Could GLP-1 agonists be more than just a treatment for diabetes?
High-profile coverage of the off-label use of Ozempic, a GLP-1 agonist, for weight loss, has meant that the type 2 diabetes drug has received a lot of bad press. As more studies into the long-term impact of this group of drugs are published, other potential benefits of the drug are emerging.
A pharmacy technician grabs a bottle of drugs off a shelve at the central pharmacy of Intermountain Healthcare on September 10, 2018 in Midvale, Utah. Image credit: George Frey/Getty Images.
Glucagon-like peptide-1 (GLP-1) agonist drugs have been prescribed for people with type 2 diabetes and obesity for nearly 20 years, as they were first licensed by the Food and Drug Administration (FDA) in 2005.
Since then, a number of long-term studies have emerged evaluating both their benefits and their risks, along with some results suggesting potential for further uses.
Glucagon is a hormone released from the islets of Langerhans in the pancreas, and it plays an important role in maintaining sugar levels balanced in the body.
When blood sugar rises, glucagon binds to a specific receptor on the surface of beta cells in the pancreas, causing them to release insulin to convert the sugar in the blood and store the excess glucose into glycogen.
Type 2 diabetes occurs when a person cannot create enough insulin for the body to function, or their cells are not sensitive to insulin meaning they need more of it than normal.
This same receptor on the pancreatic beta cells is bound to by another hormone called glucagon-like peptide. The glucagon-like peptide is released by the intestines within minutes of eating food.
Researchers initially thought this hormone only affected insulin release, but further research showed that its presence increased glucose uptake and glycogen synthesis in cells, delayed gastric emptying, and increased the feeling of fullness after eating. Glucagon levels are lower in the presence of glucagon-like peptide.
GLP-1 agonists are drugs developed to act analogously to glucagon-like peptide, by binding to the same receptor on pancreatic beta cells they increase the release of insulin.
This improves glucose metabolism and therefore blood glucose levels in people with type 2 diabetes.
These drugs are taken as injections and include:
- semaglutide, known as Ozempic
- dulaglutide, known as Trulicity
- lixisenatide, known as Lixumia
- liraglutide, known as Victoza
- exenatide, known as Bydureon and Byetta.
GLP-1 receptors are also present in the hypothalamus, a region of the brain involved in the regulation of food intake and energy balance, and activation of these receptors can reduce caloric intake leading to weight loss.
Weight loss achieved by using the drug further improves outcomes for people with type 2 diabetes, meaning this is a desirable side effect for this group of patients.
However, the drug is not currently licensed to treat obesity by the FDA in the United States, but it is sometimes prescribed off-label for this purpose. The drug is not without potential side effects, most notably, gastric upset.
Moreover, a warning issued by the FDA on May 31, 2023 emphasizes that, in the US, “there are no approved generic versions” of drugs like Ozempic, and while altered versions of the original formulation of these drugs may circulate on the market, these are apt to cause various side effects.
Such altered versions of the drug, known as compounded semaglutide, “may not contain the same active ingredient as FDA-approved semaglutide products,” and “have not been shown to be safe and effective,” the official warning states, and people should avoid purchasing these compounds.
While some people use GLP-1 agonists to attain weight loss, this may not be the only beneficial side effect of this group of drugs.
People with obesity are more likely to develop cancer, though the mechanisms that underpin this risk are myriad, and subject to intense debate. This may partly be because people with obesity have more cells in their bodies that can become cancerous.
There is an increased cancer risk associated with height in women and men globally, for the same reason. Weight loss has been shown to reduce the overall risk of cancer.
Outside of this theory, another reason why people with obesity might be more likely to develop cancer is due to the impact it can have on a type of immune cells known as natural killer cells.
These cells are crucial for detecting and destroying tumor cells. Evidence has existed since 2010 showing that obesity disrupts the ability of natural killer cells to do this, therefore increasing the risk of cancers developing.
A study in 2018 demonstrated this was linked to the accumulation of lipids in natural killer cells.
This year, a small study of 20 people with obesity published in the journal Obesity suggested that GLP-1 drug treatment restores the natural killer cell anti-tumor benefits of people with obesity, independent of a reduction in weight.
The study did not show a reduction in cancer risk in patients, just a potential mechanism by which it could restore anti-tumor mechanisms.
GLP-1: Do they lower or heighten cancer risk?
“Weight loss and better control of diabetes could potentially reduce the obesity-driven hormonal imbalances and inflammation, thereby possibly affecting the cancer-promoting pathways,” said Dr. Wael Harb, hematologist and medical oncologist at MemorialCare Cancer Institute at Orange Coast Medical Center, CA, in an email to Medical News Today.
He went on:
“Determining the impact of GLP-1 drugs on cancer risk is complex due to multiple factors. These include patient heterogeneity, the role of concomitant medications, variations in the duration and dosage of GLP-1 drugs, and the presence of other risk factors like genetics and lifestyle factors. Also, cancer is a disease that develops over a long period, making it challenging to establish a direct cause-effect relationship in clinical studies.”
The FDA currently includes a warning on the drug that it has been linked to medullary thyroid cancer and can not be used in people with a family history of this cancer.
One study showed an increase in the risk of thyroid cancer of 58% in people who had used GLP-1 drugs for 1-3 years, and a 78% increase in risk of medullary thyroid cancer.
Another observational study, which looked at data collected between 2004 and 2021, showed that while there was no overall increase in risk of tumors in patients, the data did suggest there was a trend showing increased risk of certain cancers including thyroid in GLP-1 drug users.
Its authors suggested that it is unclear whether the increased risk of thyroid cancer is due to the use of GLP-1 drugs, or whether it is potentially caused by the use of these drugs alongside dipeptidyl-peptidase IV inhibitors (DPP4i), which are a drug commonly used in people with type 2 diabetes.
Dr. Harb said: “Future research should focus on long-term studies to assess the potential impact of GLP-1 drugs on cancer risk, with particular attention to different types of cancer. These studies should account for other potential confounding factors such as the use of other medications, lifestyle changes, and genetic predispositions.”
Type 2 diabetes is associated with an increased risk of cardiovascular events, as well as damage to small blood vessels. Damage to small blood vessels due to prolonged high blood sugar levels leads to complications, such as diabetic retinopathy, that can lead to sight loss.
Heart disease is twice as likely to occur in people with type 2 diabetes and the risk of it increases the longer you have the condition, according to the Centers for Disease Control and Prevention (CDC).
Better control of blood glucose levels in people with type 2 diabetes can improve cardiovascular outcomes and limit small blood vessel damage.
Previous research published in the New England Journal of Medicine has shown that, in a United Kingdom cohort, strong blood glucose control using other diabetes drugs improved cardiovascular mortality rates due to a lower risk of heart attack, over a 10-year period.
In May 2023, a study was published in the Annals of Internal Medicine that showed that the risk of heart failure and hospital admission for major cardiac events, such as heart attack and stroke, was lower in individuals who had received GLP-1 drugs, compared to other glucose-lowering medications.
It has not yet been demonstrated how much of the findings were due to weight loss versus better glucose control. However, the findings led some expert commentators to suggest that glucose-lowering drugs should be considered more for people at risk of cardiovascular disease.
Dr. Michael Broukhim, an interventional cardiologist at Providence Saint John’s Health Center in Santa Monica, CA, told MNT that: “GLP-1 agonists help with weight loss, which improves a patient’s cardiometabolic status. Glycemic control is essential to benefit cardiovascular health. GLP-1 agonists slightly reduce blood pressure and slightly improve cholesterol levels.“
“These agents are most useful in patients with established atherosclerotic cardiovascular disease. They are thought to possibly have anti-inflammatory effects that may lead to more stabilized atherosclerotic plaques,” he added.
Both obesity and type 2 diabetes are linked to developing Alzheimer’s disease — obesity more strongly. One 2020 study of a cohort of over 6,500 individuals in England showed that obesity and a higher waist measurement were both linked to a higher rate of Alzheimer’s disease.
The link between type 2 diabetes, drugs to treat it, and Alzheimer’s risk is more complex, in part because tightly controlled blood sugar actually increases the risk of cognitive impairment, thought to be due to low levels of sugar reaching a part of the brain called the hippocampus.
However, recently, some evidence has emerged suggesting GLP-1 treatment can help to reduce the accumulation of amyloid protein in the hippocampus, the presence of which is believed to contribute to the development of Alzheimer’s disease symptoms.
This study did not investigate the possibility that GLP-1 treatment reduces the risk of developing Alzheimer’s disease due to other actions, such as the reduction in inflammation, which is also thought to contribute to Alzheimer’s disease development.
The myriad actions of GLP-1 drugs could be viewed as something of a double-edged sword. While they may have a vast range of potential effects on the body, these could be beneficial to some patient populations and problematic in others. Research needs to take a granular approach to disentangle these questions.
Dr. Michelle Pearlman, a specialist in Internal Medicine, Gastroenterology, and Obesity Medicine told us in an email:
“Further research is needed to expand the understanding of which patient groups beyond the existing ones can benefit from the use of GLP-1 medications. Specifically, there is a need to investigate the long-term effects of these medications in non-diabetic individuals, as the existing data primarily focuses on diabetic patients.“
“Determining the duration of GLP-1 medication usage once a patient achieves their target weight is another important area of study. It is crucial to explore strategies to prevent weight regain after discontinuing the medication,” she added.
A closer look needed to be taken at the risks associated with these drugs, said Dr. Harb, “to develop a comprehensive understanding of their risk-benefit profile.”
