Your Guide to Cotadutide
A New Lever for Metabolic Health: Why Cotadutide Matters
Stubborn body fat. A climbing A1C. A liver quietly stockpiling fat. That’s the modern metabolic trifecta. GLP-1 drugs get a lot of airtime for good reason. But what if you could shape metabolism from two directions at once?
Cotadutide is a dual-agonist peptide that activates GLP-1 and glucagon receptors to improve glucose control, reduce liver fat, and support weight loss. It was developed for type 2 diabetes and fatty liver disease and has moved through Phase 2 trials.
The catch? It’s investigational, not FDA-approved. So what’s the real promise when you push two metabolic levers together?
Meet Cotadutide: What It Is
Cotadutide belongs to a newer class of co-agonists inspired by our own proglucagon family (GLP-1, glucagon, oxyntomodulin). It’s a long-acting synthetic peptide designed for subcutaneous dosing in trials. Public details on its exact structure are limited, but functionally it behaves like a long-acting analog.
It has completed multiple Phase 2 studies in type 2 diabetes and NAFLD, with signals for weight, A1C, and liver fat reduction measured by MRI-PDFF. Still, there is no approved label, no pharmacy product, and no routine clinical use today.
If it’s not on the shelf, why are researchers so interested in the mechanism?
How Cotadutide Works: The Dual Signal
Think push and pull. GLP-1 smooths glucose control and appetite. Glucagon turns up energy use and mobilizes fat. Cotadutide engages both.
GLP-1 receptor activation boosts glucose-dependent insulin secretion, slows stomach emptying, and quiets appetite signals along the gut–brain axis. That combination often produces steadier post-meal glucose and fewer cravings in trials.
Glucagon receptor activation classically raises hepatic glucose output. But it also increases energy expenditure and fat oxidation. When paired with GLP-1, the thermogenic and lipid-mobilizing effects of glucagon can be harnessed while the GLP-1 signal tempers glucose excursions.
In Phase 2 research, this balance translated to clinically meaningful drops in body weight and A1C, plus lower liver fat on MRI-PDFF in people with type 2 diabetes and NAFLD. Some studies hinted at liver and weight advantages over GLP-1 alone, though head-to-head data are limited and longer outcomes are pending. Want to see how it’s studied in practice?
How It’s Given in Trials
There is no approved dosing. In studies, cotadutide has been administered as a once-daily subcutaneous injection with gradual titration to improve tolerability over several weeks to months.
There are no validated oral or nasal versions, and no evidence-based “cycling” or “stacking” protocols. Because it is investigational, dosing and safety monitoring belong inside a clinical trial.
Curious what safety looks like when you pair GLP-1 and glucagon activity?
Safety and Unknowns
Short-term tolerability looks broadly similar to GLP-1 class agents, with expected gastrointestinal effects during dose escalation in trials.
Most common effects seen in studies
- Nausea, fullness, vomiting, diarrhea
- Decreased appetite and early satiety
- Injection-site reactions
- Small increases in resting heart rate reported in some GLP-1–based programs
Hypoglycemia risk is low when used without insulin or sulfonylureas because GLP-1 enhances insulin release only when glucose is high. The glucagon receptor adds complexity, since excessive activation can raise hepatic glucose output, which is why dose balancing and monitoring are built into trial protocols.
Signals seen with GLP-1 therapies as a class inform caution: rare pancreatitis reports, gallbladder events, and rodent C-cell findings with uncertain human relevance. Cotadutide lacks long-term data, so risks are not fully defined. Exclusions in trials commonly include pregnancy and breastfeeding, prior pancreatitis or severe gastroparesis, and situations where rapid glucose changes could stress the retina.
Critically, long-term hepatic and cardiovascular outcomes have not been established and will require larger, longer trials to know whether short-term biomarker gains translate into fewer events. What do researchers measure to see if the drug is doing its job?
How It Compares
Compared with GLP-1–only drugs such as semaglutide, cotadutide is designed to add a glucagon-driven boost in energy expenditure and hepatic fat handling while retaining GLP-1’s glucose and satiety effects. The art is in balancing glucagon so you do not blunt glycemic gains.
Compared with tirzepatide, the second signal differs — tirzepatide pairs GLP-1 with GIP to amplify insulinotropic and weight effects through complementary incretin biology. Cotadutide pairs GLP-1 with glucagon to tilt toward thermogenesis and liver fat. Head-to-head trials are not available.
Natural oxyntomodulin activates both receptors but is short-lived. Cotadutide is engineered for potency and longer half-life to enable daily dosing. Amylin analogs cover satiety and gastric emptying but do not drive glucagon-like energy expenditure. Want to know if you can actually get it?
Regulatory Reality
The status is clear: investigational only. Cotadutide is not FDA-approved and is available for research through clinical trials, not pharmacies.
Compounded or “research chemical” versions sold online are unregulated — identity, purity, dose accuracy, and sterility are uncertain, and adverse events fall on the buyer. For athletes, the World Anti-Doping Agency’s S0 category prohibits non-approved pharmacologic agents at all times, which includes cotadutide.
If safety and data integrity matter, the credible paths are clinical trials or approved therapies with labeled dosing and monitoring. So how do you even tell if a dual-agonist is doing what it should?
Tracking Impact: Biomarkers
You manage metabolism by watching patterns, not single numbers. In trials, cotadutide’s signature shows up across glucose, liver, and body composition.
Glycemic control
A1C captures average glucose over about three months, though anemia, iron therapy, and hemoglobin variants can skew results. Fasting and post-meal readings show daily dynamics, while CGM reveals patterns like nocturnal highs or post-dinner spikes.
Liver health
ALT, AST, and GGT flag liver stress but are non-specific. MRI-PDFF quantifies liver fat and is the research standard. Non-invasive fibrosis scores such as FIB-4 help estimate risk but do not diagnose fibrosis.
Lipids and body composition
Triglycerides often fall as liver fat and insulin resistance improve. HDL and LDL can shift with weight loss and hormonal changes. Waist circumference and DXA help separate visceral fat from lean mass, which matters for long-term risk.
Assay caveats
Active versus total GLP-1 requires special handling and is rarely useful in routine care. Glucagon assays vary and can cross-react with other proglucagon fragments. Trends across multiple markers are more informative than any single lab. Want the bottom line?
The Takeaway on Cotadutide
Cotadutide is a two-signal play on metabolism: GLP-1 pathways to tame glucose and appetite, glucagon pathways to increase energy expenditure and mobilize fat. Phase 2 studies report reductions in A1C, weight, and liver fat in people with type 2 diabetes and NAFLD, but long-term hepatic and cardiovascular outcomes remain unknown, which is why it stays in trials.
Personalization and oversight matter. The smart move is aligning mechanism with metrics and matching any peptide strategy to your biomarker story while minimizing risk. At Superpower, we run a single comprehensive panel of 100+ biomarkers and pair it with a care team to map your path, from whether a dual-agonist approach even makes sense to how movement after meals shuttles glucose into muscle without insulin. Curious how your data might respond and what safer, evidence-based options you can use today?
