Orforglipron, Retatrutide and CagriSema: Where the Next Weight-Loss Drugs Stand

Two new weight-loss medicines reached the US market in the past ten months, and two more are close behind. The FDA approved a semaglutide pill for weight management in December 2025 and orforglipron (Foundayo), a once-daily tablet, in April 2026. CagriSema is awaiting an FDA decision expected by late 2026. Lilly plans to file retatrutide, the most-searched of the four, in the first quarter of 2027.¹⁶¹¹¹³ This guide sets out where each one stands as of 12 October 2026, what the main trials found, and why the headline numbers cannot be lined up against each other.

It describes research and regulatory status only. It contains no dosing information and is not medical advice.

Where each medicine stands

Orforglipron (Foundayo): approved, and not a peptide

On 1 April 2026 the FDA approved orforglipron, sold as Foundayo, for chronic weight management in adults with obesity, or overweight plus at least one weight-related condition.¹² The agency said the decision came 50 days after filing and was "the fastest approval of an NME [new molecular entity] since 2002," the first new molecule approved under its Commissioner's National Priority Voucher pilot program.¹

Orforglipron is a non-peptide small molecule that activates the same receptor as GLP-1.³ That matters for a peptide reference site. Peptides are broken down in the gut, which is why oral semaglutide has strict fasting rules. Orforglipron's label allows it to be taken with or without food.² See peptide bioavailability for why peptides are hard to give as pills.

Key results:

• ATTAIN-1 (3,127 adults with obesity, no diabetes, 72 weeks): average weight change of −7.5% to −11.2% across dose groups, versus −2.1% with placebo. Between 5.3% and 10.3% stopped treatment because of side effects, mostly gastrointestinal, versus 2.7% with placebo.³
• ATTAIN-2 (1,613 adults with type 2 diabetes): −5.1% to −9.6% versus −2.5%.⁴
• ATTAIN-MAINTAIN studied people who had already lost weight on tirzepatide or semaglutide injections. After switching to orforglipron, they kept more of that weight off than people switched to placebo. The authors note that the trial did not include a group that stayed on injections, so it cannot show whether switching is as good as continuing.⁵

Like other medicines in this class, the label carries a boxed warning about thyroid C-cell tumors seen in rodents.² An application for type 2 diabetes has been submitted but not yet decided.

The Wegovy pill: oral semaglutide

The FDA approved oral semaglutide for chronic weight management on 22 December 2025.⁶ Its label also includes reducing major cardiovascular events in adults with established cardiovascular disease and obesity or overweight. In OASIS 4 (307 adults, 64 weeks), average weight change was −13.6% versus −2.2% with placebo.⁷ Because it is a peptide, the tablet must be taken on an empty stomach with a small amount of water, followed by a waiting period before eating.⁶

Retatrutide: the "triple agonist"

Retatrutide activates three hormone receptors: GIP, GLP-1 and glucagon.⁸ It has produced the largest average weight loss reported so far in phase 3, and it is also the drug most often sold illegally online (see below).

TRIUMPH-1, published in the New England Journal of Medicine on 29 September 2026, enrolled 2,339 adults with obesity and without diabetes for 80 weeks. Average weight change was −17.6% to −25.0% across dose groups, versus −3.9% with placebo.⁸ Lilly's headline figure of up to −28.3% uses a different analysis, the efficacy estimand, explained below.⁹

The trial included people with knee osteoarthritis and with obstructive sleep apnea, and both groups improved more than with placebo.⁸ TRIUMPH-2, in adults with type 2 diabetes, reported −11.9% to −18.8% versus −5.1%.¹⁰

Safety signals to watch:

• Dysesthesia, an abnormal skin sensation such as burning or tingling, was reported in up to about 12% of participants at the higher doses in TRIUMPH-1, versus about 1% with placebo.⁹ In TRIUMPH-4, a knee osteoarthritis trial reported only in a press release so far, Lilly said it affected 20.9% at the highest dose.¹²
• Stopping because of side effects rose with dose. At the highest dose in TRIUMPH-1 it reached about 11%, versus about 5% with placebo.⁹
• Hypotension-related events (low blood pressure) and increases in heart rate have been reported.⁹²¹

Lilly says it plans to submit an application to the FDA in the first quarter of 2027. Until then, "Retatrutide is an investigational molecule that cannot be legally sold or marketed for human use."¹¹ Approval is not guaranteed. The FDA will weigh the dysesthesia and tolerability data against the benefits.

CagriSema: decision expected by late 2026

CagriSema combines two peptides in one weekly injection: cagrilintide, a long-acting version of the hormone amylin, and semaglutide. Novo Nordisk submitted it to the FDA in December 2025, and "an FDA decision is anticipated by late 2026."¹³

• REDEFINE 1 (3,417 adults without diabetes, 68 weeks): −20.4% versus −3.0% with placebo. Gastrointestinal side effects were common (79.6% vs 39.9%).¹⁴
• REDEFINE 2 (1,206 adults with type 2 diabetes): −13.7% versus −3.4%.¹⁵
• REDEFINE 4, a head-to-head trial against tirzepatide, "did not achieve its primary endpoint of non-inferiority compared to tirzepatide." Weight change was −20.2% with CagriSema versus −23.6% with tirzepatide. That result comes from a company announcement; the full trial has not yet been published in a journal.¹³

Compare the two components in our cagrilintide vs semaglutide guide.

Further back in the pipeline

• Amycretin (zenagamtide): a single peptide that acts on both GLP-1 and amylin receptors. An early-phase trial reported large weight reductions in small groups.¹⁶ Phase 3 trials began in 2026.
• MariTide: Amgen's peptide-antibody conjugate is designed to be injected monthly or less often. In phase 2, average weight change was −12.3% to −16.2% versus −2.5% with placebo in people without diabetes.¹⁷ Phase 3 is ongoing.
• Survodutide: a glucagon/GLP-1 dual agonist. In the phase 3 SYNCHRONIZE-1 trial, average weight change was −12.2% to −13.0% versus −5.4% with placebo.¹⁸ It is also being studied in MASH liver disease.

Why you cannot rank these drugs from headlines

The numbers above come from different trials, with different people, durations (52 to 80 weeks), dose schedules and analysis methods. FDA labels warn that adverse reaction rates in one drug's trials "cannot be directly compared to rates in the clinical trials of another drug", and the same caution applies to weight-loss results.² Only head-to-head trials such as REDEFINE 4 and SURMOUNT-5 compare drugs directly.

Watch for the estimand. Companies often headline the efficacy estimand: the result if everyone had stayed on treatment as planned. Journals usually lead with the treatment-regimen (treatment-policy) estimand, which includes people who stopped or switched treatment and is closer to real-world use. For retatrutide in TRIUMPH-1, the highest dose gave −28.3% on the first measure and −25.0% on the second.⁸⁹ Both numbers are correct, but they answer different questions. Our guide to reading clinical trial results explains more.

"Research" retatrutide is not the drug in these trials

Retatrutide is not approved anywhere, yet it is widely sold online as a "research peptide". The FDA states that "retatrutide and cagrilintide cannot be used in compounding under federal law," adding that they "have not been found safe and effective for any condition."¹⁹ In October 2026, JAMA reported on unapproved retatrutide and zenagamtide sold online.²⁰

These products have not been tested in the trials described above, and their identity, purity and sterility are unknown. See what "research use only" means and approved versus unapproved peptides.

What this means for you

• Approved now: orforglipron (Foundayo) and the semaglutide pill join existing injectable options. A licensed clinician can tell you whether any of them suits you.
• Coming soon, maybe: a CagriSema decision is expected by late 2026. If retatrutide is filed in early 2027, a standard FDA review would point to a decision around early 2028. Priority programs, like the one used for orforglipron, could shorten that.
• Bigger headline numbers are not automatically better. Tolerability, side effects such as dysesthesia, and the analysis behind a number all matter.
• Avoid unapproved versions. No online or compounded retatrutide is the product tested by Lilly.

Frequently asked questions

Is retatrutide FDA-approved?

No. Lilly plans to submit an application in the first quarter of 2027. Until it is approved, retatrutide cannot legally be sold for human use in the US.¹¹¹⁹

Is orforglipron a peptide?

No. It is a small molecule that activates the GLP-1 receptor, which is why it can be taken as a pill without the fasting rules oral semaglutide needs.²³

When will CagriSema be approved?

Novo Nordisk expects an FDA decision by late 2026. The FDA could approve it, ask for more information, or decline.¹³

Which new weight-loss drug works best?

There is no direct answer from these trials. Only head-to-head studies can compare drugs fairly, and the only direct comparison here, REDEFINE 4, found CagriSema did not match tirzepatide.¹³