GLP-1 & GIP Medications, Explained: Injections, Pills, and What They Can’t Do

FDA-approved weekly injections and daily pills have changed the field of weight management and metabolic health — and spawned a lot of marketing along with it. A concise, fully-cited look at how these medications work, what the trial data shows, and why a real evaluation belongs before a prescription.

By Jacinta Wangui, DNP, FNP · Evolving eHealth

GLP-1 and GIP receptor agonists have moved from endocrinology journals to dinner-table conversation faster than almost any drug class in modern medicine. The pharmacology is genuinely remarkable — but the marketing behind it often outruns the evidence. Here’s what the data actually shows, and what it doesn’t.

How They Work

GLP-1 and GIP are gut hormones (“incretins”) released after eating that amplify insulin release, suppress glucagon, slow gastric emptying, and reduce appetite via receptors in the brain. GLP-1 receptor agonists mimic this signal but resist the rapid breakdown that limits the natural hormone to a two-minute half-life. Tirzepatide adds GIP co-agonism on top of GLP-1, and investigational retatrutide adds a third target, glucagon receptor agonism — each addition appears to boost weight loss further, though the precise mechanism of GIP’s contribution in humans is still being studied.

What’s Actually FDA-Approved

Not approved: Retatrutide (triple agonist) remains investigational; Lilly plans an FDA filing in Q1 2027 [13].

The Efficacy Data

• Semaglutide (STEP 1, NEJM 2021): 14.9% mean weight loss at 68 weeks vs. 2.4% placebo [1].
• Tirzepatide (SURMOUNT-1, NEJM 2022): 16.0–22.5% weight loss by dose vs. 2.4% placebo [4].
• Oral semaglutide 25mg (OASIS 4): 16.6% mean weight loss with adherence [9].
• Orforglipron (ATTAIN program): 12–15% weight loss [11,12].
• Zepbound for OSA (SURMOUNT-OSA): ~5x greater reduction in breathing disruptions than placebo; up to 50% remission at one year [10].
• Semaglutide cardiovascular outcomes (SELECT, NEJM 2023): 20% reduction in major cardiac events (HR 0.80, 95% CI 0.72–0.90) in 17,604 adults with cardiovascular disease, plus a 73% reduction in incident diabetes [5,6].

What They Can’t Do

They don’t cure obesity. In the STEP 1 extension, patients regained two-thirds of lost weight within a year of stopping — net loss fell from 17.3% to 5.6% [3]. For most patients this is long-term therapy, not a short course.

Some of the loss is muscle. Lean mass makes up roughly 25–31% of total weight lost across the class, which is the clinical case for resistance training and adequate protein, not a reason to avoid treatment [15,16].

Real risks require real screening: a boxed warning for thyroid C-cell tumors (contraindicated with personal/family history of medullary thyroid carcinoma or MEN2) [17,18]; a 28% increased relative risk of gallstones [20]; no significant increase in pancreatitis in pooled trial data (OR 0.99) [19]; an emerging but still-unsettled eye-safety signal (NAION) with a very small absolute risk [21,22]; and perioperative guidance that reversed in 2024 to favor continuing the medication for most patients before surgery, with an extended clear-liquid fast instead of stopping it outright [23,24].

Response varies. A meaningful minority of patients on any agent don’t reach even 5% weight loss — this has to be measured per patient, not assumed.

Who’s a Candidate — and Why Labs Come First

FDA labeling covers adults with BMI ≥30, or ≥27 with a weight-related comorbidity — that’s the regulatory floor, not sufficient grounds to prescribe alone. A responsible evaluation adds: family history screening for thyroid cancer/MEN2, a pancreatitis/gallbladder history, baseline labs (A1C, renal function, lipids), a pregnancy check, and a candid conversation about what happens if treatment stops. That evaluation is the difference between a prescription and real care — and it’s the part a landing page or symptom questionnaire isn’t built to do.

Bottom line: A 15–22% mean weight reduction and a 20% cut in cardiovascular events are real, transformative numbers. Whether this is right for you, at what dose, with what monitoring plan — that only gets answered by an actual evaluation. That’s where the conversation should start.

References

ASA multi-society guidance reversal, Oct 2024. asahq.org

Wilding JPH, et al. STEP 1. N Engl J Med 2021. nejm.org/doi/full/10.1056/NEJMoa2032183

Garvey WT, et al. STEP 5. Nat Med 2022. nature.com/articles/s41591-022-02026-4

Wilding JPH, et al. STEP 1 extension (withdrawal). Diabetes Obes Metab 2022. PMC9542252

Jastreboff AM, et al. SURMOUNT-1. N Engl J Med 2022. investor.lilly.com

Lincoff AM, et al. SELECT trial. N Engl J Med 2023. nejm.org

SELECT trial kidney/diabetes subanalyses. PMC11271413

FDA approves Wegovy CV indication, March 8, 2024. dicardiology.com

WEGOVY FDA label, CV indication. accessdata.fda.gov

FDA approves oral Wegovy (OASIS 4), Dec 22, 2025. endocrinologyadvisor.com

FDA approves Zepbound for OSA, Dec 2024. investor.lilly.com

FOUNDAYO FDA label, 2026. accessdata.fda.gov

FDA approves Foundayo, April 1, 2026. investor.lilly.com

Lilly to file retatrutide BLA, 2027. CNBC, July 23, 2026. cnbc.com

GLP-1 muscle health meta-analysis. Int J Obes 2026. nature.com

Body composition network meta-analysis. PubMed 39719170

MOUNJARO FDA label, boxed warning. accessdata.fda.gov

WEGOVY FDA label, boxed warning. accessdata.fda.gov

GLP-1 pancreatitis meta-analysis. medRxiv 2026. medrxiv.org

Ramírez-Mejía MM, et al. Gallbladder disease risk. 2025. journals.sagepub.com

AAO/NANOS consensus statement, NAION. aao.org

Danish–Norwegian NAION cohort study. medRxiv. medrxiv.org

ASA GLP-1 perioperative guidance, June 2023. asahq.org