From the Guidelines
Off-label microdosing of GLP-1 agonists is not a medically recommended practice for any disease, including nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), due to the lack of clinical evidence for safety and efficacy at sub-therapeutic doses. GLP-1 agonists like semaglutide (Ozempic, Wegovy), liraglutide (Victoza, Saxenda), dulaglutide (Trulicity), and tirzepatide (Mounjaro) are FDA-approved for type 2 diabetes and, in some cases, obesity at specific therapeutic doses 1. The use of GLP-1 agonists in patients with NAFLD or NASH has been studied, with semaglutide showing promise in a phase 2 trial of 320 patients with biopsy-proven NASH, where it achieved greater NASH resolution without worsening of fibrosis compared to placebo 1. However, these studies used therapeutic doses, not microdoses, and the benefits and risks of microdosing GLP-1 agonists are unknown.
The mechanism of GLP-1 agonists involves mimicking the incretin hormone to increase insulin secretion, decrease glucagon, slow gastric emptying, and promote satiety—effects that require appropriate dosing to be effective 1. If experiencing side effects with GLP-1 agonists, patients should consult their healthcare provider about proper dose titration rather than self-adjusting medication doses. The most recent and highest quality study on the use of GLP-1 agonists in patients with NAFLD or NASH is the phase 2 trial of semaglutide, which demonstrated significant benefits in NASH resolution and fibrosis improvement at therapeutic doses 1.
Some key points to consider when using GLP-1 agonists include:
- GLP-1 agonists have been shown to reduce albuminuria and slow eGFR decline in patients with chronic kidney disease (CKD) 1
- The most common side effects of GLP-1 agonists are nausea, vomiting, and diarrhea, which can be managed with dose titration and usually abate over time 1
- GLP-1 receptor agonists do not cause hypoglycemia per se, but may increase the risk of hypoglycemia when used with insulin or insulin secretagogues 1
- The use of GLP-1 agonists in patients with CKD requires careful consideration of the benefits and risks, and patients should be closely monitored for adverse effects 1.
From the Research
Off-Label Microdosing for Diseases Using GLP-1 Agonists
- GLP-1 agonists have been explored for their potential in treating various diseases beyond their approved indications, including obesity, non-alcoholic steatohepatitis (NASH), and neurodegenerative diseases such as Parkinson's and Alzheimer's disease 2.
- Semaglutide, a GLP-1 receptor agonist, has shown therapeutic potential in abating obesity, NASH, and neurodegenerative diseases, with significant weight reduction ability demonstrated in various phase-3 clinical trials 2.
- GLP-1 receptor agonists have also been investigated for their role in preventing cardiovascular disease, with evidence suggesting that they can decrease cardiovascular risk and have cardioprotective effects 3, 4.
- The use of GLP-1 agonists for off-label indications requires careful consideration of the ethical, practice, and policy implications, including informed consent and documentation of the reason for off-label use 5.
- Real-world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of GLP-1RA-based weight-loss therapies is emerging, with studies suggesting that these medications can be effective in achieving significant weight loss, but may have limitations in real-world settings due to factors such as discontinuation rates and dosing 6.
Diseases Treated with GLP-1 Agonists
- Obesity: GLP-1 agonists such as semaglutide and liraglutide have been approved for the treatment of obesity, with significant weight reduction ability demonstrated in clinical trials 2, 4.
- Non-alcoholic steatohepatitis (NASH): GLP-1 agonists have shown therapeutic potential in treating NASH, with evidence suggesting that they can improve insulin resistance and reduce liver inflammation 2.
- Neurodegenerative diseases: GLP-1 agonists have been investigated for their potential in treating neurodegenerative diseases such as Parkinson's and Alzheimer's disease, with evidence suggesting that they may have neuroprotective effects 2, 3.
- Cardiovascular disease: GLP-1 agonists have been shown to have cardioprotective effects and may be used to prevent cardiovascular disease in patients with type 2 diabetes or obesity 3, 4.