Chapter 9 — Further Reading
Tier 1 — Verified canonical
Primary sources.
DailyMed — complete approved labeling for Mounjaro (tirzepatide, type 2 diabetes) and Zepbound (tirzepatide, weight management). Same molecule, two labels; comparing them is the fastest way to see how an indication is written.
Drugs@FDA — approval records for tirzepatide (type 2 diabetes 2022; weight management 2023), including review documents.
ClinicalTrials.gov — search "SURMOUNT tirzepatide," "SURPASS tirzepatide," "retatrutide," and "orforglipron." For SURMOUNT-1 specifically, the registry entry lists the analysis populations, which is where the estimand distinction becomes visible in a primary source rather than in commentary.
PubMed — the SURMOUNT and SURPASS trial publications, and the retatrutide Phase 2 report.
On estimands as a methodological standard. The ICH E9(R1) addendum on estimands and sensitivity analysis in clinical trials is the international guidance that formalized this framework. It is freely available, it is dry, and it is the authoritative source for why trials now report multiple analyses. If you want to understand §9.4 properly, this is the document.
CONSORT — the reporting standard for randomized trials, which requires that analysis populations be specified.
Tier 2 — Attributed, specifics unverified
On tirzepatide. A 39-amino-acid peptide, molecular weight approximately 4,800 Da, agonist at both the GIP and GLP-1 receptors, with a sequence based on GIP and a fatty acid modification for albumin binding. Its receptor activity is not balanced between the two targets; whether the specific ratio is optimal is not established.
On SURMOUNT-1. Tirzepatide 15 mg over 72 weeks in adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes, all arms receiving lifestyle intervention: about −21% on the treatment-regimen estimand and about −22.5% on the efficacy estimand. Manufacturer-sponsored.
On SURPASS-2. Tirzepatide versus semaglutide 1 mg in type 2 diabetes over 40 weeks: greater A1C reduction and greater weight loss at all three tirzepatide doses. This book states the direction and does not quote decimals.
On retatrutide. A triple agonist at GLP-1, GIP, and glucagon receptors; approximately −24% body weight at 48 weeks at the highest dose in a Phase 2 trial. Phase 3 programs ongoing as of this writing.
On CagriSema. Cagrilintide (a long-acting amylin analog) combined with semaglutide; late-stage program ongoing as of 2026, with reported results that in some analyses were less dramatic than earlier figures suggested. Specific figures should be checked against current sources, as this book's information is current only to 2026.
On orforglipron. An oral small-molecule GLP-1 receptor agonist in late-stage clinical development as of 2026, not approved, with reported results supporting meaningful glycemic and weight effects. Comparative efficacy against injectable peptide agonists is not settled.
On Phase 2 optimism. That Phase 2 effect sizes systematically exceed subsequent Phase 3 results is well described across therapeutic areas and attributed to small samples, best-dose selection, favorable populations, shorter durations, and regression to the mean. Magnitudes vary by field and no specific figure is quoted here.
On attrition. Roughly nine in ten compounds entering human trials never reach approval, with substantial attrition at the Phase 2 to Phase 3 transition.
Tier 3 — Illustrative and constructed
- Case Study 1's transmission chain is a constructed reconstruction of a documented general pattern. No specific publication, press release, outlet, or post is described or quoted. The stage-0 text is a paraphrase of how such a result is reported, not a quotation.
- The one-molecule-versus-two-drugs comparison diagram, the two-estimand box, the Phase 2 versus Phase 3 comparison, the five-mechanism list, the pipeline table, the six-question protocol, and the comparison worksheet are all this book's own teaching devices.
- The worked semaglutide-versus-tirzepatide comparison is a demonstration constructed for this book from the Tier 1–2 sources above.
- Figure 9.3 renders a real published trial in this book's six-field format; the format is the book's own.
If you only do one thing
Open SURMOUNT-1 on ClinicalTrials.gov and find the analysis populations.
Then read the trial publication's methods section for how the two estimands are defined. It will take twenty minutes and it will be the last time you accept a weight-loss figure without asking which one it is.
If you have another twenty minutes: read the first few pages of the ICH E9(R1) estimand addendum. It is written for statisticians and regulators, it is not enjoyable, and it explains precisely why a trial now has to state what question its analysis is answering — a reform that exists because the ambiguity this chapter describes was causing real confusion in regulatory decisions, not just in journalism.
Looking ahead
Chapter 10 covers GLP-1 agonists beyond weight and glucose: cardiovascular, kidney, liver, sleep apnea, Alzheimer's, and addiction.
Useful preparation: search ClinicalTrials.gov for "semaglutide" and sort by condition. The breadth of what is being tested is itself the chapter's opening observation — and noticing how many of those trials are ongoing rather than completed is the discipline the chapter is built on.