For some people taking injectable GLP1 medications tirzepatide (Mounjaro/Zepbound) or semaglutide (Wegovy) for weight management, switching to a GLP1 medication in a pill form may look attractive. A pill does not need to be refrigerated, there are no bulky pens to carry around, traveling with them is easier, and they may be cheaper to purchase. (Note to Canadians – GLP1s in a pill are not yet available, but expected to come to Canada soon). For a background on GLP1 pills, check out my prior blog here.

Hot off the presses in Nature Medicine, the ATTAIN-MAINTAIN study aimed to answer this question: Can people maintain weight and health benefits after switching from injectable GLP1 to oral GLP1 orforglipron? And will a switch be well tolerated from a side effect perspective?

First, I’ll say that this study had a complicated protocol, and extremely complicated set of analyses conducted. This isn’t the kind of study where one can just read the main findings to understand what it teaches us. So let’s walk through it together, and I’ll highlight the findings that can really guide clinicians and patients in their decision making!

The ATTAIN-MAINTAIN study looked at people who had stuck with treatment in the SURMOUNT-5 study (blogged here) with either tirzepatide (maximum tolerated dose, 10mg or 15mg weekly, 205 people) or semaglutide (maximum tolerated dose, 1.7mg or 2.4mg weekly, 171 people). They randomized people in a 3:2 ratio to receive either orforglipron (started at 12mg daily and titrated up to 36mg or max tolerated dose of 24mg or 36mg) or placebo for 1 year. Participants had to have lost at least 5% weight during the SURMOUNT-5 study, and had to have a BMI of at least 22 at the end of SURMOUNT-5 (ie at the start of ATTAIN MAINTAIN).

First, let’s look at the two groups at the start of the ATTAIN-MAINTAIN study (ie, at the end of the SURMOUNT-5 study). People who finished the SURMOUNT-5 study on tirzepatide had a lower average weight (90.1kg) and BMI (31.2) at the start of ATTAIN-MAINTAIN than those who had been on semaglutide (94.4kg and BMI 33.2). Metabolic health was similar in the two groups, with the exception that 15% of the sema group had prediabetes range A1c at the start of ATTAIN-MAINTAIN, vs 5.9% of the tirzepatide group.

Before we get into the results of ATTAIN-MAINTAIN, here’s a KEY point to note: starting at week 24, if 50% of weight lost during SURMOUNT-5 was regained during ATTAIN-MAINTAIN, orforglipron rescue therapy was started – meaning that the placebo group would get orforglipron (a very patient-centric protocol, which is great!).

THE RESULTS: The primary endpoint of the study showed that for people who initially lost 21.5% weight and were weight stable with tirzepatide, when switched to orforglipron, they maintained 74.7% of their weight lost with tirzepatide. The people switched to placebo maintained 49.2% of their weight lost with tirzepatide. However, 65% of people in the placebo group received orforglipron rescue therapy because they had regained at least 50% of their weight lost originally, so the weight maintenance in the placebo group reflects that many people in this group switched from placebo to orforglipron. Also, in the group assigned to switch directly from tirzepatide to orforglipron from the start, 16.8% of participants regained at least 50% weight. For people who were adherent to treatment with the direct switch to orforglipron, their weight loss from baseline of beginning of tirzepatide to the end of the orforglipron treatment was 16.8% (so up about 5kg with switch from tirzepatide to orforglipron). Much of the metabolic health improvements (eg blood sugars, cholesterol, BP) seen with tirzepatide were well maintained with orforglipron therapy, except for blood pressure which was lowest at the end of tirzepatide treatment.

For people who initially lost 16.5% weight and were weight stable with semaglutide, when switched to orforglipron, they maintained 79.3% of their weight lost with semaglutide. The people switched to placebo maintained 37.6% of their weight lost with semaglutide. However, 64.6% of people in the placebo group received orforglipron rescue therapy. In the group assigned switch directly from semaglutide to orforglipron from the start, 21.9% regained at least 50% weight. In the group adherent to treatment with the direct switch to orforglipron, weight loss from the baseline of starting semaglutide to the end of the orforglipron treatment was 15.1% (so up about 1kg with switch from semaglutide to orforglipron). Metabolic health improvements (eg blood sugars, cholesterol, BP) seen with semaglutide were well maintained with orforglipron therapy.

Another interesting data point is this: for people initially on tirzepatide and switched to orforglipron, 43.7% were able to maintain at least 80% of the weight loss they had achieved with tirzepatide. For people intially on semaglutide and switched to orforglipron, 55% were able to maintain at least 80% of the weight loss they had achieved with semaglutide.

There were no new safety concerns with orforglipron in this study. The direct switch from either tirzepatide or semaglutide to a ‘medium’ dose of orforglipron of 12mg daily (and titrated up from there) was well tolerated.

BOTTOM LINE: People switched from either tirzepatide (Zepbound/Mounjaro) or semaglutide (Wegovy) to oral GLP1 orforglipron were able to maintain much of their weight loss and metabolic health benefits, with some regression of both on average, and a wide range of response from one person to the next (as is typical of weight management medication). For people wanting the most possible weight and metabolic health benefit, this study suggests that it’s best to stick with the injectable. For those who feel a pill would be more convenient, or potentially cheaper, some will do quite well with a switch to orforglipron. It’s important to also remember that, per our Obesity Canada Clinical Practice Guidelines and other guidelines around the world, we should be guiding medication choice according to the health benefits that are proven for each medication.

Disclaimer: I am/have been an investigator in clinical trials of orforglipron, semaglutide and tirzepatide.   I receive honoraria as a continuing medical education speaker and consultant from the makers of orforglipron and tirzepatide (Eli Lilly) and semaglutide (Novo Nordisk).

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