In a phase 3 trial, the GLP-1 pill orforglipron cut HbA1c about 1.1 points beyond placebo when added to titrated basal insulin

In ACHIEVE-5, 546 adults with type 2 diabetes on titrated insulin glargine took Eli Lilly's once-daily oral orforglipron — approved for weight loss but still investigational for diabetes — and gained better glycemic control and modest weight loss over placebo, without more clinically significant hypoglycemia; gastrointestinal events were the main adverse effect and led up to 9.6% of treated patients to discontinue.

Most people with type 2 diabetes who add a GLP-1 medicine to basal insulin still face an injection. The phase 3 ACHIEVE-5 trial, published in JAMA, tested whether a pill could do the job instead. The answer was yes — but the comparison matters. Every arm, placebo included, received insulin glargine that was actively titrated throughout, so this is an add-on study, not a head-to-head test of the pill against insulin.

A note on regulatory status: orforglipron (brand Foundayo, from Eli Lilly) was FDA-approved on April 1, 2026 for chronic weight management only — in adults with obesity, or with overweight plus a weight-related condition. It is not approved for type 2 diabetes. Lilly has said it plans to file for a diabetes indication on the strength of the ACHIEVE program, but that submission has not been made or cleared. The use studied here remains investigational and is not currently available.

The randomized, double-blind trial enrolled 546 adults whose HbA1c stayed between 7.0% and 10.5% despite insulin glargine, with or without metformin and an SGLT-2 inhibitor, across 72 sites in five countries. Participants took once-daily oral orforglipron at 3 mg (n=137), 12 mg (n=132), or 36 mg (n=136), or placebo (n=141), each alongside titrated glargine. The primary endpoint was the change in HbA1c from a baseline of 8.50% to week 40 for the 12-mg and 36-mg doses; the 3-mg dose was a key secondary endpoint. Of those randomized, 92.9% completed the trial.

The numbers

“At week 40, the mean changes from baseline in HbA1c were −1.58%, −1.88%, and −1.82% with orforglipron, 3 mg, 12 mg, and 36 mg once daily, respectively, vs −0.79% with placebo.”

Because placebo plus titrated glargine alone lowered HbA1c by 0.79 points, the drug’s own contribution is the placebo-subtracted treatment difference: −1.08 points (95% CI, −1.33 to −0.83) at 12 mg and −1.03 points (95% CI, −1.28 to −0.77) at 36 mg, each P<.001. Both higher doses met the primary endpoint and were superior to placebo. The 3-mg dose, a key secondary, produced a difference of −0.78 points (95% CI, −1.02 to −0.55). The authors report that every key secondary outcome — including the share of participants reaching HbA1c targets below 7.0% and at or below 6.5% — favored orforglipron over placebo with statistical significance. Body weight fell 4.8% at 12 mg and 5.4% at 36 mg, while the placebo group gained 0.2%.

Gastrointestinal events, mostly mild to moderate, were the most common adverse effect among orforglipron-treated patients. Treatment discontinuation for any adverse event ranged from 3.6% to 9.6% across the orforglipron doses, versus 3.6% on placebo; discontinuation for GI events specifically ranged from 1.5% to 6.7% across doses, versus 0.7% on placebo. The authors report no increase in clinically significant (level 2) hypoglycemia among orforglipron-treated patients versus placebo. As a 40-week efficacy study, ACHIEVE-5 was not designed to assess cardiovascular outcomes or long-term safety.

Trials Today

Phase 3 VENTURA-5 (aticaprant, J&J) — NCT06635135 — TERMINATED, results posted; relapse-prevention arm of the discontinued VENTURA depression program (only 47 enrolled).

Phase 3 HYPERION (sotatercept/WINREVAIR, Merck) — NCT04811092 — TERMINATED by design (Amendment 11) to move newly diagnosed PAH patients onto the approved drug — not a safety or futility stop.

Phase 3 LoTam / Alliance A012301 (low-dose tamoxifen) — NCT06671912 — SUSPENDED; ~1,556 planned in molecular low-risk early breast cancer. No reason given in the registry.

At the Agencies

FDA approval — vepdegestrant (VEPPANU), first PROTAC degrader — Cleared for ESR1-mutant ER+/HER2- advanced breast cancer; label confined to the ESR1-mutant subgroup (VERITAC-2).

EMA CHMP positive opinion — camizestrant (Etcamah) — 18-21 May 2026 meeting; recommends EU authorisation in ESR1-mutant ER+/HER2- breast cancer (also Jascayd/nerandomilast, oral Wegovy) — a recommendation, not a final marketing authorisation.

FDA Early Alert — Insulet Omnipod cannula tear — Potentially high-risk: cannula tear can cause silent insulin under-delivery with no Pod alert; certain Pod lots recalled (24 serious injuries, no deaths as of May 20, 2026).