Chapter 8 — Quiz

Twenty-four questions.

Multiple choice

1. Semaglutide's position-8 modification (Ala→Aib) primarily: a) increases receptor affinity b) blocks DPP-4 cleavage c) enables albumin binding d) improves oral absorption

2. Ozempic and Wegovy differ in: a) active molecule b) dose and approved indication c) route d) manufacturer

3. STEP 1 studied adults with overweight or obesity: a) with type 2 diabetes b) without diabetes c) with cardiovascular disease d) over 65 only

4. STEP 1's mean weight change at 68 weeks was approximately: a) −5% b) −10% c) −15% d) −25%

5. STEP 2, in adults with type 2 diabetes, produced approximately: a) −5% b) −10% c) −15% d) −22%

6. SELECT's population was adults with: a) type 2 diabetes b) established cardiovascular disease and overweight/obesity, without diabetes c) no cardiovascular disease d) severe obesity only

7. SELECT's cardiovascular result was approximately: a) 20% relative, ~1.5 percentage points absolute b) 20% absolute c) 1.5% relative d) 50% relative

8. Oral semaglutide's bioavailability is approximately: a) 1% b) 15% c) 40% d) 90%

9. SUSTAIN 6 was designed primarily to: a) demonstrate weight loss b) rule out cardiovascular harm c) test oral delivery d) compare against insulin

10. The class's boxed warning is based on: a) human trial data b) rodent thyroid C-cell tumors c) post-marketing reports d) case-control studies

11. The boxed warning contraindicates use in people with: a) any thyroid condition b) personal or family history of medullary thyroid carcinoma or MEN2 c) hypothyroidism d) goiter

12. Gastrointestinal side effects arise primarily from: a) an allergic response b) slowed gastric emptying plus hindbrain receptor activation c) the fatty acid modification d) hypoglycemia

13. Titration exists primarily to: a) improve efficacy b) allow gastrointestinal tolerance to develop c) reduce cost d) meet regulatory requirements

14. Aspiration risk under anesthesia emerged from: a) Phase I b) Phase III c) post-marketing experience d) animal studies

15. Lean mass loss on GLP-1 therapy is: a) unique to this drug class b) a property of weight loss generally c) not observed d) always functionally significant

16. After discontinuation, weight: a) remains stable b) continues to fall c) substantially returns d) returns only in diabetics

17. The chapter argues weight regain after stopping: a) shows the drug does not work b) is expected physiology and changes what the drug is for c) is a manufacturing issue d) occurs only with poor adherence

18. The pancreatitis signal has been: a) confirmed at high magnitude b) examined extensively and not established at the feared magnitude c) ignored d) shown to be protective

Short answer

19. Explain why STEP 1 and STEP 2 differ, and what error quoting one for the other produces.

20. State the accurate version of the thyroid warning in under 60 words.

21. Explain why SELECT mattered more than the STEP weight results, using the surrogate/hard endpoint distinction.

22. Explain why the weight returns, using the override-versus-replace rule.

Applying the rating discipline

23. This chapter issues three ✅ ratings and explicitly declines to rate one claim. Name the unrated claim and explain why declining is substantive rather than evasive.

24. The weight-loss ✅ states that regain after discontinuation does not change the rating. Explain the reasoning, and identify what would.

Answer key **1.** b. **2.** b. **3.** b. **4.** c. **5.** b. **6.** b. **7.** a. **8.** a. **9.** b. **10.** b. **11.** b. **12.** b. **13.** b. **14.** c. **15.** b. **16.** c. **17.** b. **18.** b. **19.** STEP 1 studied adults with overweight or obesity **without diabetes** and produced about −15% at 68 weeks. STEP 2 used the same drug, dose, and duration in adults **with type 2 diabetes** and produced about −10%. Contributing explanations include altered incretin responsiveness in type 2 diabetes, concurrent weight-promoting diabetes medications such as insulin and sulfonylureas, and differences in metabolic state. **Quoting the −15% figure to a person with type 2 diabetes is a population swap** — it sets an expectation the evidence does not support for them, and it is the most common error in popular coverage of this drug. **20.** In rodents, GLP-1 receptor agonists produced thyroid C-cell tumors. Rodent thyroid C-cells express far more GLP-1 receptors than human ones, giving a plausible reason the finding may not transfer, and no human increase has been demonstrated. The drug is nonetheless contraindicated in people with a personal or family history of medullary thyroid carcinoma or MEN2, where the theoretical concern concentrates. **21.** The STEP weight results establish a change in a **surrogate**: weight stands in for the outcomes weight is supposed to affect. That surrogate is better supported than most, but obesity pharmacology has a history of drugs that improved weight and harmed patients — which is precisely why the surrogate is insufficient. SELECT measured a **hard endpoint** (cardiovascular death, myocardial infarction, stroke) in a population without diabetes, over about three years. That converts "reduces a risk factor" into "reduces events," which is a categorically stronger claim and is why coverage decisions and guideline positions shifted afterward. **22.** Semaglutide **overrides an intact system** rather than replacing an absent one. Appetite regulation is working; the drug outweighs it. The set point was never removed. When the drug stops, the override is removed and the intact system resumes, so weight substantially returns. Compare insulin in type 1 diabetes, which **replaces** an absent signal — there is no intact system being overridden, no counter-regulation provoked, and the effect persists indefinitely. Chapter 2 §2.8 predicted this pattern, and Chapter 13 shows a long history of appetite drugs defeated by it. **23.** The unrated claim is **cardiovascular benefit in primary prevention** — people **without** established cardiovascular disease. SELECT studied people who already had it, so the trial says nothing about a lower-risk population. **Declining is substantive because:** the absolute benefit of any intervention scales with baseline risk (Chapter 5 §5.8). In a lower-risk population, the same relative reduction would produce a much smaller absolute benefit, and the same adverse effects. Extending the rating would assume a benefit whose magnitude is unknown against harms whose magnitude is known — which is exactly the reasoning error the rating system exists to prevent. **A rating that covers claims it was not built for is worse than no rating**, because the reader cannot tell which parts were earned. **24.** **The reasoning:** the claim being rated is that semaglutide produces substantial sustained weight loss **for as long as treatment continues.** Regain after stopping is consistent with that claim, is predicted by the physiology, and is the normal behavior of chronic therapy — an antihypertensive's effect also ends on discontinuation, and nobody counts that against it. Regain changes what the drug is *for* (chronic management rather than a completed course), which is a different and important fact, but it is not evidence about whether the drug works while taken. **What would change it:** long-term data showing that the effect does not persist **during continued treatment** — that is, tolerance or escape while still on the drug — or a serious harm emerging with multi-year use at a rate outweighing the benefit.