4 New Weight Loss Drugs That Could Beat Wegovy & Mounjaro (2026–2027)

Manufacturer: Eli Lilly
Type: Once-daily oral tablet
Class: Non-peptide GLP-1 receptor agonist (small molecule)

Orforglipron is a new oral GLP-1 medicine designed for weight management. Unlike semaglutide, it is not a peptide-based drug. It is a small-molecule compound, meaning it is designed to avoid the strict fasting and water timing rules required by current oral semaglutide tablets.

How it works

Orforglipron activates GLP-1 receptors in the brain and gut. This helps to:

• Reduce appetite and overall food intake
• Slow gastric emptying, so you feel full longer
• Improve blood sugar control and insulin sensitivity

Its mechanism is similar to injectable GLP-1 treatments, but delivered in tablet form.

Effectiveness (clinical trials)

In phase 2 and phase 3 obesity studies, Orforglipron has shown:

• Around 14–15% average body weight loss
• Results achieved over approximately 9–18 months, depending on dose and patient group
• Improvements in glucose control in people with type 2 diabetes

Side effects are similar to those of other GLP-1 medicines, primarily gastrointestinal symptoms such as nausea, vomiting, diarrhoea, or constipation, especially during early treatment.

UK-availability

Eli Lilly has stated that a regulatory submission for obesity is planned in 2025. UK experts have suggested that, if approved, the UK could be among the first countries to receive Orforglipron, potentially in 2026.

The National Institute for Health and Care Excellence (NICE) has already included Orforglipron in its provisional programme for the management of overweight and obesity, indicating that a formal UK appraisal is expected.

At present, Orforglipron is not licensed in the UK.

Manufacturer: Novo Nordisk
Type: Once-weekly injection
Class: GLP-1 receptor agonist + Amylin analogue

CagriSema is a combination injection that combines two appetite-regulating hormones in a single weekly dose. It contains semaglutide (the same GLP-1 medicine used in Wegovy) and cagrilintide, an amylin analogue that enhances post-meal fullness.

How it works

CagriSema works through two distinct pathways:

GLP-1 component (semaglutide):

• Suppresses appetite
• Slows gastric emptying
• Improves glycaemic control
• Amylin component (cagrilintide):

Acts on brain satiety centres

1. Sends an additional “fullness” signal separate from GLP-1
2. Reduces meal size and portion intake
   Together, these pathways produce stronger appetite suppression and portion control than GLP-1 alone.

Effectiveness (REDEFINE-1 Trial)

In the large phase 3 REDEFINE-1 obesity trial (patients without diabetes):

• 22.7% mean weight loss at 68 weeks on the highest CagriSema dose
• 16.1% with semaglutide 2.4 mg alone
• 11.8% with cagrilintide alone
• 2–3% with placebo

Additional findings included:

• Greater waist circumference reduction
  Systolic blood pressure reduction (~10.9 mmHg vs ~8.8 mmHg with semaglutide alone)
• Improvements in cardiometabolic markers

These results position CagriSema among the most potent obesity medicines studied to date.

UK-availability

Novo Nordisk has stated it expects to file for regulatory approval in early 2026. Global filings are planned across major markets, including the EU.

There is no official MHRA approval date yet. However, if phase 3 data remain positive and regulators prioritise obesity medicines as they did with Wegovy, a UK launch in 2027 is realistic.

CagriSema is not currently licensed in the UK.

Manufacturer: Eli Lilly
Type: Once-weekly injection
Class: Triple-agonist (GLP-1 + GIP + Glucagon receptor agonist)

Retatrutide is unique because it targets three metabolic hormones simultaneously, rather than one or two, as most current weight-loss injections do. This triple action creates a broader metabolic effect.

How it works

Retatrutide activates:

• GLP-1 receptors – reduce hunger and slow digestion, helping you eat less
• GIP receptors – improve insulin response and support better metabolic balance
• Glucagon receptors – increase energy expenditure and promote fat burning

The added glucagon activity is what makes it different. Most weight-loss medicines mainly reduce appetite. Retatrutide reduces appetite and may increase the number of calories your body burns, even at rest.

By working on both sides of energy balance — intake and expenditure — retatrutide represents a next-generation approach to weight regulation.

Effectiveness (Clinical Trials)

In phase 2 obesity trials:

• Up to 24% average body weight loss at 48 weeks at higher doses
• Significant reductions in liver fat
• Improvements in triglycerides and insulin resistance
• These are among the highest weight-loss results seen in drug studies to date. Larger phase 3 trials are ongoing to confirm long-term effectiveness and safety.

Side Effects

So far, side effects appear similar to other GLP-1-based medicines, mainly:

• Nausea
• Vomiting
• Diarrhoea or constipation
• Gastrointestinal discomfort during dose escalation

Because retatrutide also activates glucagon receptors, heart rate and metabolic effects are being closely monitored in ongoing trials.

UK Availability and Timing

Retatrutide is currently investigational and not licensed in the UK. It remains in phase 3 clinical development.

If trials remain positive and regulatory approval is granted, the earliest realistic UK availability would be late 2026 or 2027, subject to MHRA approval and NICE guidance.

⚠ Retatrutide cannot legally be purchased in the UK at present. Any online or overseas “Triple G” pens are unregulated and potentially unsafe.

Manufacturer: Novo Nordisk
Type: Once-daily oral tablet
Class: GLP-1 receptor agonist (higher-dose, new indication)

This is not a completely new medicine, but a new treatment approach using higher-dose oral semaglutide. It is being evaluated for people with established cardiovascular disease (CVD) who also have overweight or obesity.

Unlike injectable GLP-1 treatments that are marketed mainly for weight loss, this approach may be positioned primarily for heart protection, with weight reduction as a major added benefit.

For patients, it may feel like a weight-loss tablet with cardiovascular advantages — even if the formal indication focuses on CVD prevention.

How it works

High-dose oral semaglutide uses the familiar GLP-1 pathway to:

• Reduce appetite and food intake
• Slow gastric emptying
• Improve insulin sensitivity
• Support cardiovascular risk reduction

At higher doses, weight loss becomes more clinically significant alongside heart protection.

Effectiveness (Current Evidence)

• Cardiovascular benefit already demonstrated in high-risk type 2 diabetes populations
• Higher oral doses studied in obesity trials show around 15% average weight loss, depending on dose and population
• Improvements in blood pressure and metabolic markers
• It is not yet approved specifically as a weight-management tablet at those higher doses.

UK Availability

National Institute for Health and Care Excellence (NICE) is currently reviewing semaglutide for preventing major cardiovascular events in people with CVD and overweight or obesity.

This suggests a potential UK decision in the 2026–2027 period, subject to MHRA approval and NICE guidance.

High-dose oral semaglutide is not currently licensed in the UK for this specific use.

Is Orforglipron approved in the UK?

No. It is currently under clinical development and not yet licensed by the MHRA.

When could Orforglipron become available in the UK?

Regulatory submission is expected in 2025. If approved, it may become available in 2026, subject to NICE review.

Will Orforglipron be available on the NHS?

That will depend on NICE’s cost-effectiveness decision. It may initially be available privately.

Who might qualify for Orforglipron?

If approved, eligibility would likely follow existing GLP-1 criteria, such as BMI ≥30, or ≥27 with weight-related health conditions.

Is CagriSema stronger than Wegovy?

In trials, average weight loss was higher than semaglutide alone. Final comparisons will depend on head-to-head data and dosing.

Who might be offered CagriSema first?

It may be considered for patients needing greater weight reduction or those who did not respond adequately to GLP-1 alone.

When might Retatrutide be approved?

If phase 3 trials remain positive, approval could be possible in late 2026 or 2027.

Is Retatrutide more effective than Mounjaro?

Early trials suggest higher average weight loss, but there are no definitive head-to-head phase 3 results yet.

Is triple-agonist therapy safe long-term?

Long-term safety data are still being collected in ongoing trials.

Is high-dose oral semaglutide different from Rybelsus?

High-dose oral semaglutide is based on the same active ingredient as Rybelsus (semaglutide). However, it is being studied at higher doses and for a different purpose — reducing cardiovascular risk in people with overweight or obesity.

Who might qualify for high-dose oral semaglutide for CVD + obesity?

If approved, high-dose oral semaglutide may be considered for adults with established cardiovascular disease who also have overweight or obesity, depending on final MHRA authorisation and National Institute for Health and Care Excellence (NICE) guidance.

Will high-dose oral semaglutide replace injectable treatments?

High-dose oral semaglutide is unlikely to fully replace injectable GLP-1 treatments. Instead, it may provide a tablet alternative for certain higher-risk patients, particularly those prioritising cardiovascular protection.