#372 Mission Slimpossible Part 2: Oral GLP-1 agonists for weight loss
CLINICAL QUESTION
Are oral GLP-1 agonists effective for weight loss?
BOTTOM LINE
In adults with obesity, oral semaglutide in a new high-dose formulation (50mg daily; not available in Canada) can result in ~15% body weight loss at 68 weeks (versus 2% placebo), with 69% of people losing at least 10% of their body weight (versus 12% placebo). Mean weight loss with the currently available 14mg formulation is ~5%.
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EVIDENCE
- Results statistically different unless indicated.
- One industry-funded randomized, controlled trial (RCT)1 on weight loss:
- 667 adults with obesity and no diabetes (105 kg, BMI=38), given semaglutide 50mg (modified formulation) orally or placebo for 68 weeks, plus lifestyle intervention. At 68 weeks:
- Mean weight loss: 15% (16kg) versus 2% (2.5kg) placebo.
- Proportion of patients with >10% weight loss: 69% versus 12% placebo.
- Withdrawals due to adverse events: 6% versus 4% placebo (statistics not provided):
- Mainly gastrointestinal.
- Gallbladder disorders (mainly cholelithiasis) 4% versus 1% placebo (no statistics).
- “Altered skin sensation” (examples: paresthesia, sensitive skin): 13% versus 1% placebo (no statistics).
- 667 adults with obesity and no diabetes (105 kg, BMI=38), given semaglutide 50mg (modified formulation) orally or placebo for 68 weeks, plus lifestyle intervention. At 68 weeks:
- Systematic reviews (3-11 RCTs, 1300-9890 patients) where weight loss was secondary outcome (up to 14mg semaglutide):
- ~3kg more weight lost than placebo at 26-82 weeks.2-5
- Gastrointestinal side effects 4-9% versus 1-2% placebo.3
- Industry-sponsored RCT (weight loss as secondary outcome) not in above reviews.6 1606 patients with diabetes (96kg, BMI=34), given semaglutide 14mg, 25mg, or 50mg. At 52 weeks:
- Mean weight loss: 5.4% [4.4kg (14mg)], 6.6% [6.7kg (25mg)], 7.3% [8kg (50mg)]. No statistics 25 versus 50mg doses.
- >10% weight loss: 14% (14mg), 29% (25mg), 37% (50mg), no statistics 25 versus 50mg.
- Withdrawals due to adverse events: 10% (14mg), 12% (25mg), 13% (50mg). No statistics.
CONTEXT
- Weight loss is dose dependent, with efficacy similar between semaglutide 50mg oral daily and 2.4mg subcutaneous weekly.6,7
- Oral semaglutide used in RCTs (i.e., 50 mg) is a different formulation than the one currently available (i.e., 3-14mg) (altered to improve bioavailability).1
- Low-dose oral semaglutide (14mg) daily costs~$250/month; not covered by most insurance plans. Cost of higher dose not yet known.
- Other oral GLP-1 agonists in development; may have similar benefits.8
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Cost may prohibit patients use. Oral use may be an option for patients who do not want T to give injections. Weight loss occurs with oral dosing.
Too many questions to answer.
Worried about side effects at higher dose
The side effects are concerning as well as the costs.
Cost is definitely an issue
Oral Semaglutide may have a role in weight-loss management in patients who are needle-phobic, but there are no other advantages otherwise.
Seems to fit with what we know. But you are on them for life or the weight comes back.
So, in Knop et al: the typical patient weighed 231 lbs – after 68 weeks (more than 15 months) had lost 35 lbs, subsequent body mass 196 lbs. Once this becomes available, there will likely be many who weigh less who will consider this therapy. They almost certainly will lose less than 35 lbs, and likely lose less than 15% of body weight, although perhaps a similar proportion of excess weight – weight over and above what would be considered normal.
didn’t know about skin sensitivity
Il serait intéressant d’avoir un suivi cardio-vasculaire chez les répondants après 1 an ou davantage.
Oral semaglutide has some drawbacks.
Rebound weight gain on discontinuing the medication can often be 100% of the weight lost. If a patient wants to keep the weight off they generally must stay on the medication. “Like taking BP medication”, the drug rep told me. Having to stay on the medication a lifetime raises a lot of questions.