Can GLP-1 medications cause funky skin sensations (dysesthesia)?

GLP-1 based medications are used for treatment of type 2 diabetes, and for weight management. An unexpected potential side effect that has emerged is altered skin sensations, called ‘dysesthesia’. This can include:

increased or altered sensation when skin is touched
altered sense of pain in the skin
abnormal sensation in the skin
a burning sensation in the skin
sensitive skin
skin discomfort

Dysesthesia was first noted in 2023 in studies of high dose oral semaglutide (as blogged here) and the highly efficacious retatrutide, which is a GLP1/GIP/glucagon triple agonist weight management medication currently under development. There are postmarketing reports with tirzepatide (Zepbound/Mounjaro) and injectable semaglutide (Wegovy) as well. Recently, the STEP-UP obesity trials of high dose semaglutide in people without type 2 diabetes and with type 2 diabetes, give us more information on this topic.

In the STEP UP trials, semaglutide 7.2mg weekly [yes, a triple dose of the current maximum dose of injectable semaglutide (Wegovy – 2.4mg)] was evaluated, in people with obesity without type 2 diabetes (STEP UP) and in people with obesity with type 2 diabetes (STEP UP T2D).

In STEP UP, dysesthesia was seen in 22.9% of people with semaglutide 7.2mg, vs 6% of people in the semaglutide 2.4mg group (Wegovy dose), and 0.5% of the placebo group. In STEP UP T2D, dysaesthesia was seen in 18.9% of the semaglutide 7.2mg group, vs 4.9% with semaglutide 2.4mg (Wegovy dose), and none in placebo. For most people who experienced dysesthesia, it was mild or moderate in severity, and resolved before the end of the trial. However, in the STEP UP trial, one in five people who had dysesthesia in the 7.2mg group needed a dose reduction, and four people in the 7.2mg group stopped treatment due to dysesthesia. There were no serious events related to dysesthesia.

So why can altered skin sensation happen? At this time, no one knows. It does appear to be dose-dependent, and more prevalent with use of very high doses, or very highly efficacious, GLP1-based medications. Some have wondered if it could be due to loss of fat tissue under the skin. However, in STEP UP, the increase in dyesthesia at the 7.2mg dose came on fairly soon after increasing the dose from 2.4mg directly to 7.2mg, suggesting that it is NOT related to weight or fat loss. It has been hypothesized that it may be a GLP-1 agonist effect on nerve signaling, or that it may be an effect of GLP-1 medications on small blood vessels. I heard one neuroscientist wonder whether there could be stimulation of the temperature regulation center of our brain (re the ‘burning’ variant), which is very close to the appetite center. While it remains a mystery as to why dysesthesia can happen, based on the existing data, it does not appear to be harmful to health.

BOTTOM LINE: GLP-1 medications can cause altered skin sensations (dysesthesia). This appears to be more common with higher doses and/or more potent GLP-1 based therapies. If it occurs, it seems to be mild to moderate in most cases during dose escalation and resolves on its own, but some people may need to decrease the dose or stop treatment entirely if it is sufficiently bothersome. While we don’t yet understand why it occurs, dyesthesia caused by GLP-1 based medications does not appear to be harmful to health based on the currently available evidence.

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

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