List of possible side effects of GLP-1 receptor agonists.
Conventionally, side effects can be divided into short-term and long-term (associated with stimulation of the growth of various cells and a potential increase in the risk of cancer, the full development of which may take 10-25 years). It is important that these drugs not only affect satiety but also increase (insulin release) and block (ghrelin release), which have a wide range of effects.
1. Distortion of taste.
A change to your sense of taste. The taste changes and the taste is distorted, what was salty or sweet is now bitter, and aversion to favorite food tastes, the appearance of a sulfurous, rotten, or metallic taste of food. There's no research yet on exactly what might be going on but some say their taste buds have changed.
2. Rapid return of weight and disappearance of metabolic benefits after withdrawal.
The data shows that the majority of patients will regain the weight they lose when they discontinue use. This paper reported that one year after semaglutide injections were stopped, participants regained two-thirds of the weight they lost. Even worse is that the cardiometabolic improvements displayed while on the drug also returned to baseline. Even those taking GLP-1s eventually plateau after losing weight for a year. https://pubmed.ncbi.nlm.nih.gov/35441470/ The more often weight jumps occur, the higher the risk of weight gain in the long term.
3. Muscle loss.
In a 2021 clinical trial testing the weight loss effects of Wegovy, it was found that about 40% of the weight participants lost tended to be lean mass, including muscle. The data also demonstrated that 39% of the total weight loss from semaglutide came from muscle. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183, https://link.springer.com/article/10.1007/s00125-019-05065-8
4. Gastrointestinal disorders
(typically nausea, diarrhea, vomiting, and constipation). Around 2% of patients taking semaglutide in clinical trials reported gallbladder impairment or gallstones. Once-Weekly Semaglutide in Adults with Overweight or Obesity. The New England Journal of Medicine, [online] 384(11)
5. Pancreatitis.
Incretin mimetics have previously been linked to a risk of severe pancreatitis. In clinical trials of Victoza, there were 13 cases of pancreatitis reported vs. one for a comparison drug. In clinical trials of Saxenda, there were nine cases of acute pancreatitis among 3,291 people who got the drug vs. one case in the 1,843 who got a placebo. An increase in pancreatic enzymes, such as lipase and amylase https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017323/
6. Fatigue, depression and suicidal thoughts
The development of fatigue, fatigue, depression and an increase in the number of suicidal thoughts. Adult clinical trials showed that 0.3% of patients taking Saxenda reported thoughts of suicide while 0.1% of the patients taking the placebo reported the same. In the United States, it is recommended that patients be monitored for suicidal thoughts and depression and that the drug be stopped immediately if symptoms develop.
Incretin GLP-1 non-specifically inhibits the activity of dopamine VTA neurons, the production of dopamine, and the activity of the nucleus accumbens. GLP-1 agonists suppress the activity of the hunger hormone ghrelin, and through this indirectly reduce the release of dopamine - and you want to eat less, but also live less.
EMA statement on ongoing review of GLP-1 receptor agonists https://www.ema.europa.eu/en/news/ema-statement-ongoing-review-glp-1-receptor-agonists
Long-term side effects.
These studies assess risk, but a reliable assessment is difficult. Drug receptors are found on many tumor and normal cells, so they can stimulate their growth or malignant transformation. However, cancer development is long, so it is difficult to assess. For example, development of pancreatic cancer is a multistage process which takes 10 to 15 years.
1. Pancreas cancer.
Evidence is unclear, the risk is higher for people without diabetes. Knapen et al. found that the risk of pancreatic cancer almost doubled in those who had recently initiated GLP-1 analogs therapy. This risk was almost doubled among current incretin users compared to control subjects. Incretin use was not associated with pancreatic cancer when compared with control subjects with diabetes; however, the 'new user' design did show an association between incretin use and pancreatic cancer when compared with control subjects with diabetes.
No risk in this study: Use of incretin agents and risk of pancreatic cancer: a population-based cohort study. Diabetes Obes Metab (2016) 18:258–65.
2. Thyroid cancer.
Increased risk of thyroid cancer in animals; in humans, a small, non-statistically significant increase in risk. The odds ratio for thyroid cancer occurrence associated with liraglutide treatment was 1.54, but that was not statistically significant. But these instances have led to warnings on the labels of GLP-1 medications and recommendations against taking these drugs for individuals with a family or personal history of thyroid cancer.
3. Breast cancer.
Does not increase risk, but potentially accelerated tumor growth. Use of GLP-1 analogues was not associated with an overall increased risk of breast cancer. Although it is not possible to rule out a tumour promoter effect, the observed duration-response associations are likely the result of a transient increase in detection of breast cancers in GLP-1 analogue users.
Glucagon-like peptide-1 analogues and risk of breast cancer in women with type 2 diabetes: population based cohort study using the UK Clinical Practice Research Datalink https://www.bmj.com/content/355/bmj.i5340
4. Colon cancer.
Animal studies, no human data yet. Drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists may increase cell division in the gut, increasing the risks of colon cancer. https://www.cell.com/cell-metabolism/fulltext/S1550-4131(15)00057-1