The evolution of incretin therapies: from GLP-1 to dual and triple agonists
How a hormone discovered decades ago became the basis for today's most effective metabolic drugs.
Incretins and DPP-4
Researchers found that nutrients trigger gut hormones — incretins — that amplify insulin release. The challenge was that these hormones are destroyed within minutes by the enzyme DPP-4. Early drug development pursued two routes: DPP-4 inhibitors (to slow breakdown) and engineered GLP-1 receptor agonists (resistant to breakdown).
Short to long acting
The first GLP-1 receptor agonists required daily or twice-daily injection. Chemistry then enabled once-weekly formulations and, eventually, an oral GLP-1 option. Semaglutide became the most effective widely used GLP-1 agonist, with strong glucose and weight effects.
Adding GIP
Tirzepatide combined GIP and GLP-1 activity in a single molecule. In head-to-head data it outperformed a leading GLP-1-only drug on glucose and weight, validating multi-receptor agonism as a strategy and reshaping expectations for how much weight loss medication can achieve.
Triple agonists and beyond
The pipeline now includes triple agonists that add glucagon-receptor activity (intended to increase energy expenditure), oral small molecules, and combinations aimed at preserving muscle. The field is evolving rapidly, so today's options are unlikely to be the last word.
Caveats
This is background, not advice; approved uses and suitability are clinical questions. Compounded tirzepatide and other compounded incretins are not FDA-approved.
What the pipeline implies for patients
The rapid evolution of this drug class has a practical implication: today's options are a snapshot, not an endpoint. Triple agonists adding glucagon activity, oral formulations of potent agents, longer-acting molecules dosed monthly, and combinations designed to preserve muscle are all in development. If several succeed, patients may eventually choose among agents with different efficacy, side-effect and convenience profiles, and prices may shift as competition grows. For now, that argues for two things. First, avoid treating any single product as the permanent “best” — the landscape is moving. Second, focus comparisons on what is verifiable today: published evidence, approved status, pharmacy transparency for compounded products, and real recurring cost. The history of the class — from short-acting daily injections to weekly dual agonists in barely over a decade — suggests the pace will continue, which is exactly why an independent, regularly updated resource matters more than a one-time ranking.
Primary sources
- Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist. Mol Metab. 2018;18:3-14.
- Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in type 2 diabetes (SURPASS-2). N Engl J Med. 2021;385(6):503-515.
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387(3):205-216.
Citations are provided for educational reference. This article summarizes published research in plain language and is not medical advice. Always consult a licensed clinician.
Common questions
What was the first incretin drug?
The first incretin-based therapies were short-acting GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes, which evolved into weekly GLP-1 drugs and then dual agonists.
What is a dual agonist?
A medication that activates two receptors — tirzepatide activates both the GIP and GLP-1 receptors, unlike GLP-1-only drugs.
Are triple agonists available?
Triple agonists (adding glucagon-receptor activity) are in development; tirzepatide is the approved dual GIP/GLP-1 agonist.