Altered skin sensation with GLP1 - could it be something other than dyesthesia?

As blogged previously, GLP-1 based medications can sometimes cause dysesthesia, meaning unusual or altered skin sensations. This may feel like burning, tingling, sensitivity to touch, pain, or simply a strange sensation of skin discomfort. We don’t yet understand why this happens, but it appears to be related to exposure to GLP-1 based medications rather than weight loss itself. The risk of dysesthesia seems to be particularly with higher doses or more highly efficacious GLP1 medicines, having been noted in clinical trials of high dose semaglutide and retatrutide, and in postmarketing reports of tirzepatide.

While dysesthesia related to GLP-1 treatment does not appear to be harmful to health, there may be other possibilities to consider when a person develops symptoms of altered skin sensation.

One possibility to consider is nutritional deficiency. GLP-1 medications can substantially reduce food intake, and if the amount or variety of food being consumed decreases enough, vitamin or mineral deficiencies could potentially develop. Some deficiencies can cause neurological symptoms that could be mistakenly diagnosed as dysesthesia.

Examples include:

Vitamin B1 (thiamine) deficiency can cause tingling, burning sensations and neuropathic pain. Thiamine deficiency can also cause vomiting, diarrhea, and heart failure.

Vitamin B12 deficiency can cause peripheral neuropathy, often with numbness or tingling in a “stocking-glove” distribution.

Vitamin B6 (pyridoxine) deficiency can be associated with peripheral neuropathy.

Copper deficiency can cause numbness, tingling and burning (often “stocking-glove” distribution), sometimes accompanied by problems with balance or walking, spasticity, and/or hematologic (blood count) clues (eg low hemoglobin, low neutrophils).

Folate deficiency can also occur alongside other nutritional deficiencies and may cause neurological symptoms.

There are also many other potential explanations for altered skin sensations, including diabetic neuropathy, kidney disease, alcohol-related or chemotherapy-related neuropathy, infections, other neurological disorders, or skin conditions such as shingles. In people with diabetes, rapid improvement in blood sugars can itself sometimes precipitate neuropathy symptoms.

So how do we decide if a person’s symptoms are dyesthesia, or whether there is something else going on? There is currently no standardized published approach to diagnose GLP-1 associated dysesthesia – we are learning as we go! That being said, the timing could provide an important clue. As blogged previously, in the STEP UP study of semaglutide 7.2mg weekly, the increase in dysesthesia came on fairly soon after increasing the dose from 2.4mg (Wegovy dosing) to 7.2mg. Based on these data, if the symptoms begin soon after increasing the GLP-1 medication dose, this may be more in keeping with dysesthesia.

Features that suggest that the skin symptoms are NOT dysesthesia may include (note this is not an exhaustive list):

Symptoms that are in stocking/glove distribution, or asymmetrical
Abnormalities on neurological examination
Rash or other visible skin finding
Additional symptoms or physical exam findings are present (for example, as per nutritional deficiencies above, or in relation to other health issues listed above).

Depending on the history and physical exam, bloodwork/other appropriate investigations may be needed to check for nutritional deficiencies or to evaluate for other health issues.

If dyesthesia is suspected to be the cause of the symptoms, the clinical trials of semaglutide and retatrutide have shown that for most people, the symptoms were mild to moderate, and most resolve while people remain on treatment. However, for some people, dose reduction (or occassionally stopping treatment entirely) was required due to severity of symptoms. If symptoms are substantially bothersome and the dose is decreased/stopped, GLP-1 associated dysesthesia would be expected to resolve.

BOTTOM LINE: GLP-1 medications can cause dysesthesia, but don’t automatically assume that every new burning, tingling or unusual skin sensation is dysesthesia. Consider nutritional deficiencies and other neurological or medical causes, particularly if the symptoms or examination aren’t typical, or if there are symptoms or examination findings suggesting that something else is going on. The timing relative to GLP-1 dose changes, clinical assessment and appropriate investigations can help sort this out.

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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