to rate is a substantive act rather than an evasion.
H. Evidence Dossier extension
8.30 † Write one complete twelve-field entry for a peptide in your dossier, to the standard of the worked semaglutide entry.
8.31 Compare your entry to the model. Identify where yours is thinner because of your effort and where it is thinner because of the compound's evidence base. Write one paragraph distinguishing them.
8.32 For your entry, check whether Field 5's "what does not exist" line is longer than the rest of Field 5. If so, say what that tells you.