The Next Generation of GLP-1s: Orforglipron, Retatrutide, CagriSema, and Oral Semaglutide

Two of these four are not "coming soon" any more

This page used to describe four drugs in testing. Two of them have since been approved and are being prescribed in the US: orforglipron, the first oral non-peptide GLP-1, approved on 1 April 2026 and sold as Foundayo, and high-dose oral semaglutide, approved on 22 December 2025 and sold as Wegovy tablets. Retatrutide and CagriSema are still not approved. Approval status for all four was re-checked in the FDA's own database on the date at the top of this page⁷ — this field moves faster than articles about it, so treat any status claim you read anywhere, including this one, as perishable.

Here is what the trials actually found, with the placebo arm attached to every figure. A placebo group on the same lifestyle program loses two to three percent, and a headline that hides that is inflating the drug by that much.

Orforglipron: the oral GLP-1 that is not a peptide

Today's GLP-1 drugs are peptides, which is why most are injected — peptides are poorly absorbed by mouth. Orforglipron is a small molecule instead, and that changes the practicalities more than the pharmacology. The approved label instructs patients to take it once daily with or without food, with no water limit and no waiting period². Set that against the semaglutide tablet below and you can see what the chemistry buys.

The phase 3 ATTAIN-1 trial randomized 3,127 adults with obesity and without diabetes to 6 mg, 12 mg or 36 mg of orforglipron or placebo for 72 weeks. Mean weight change was −7.5%, −8.4% and −11.2% across the three doses against −2.1% with placebo. At the top dose, 54.6% of participants lost at least 10%, 36.0% at least 15% and 18.4% at least 20%, against 12.9%, 5.9% and 2.8% on placebo. Gastrointestinal effects were the most common adverse events, and 5.3% to 10.3% of participants stopped the drug because of adverse events, against 2.7% on placebo¹.

Read the size of that honestly: about 11% is meaningfully less than injectable tirzepatide's roughly 20%, and less than the semaglutide tablet's 13.6%. Orforglipron's argument is availability, not potency — a small molecule is far easier to manufacture at scale than an injectable peptide, which is the constraint that has produced years of shortages.

One thing specifically worth knowing if you are a mother: being a pill does not make it gentler on your contraception. The Foundayo label carries the same warning tirzepatide does, telling patients on oral hormonal contraceptives to switch to a non-oral method or add a barrier method for 30 days after starting and 30 days after each dose increase². It also says to discontinue when a pregnancy is recognized.

Oral semaglutide: approved at 25 mg, not the 50 mg you may have read

Semaglutide has existed as a low-dose tablet for years, but the weight-management version is new. The OASIS 4 trial randomized 307 adults 2:1 to oral semaglutide 25 mg daily or placebo; mean weight change at week 64 was −13.6% against −2.2% with placebo, with gastrointestinal adverse events in 74.0% of the semaglutide group and 42.2% of the placebo group³. That is close to injectable territory from a daily tablet.

Two details get garbled constantly. First, the dose: earlier trials tested 50 mg and reported around 15%, but 25 mg is the dose that was approved — if you see a 15% figure attached to an oral semaglutide, check which dose it belongs to. Second, the conditions. Wegovy tablets are taken on an empty stomach in the morning, swallowed whole, with no more than four ounces of water and nothing else to drink, followed by at least 30 minutes with nothing to eat, drink or take by mouth⁴. And the tablet formulation contains an absorption enhancer, SNAC, which is present in human milk — so the label states that breastfeeding is not recommended on tablets, while the injection, which contains no SNAC, is not restricted that way⁴. The pen and the pill are the same molecule and are not interchangeable for a nursing mother. How this sits against the other approved brand is covered in Zepbound vs Wegovy.

Don't confuse the approved tablet above with a compounded oral tablet sold under the same "no injection" pitch — different product, no label. Wellorithm sells one for both molecules at its injection price, minus the approved tablet's fasting rules or lactation guidance. Confirm which one you're actually buying.

Retatrutide: still the biggest number, still phase 2

Retatrutide hits three receptors — GIP, GLP-1 and glucagon — the last adding an energy-expenditure lever on top of appetite suppression. In its phase 2 trial, 338 adults were randomized across five dose arms and placebo for 48 weeks: mean weight change was −8.7%, −17.1%, −22.8% and −24.2% at 1 mg, 4 mg, 8 mg and 12 mg respectively, against −2.1% with placebo. At 48 weeks, 60%, 75% and 83% of the 4 mg, 8 mg and 12 mg groups had lost at least 15%, against 2% on placebo. Gastrointestinal effects were dose-related, and heart rate rose dose-dependently, peaking at 24 weeks before declining⁵.

That −24.2% is the largest figure in the class, and it comes from a 338-person dose-finding study, not a confirmatory trial. Phase 2 exists to pick a dose; phase 3 exists to find out whether the effect and the safety profile hold at scale, and they frequently shrink. Drugs@FDA lists no approved retatrutide product⁷. That database records approvals rather than pending submissions, so it cannot tell you nothing has been filed — only that nothing has been cleared.

Which matters, because products labeled retatrutide are already being sold online. An unapproved drug has no FDA-reviewed prescribing information behind it, which means no verified contents, no established dose, and no reproductive or lactation pharmacology at all — none of that work has been published for this molecule. For a woman who is nursing, pregnant, or might become pregnant, that is not a small gap to accept in exchange for a bigger number. Nothing on this page should be sourced from anywhere other than a licensed prescriber and a real pharmacy.

CagriSema: phase 3 data, no US approval

CagriSema pairs semaglutide with cagrilintide, a long-acting analogue of amylin — a second satiety hormone — so it works through two complementary appetite pathways rather than one. REDEFINE 1 randomized 3,417 adults with overweight or obesity across four arms: the combination, semaglutide alone, cagrilintide alone, or placebo, for 68 weeks. Mean weight change with the combination was −20.4% against −3.0% with placebo. Gastrointestinal adverse events affected 79.6% of the combination group and 39.9% of the placebo group — mainly transient and mild to moderate, but that is four in five people⁶. Drugs@FDA lists no approved cagrilintide or CagriSema product⁷.

How to read numbers like these

• Never compare across trials as if it were a ranking. Retatrutide's −24.2% came from 338 people in phase 2; CagriSema's −20.4% came from 3,417 in phase 3. Different populations, durations and designs. Only a randomized head-to-head settles an order, and none has been run among these four.
• Subtract the placebo arm. Every one of these trials landed between −2.1% and −3.0% on placebo. That is the floor a drug has to clear before any of its number is its own.
• Phase is not a formality. Two of these four have now cleared phase 3 and a regulator. Two have not, and one of those has no phase 3 result published at all.

Where this sits on the evidence scale

The strongest claims on this page are the two approvals: orforglipron and oral semaglutide each have a large phase 3 trial with a placebo comparator and an FDA-reviewed label, which is as much certainty as anything in obesity medicine currently offers. CagriSema has trial evidence of the same quality and no regulator's verdict yet. Retatrutide has one mid-stage study and a headline figure that has never been tested at scale.

What none of this research covers is the population reading it. Every trial above excluded pregnancy, none enrolled nursing mothers, and the reproductive pharmacology of the two unapproved agents is simply unstudied — so for the questions mothers ask most, the honest answer is that the data does not exist yet rather than that it is reassuring. That will change as phase 3 programs report and labels accumulate lactation studies, and this page will need rewriting again when they do. Until then, take any of these to a clinician who knows your pregnancy and nursing plans before you take it at all.