Dual GLP‑1/Glucagon Peptide for Metabolic Li

Efinopegdutide (MK‑6024) is a dual GLP‑1/glucagon receptor agonist under investigation for treating metabolic-associated fatty liver disease (MAFLD) and related metabolic disorders. Developed by Merck, this synthetic, PEGylated peptide is engineered to improve liver fat reduction, glucose control, and cardiometabolic health.

While GLP‑1 agonists like semaglutide and liraglutide have transformed the treatment of obesity and type 2 diabetes, Efinopegdutide adds glucagon receptor activation into the mix — aiming for enhanced energy expenditure and fat oxidation alongside appetite suppression.

In this guide, we’ll cover:

→ The science and mechanism of Efinopegdutide
→ How PEGylation extends its half-life
→ Potential benefits for metabolic liver disease
→ Current clinical trial status and safety considerations

What Is Efinopegdutide (MK‑6024)?

Efinopegdutide is a synthetic peptide drug designed to mimic and amplify the effects of two natural hormones:

• GLP‑1 (Glucagon‑Like Peptide‑1) – Promotes insulin secretion, reduces appetite, and slows gastric emptying.

• Glucagon – Stimulates hepatic fat oxidation and increases energy expenditure.

The peptide backbone is PEGylated — meaning it is chemically bonded to polyethylene glycol (PEG) molecules. This modification:

→ Protects it from rapid enzymatic degradation
→ Extends circulation time and dosing intervals
→ Improves metabolic stability and patient compliance

“PEGylation can prolong the half-life of peptide drugs from hours to days, reducing dosing frequency while maintaining efficacy.”
— Veronese & Mero, BioDrugs

Mechanism of Action: How Efinopegdutide Works in the Body

Efinopegdutide’s clinical potential lies in its dual receptor activation — simultaneously targeting GLP‑1 receptors and glucagon receptors to influence both metabolic control and energy balance.

→ GLP‑1 Receptor Agonism

Like other GLP‑1 analogs, Efinopegdutide binds to GLP‑1 receptors in the pancreas, brain, and gastrointestinal tract. This leads to:

• Enhanced insulin secretion in a glucose-dependent manner

• Inhibition of glucagon release from pancreatic α-cells (under hyperglycemic conditions)

• Slowed gastric emptying, increasing satiety and reducing caloric intake

• Neuroendocrine appetite suppression via hypothalamic signaling

→ Glucagon Receptor Agonism

Unlike pure GLP‑1 drugs, Efinopegdutide also activates hepatic glucagon receptors, triggering:

• Increased fatty acid oxidation in the liver

• Enhanced energy expenditure through thermogenesis

• Mobilization of stored triglycerides, potentially reducing liver fat accumulation

• Mild glucose production, balanced by the insulinotropic effect of GLP‑1 activity

“Dual activation of GLP‑1 and glucagon receptors can produce greater reductions in liver fat and body weight than GLP‑1 agonism alone.”
— Tillner et al., Diabetes, Obesity and Metabolism

→ Role of PEGylation

Efinopegdutide’s PEGylated structure protects it from enzymatic breakdown and renal clearance, leading to sustained plasma levels and allowing for once-weekly or less frequent dosing.

Potential Benefits of Efinopegdutide for Metabolic Liver Disease

Efinopegdutide is being developed primarily for metabolic-associated fatty liver disease (MAFLD) and metabolic-associated steatohepatitis (MASH) — conditions closely tied to obesity, insulin resistance, and systemic inflammation. By targeting both GLP‑1 and glucagon receptors, it offers a multi‑pathway approach to improving liver and metabolic health.

→ 1. Reduction in Liver Fat Content

Dual receptor agonism promotes hepatic fat oxidation while decreasing de novo lipogenesis (new fat formation). Clinical data from similar dual agonists suggest significant reductions in intrahepatic triglyceride content, which is critical for halting MAFLD progression.

“Dual GLP‑1/glucagon agonists demonstrate marked decreases in liver fat, potentially surpassing the effects of GLP‑1 monotherapy.”
— Finan et al., Nature Medicine

→ 2. Weight Loss & Body Composition Improvement

GLP‑1 activity suppresses appetite and lowers caloric intake, while glucagon receptor activation boosts energy expenditure. This two-pronged approach can lead to greater weight loss and a higher proportion of fat mass reduction compared to GLP‑1 therapy alone.

→ 3. Improved Insulin Sensitivity & Glycemic Control

Efinopegdutide’s GLP‑1 agonism enhances insulin secretion and reduces postprandial glucose excursions, potentially improving insulin sensitivity in patients with metabolic syndrome or prediabetes.

→ 4. Cardiometabolic Risk Reduction

By lowering liver fat, reducing body weight, and improving glucose control, Efinopegdutide may reduce cardiovascular risk factors such as elevated triglycerides, hypertension, and systemic inflammation.

Current Clinical Trial Status & Research Findings

Efinopegdutide (MK‑6024) is currently in Phase 2 clinical development for metabolic liver disease and related metabolic disorders. While Merck has not positioned it as a first‑line obesity drug, early studies suggest meaningful improvements in liver health, weight reduction, and metabolic markers.

→ Early-Phase Human Trials

Initial clinical evaluations have shown:

• Significant reductions in intrahepatic triglyceride content in patients with fatty liver disease

• Sustained weight loss over multiple weeks of therapy

• Favorable effects on glycemic control, without severe hypoglycemia

• Acceptable tolerability profile, with gastrointestinal side effects similar to other GLP‑1 analogs

“Efinopegdutide demonstrated potent dual GLP‑1/glucagon activity in humans, with promising reductions in hepatic fat and improvements in metabolic parameters.”
— Tillner et al., Diabetes, Obesity and Metabolism

→ Target Patient Population

• Individuals with metabolic-associated fatty liver disease (MAFLD)

• Patients at risk of metabolic-associated steatohepatitis (MASH)

• Adults with obesity and insulin resistance seeking improved liver health

• Potential secondary use in type 2 diabetes management

→ Next Steps in Development

Merck’s ongoing Phase 2 trials will determine:

• Optimal dosing for maximal liver fat reduction with minimal side effects

• Long-term safety profile over 6–12 months of use

• Comparative efficacy against existing GLP‑1 monotherapy drugs

If Phase 2 results confirm early findings, Phase 3 trials could begin within the next few years, potentially positioning Efinopegdutide as a specialty therapy for metabolic liver disease.

Safety Considerations & Potential Side Effects

As with other GLP‑1 receptor agonists, Efinopegdutide’s side effect profile is primarily gastrointestinal, particularly during dose escalation phases. Its glucagon receptor activity may also introduce unique metabolic effects that require monitoring.

→ Commonly Reported Side Effects in Trials

• Nausea

• Vomiting

• Diarrhea

• Constipation

• Decreased appetite

• Abdominal discomfort

These symptoms are generally dose-dependent and tend to improve over time as the body adjusts.

→ Potential Risks

• Gallbladder disease (reported in some GLP‑1 therapies)

• Pancreatitis (rare but possible)

• Mild elevations in heart rate due to glucagon activity

• Potential lean mass loss if weight reduction is too rapid

“The safety profile of dual GLP‑1/glucagon agonists aligns closely with that of GLP‑1 monotherapy, with gastrointestinal events being the most frequent adverse effects.”
— Tillner et al., Diabetes, Obesity and Metabolism

Legal Status & Availability

Efinopegdutide (MK‑6024) is not currently approved by the FDA, EMA, or any other major health authority. It remains an investigational drug and is only available through clinical trials.

→ Current Availability

• Not sold commercially in any country

• Accessible only to eligible participants in Merck-sponsored clinical trials

• Compounding pharmacies and research peptide suppliers do not legally distribute it

→ Expected Timeline

If ongoing Phase 2 studies are successful and Phase 3 trials proceed without delays:

• Earliest possible approval: mid‑to‑late 2028

• Likely initial indication: Metabolic-associated fatty liver disease (MAFLD) and related metabolic disorders

“Efinopegdutide is several years from potential commercialization, with approval contingent on long-term safety and efficacy outcomes.”
— Veronese & Mero, BioDrugs

Key Takeaways: Efinopegdutide (MK‑6024) in Metabolic Liver Disease

→ Efinopegdutide is a PEGylated dual GLP‑1/glucagon receptor agonist designed to improve liver fat metabolism, energy expenditure, and overall metabolic health.
→ Dual receptor activation may offer greater reductions in liver fat and body weight compared to GLP‑1 monotherapy.
→ Early clinical data show improvements in liver fat content, weight loss, and glycemic control, with a tolerability profile similar to existing GLP‑1 drugs.
→ Currently in Phase 2 trials, Efinopegdutide is not yet approved and is only available through clinical studies.
→ Projected earliest availability — mid-to-late 2028, pending successful Phase 3 outcomes and regulatory approval.