Glucagon-like Peptide-1 Receptor Agonists: Possible Panacea?

/ lionstalkscience

By Brianna Evans

A glucagon-like peptide-1 receptor agonist (GLP-1RA) is becoming the hot new wonder-drug! Heard of it? No? Perhaps its more common name, then – let’s talk about Ozempic®. The GLP-1RA Ozempic (semaglutide) treats Type II Diabetes and has lately been highly prescribed for weight loss. Many celebrities including Oprah Winfrey and Elon Musk have been open about their use of Ozempic for weight management. As a further testament to how quickly and powerfully the drug has made a cultural impact, the Hulu program IMPACT x Nightline  examines ‘The Real Housewives of Salt Lake City’ star, Heather Gay, and her lifechanging experience from Ozempic. Moreover, “Budget Ozempic” has become a TikTok trend. But what do we know about this drug?

GLP-1RAs mimic the effects of endogenous GLP-1, a protein discovered in humans in 1987. GLP-1 is produced in the L-cells, a special type of cell in the small intestines, or in the nucleus tractus solitarius (NTS) region of the brain stem. To understand how GLP-1 works, it is important to understand glucose metabolism, especially when it comes to insulin and glucagon. When we get glucose – a type of sugar – into our bloodstream from eating a meal, it triggers insulin release from beta cells of the pancreas.  The insulin, now circulating around the body, induces cells to take in that glucose from the meal, which cells can use as an energy source. This causes our blood glucose levels to drop – there’s less in our bloodstream since it’s being used by our cells. If we have not eaten for a while, glucagon is released from the alpha cells of the pancreas and induces glucose production to increase glucose in our blood stream. Essentially insulin and glucagon are the yin and yang of our metabolism. GLP-1 is a type of gut peptide that increases the release of insulin and decreases the release of glucagon after food intake. This means GLP-1 decreases the amount of glucose in our bloodstream, increases thermogenesis in brown adipose tissue, and decreases gastric emptying (Figure 1).  Thermogenesis in brown adipose tissue helps us maintain our body temperature when in a cold environment. Reduced gastric emptying helps one feel full and reduces their calorie intake.

Figure 1: Demonstrates the many activities of GLP-1RA particularly when it comes to food intake and metabolism. GLP-1Rs are found throughout the brain, particularly in areas implicated in satiety (Hyp=hypothalamus) and reward (Nucleus Accumbens (NAc) and Ventral Tegmental Area (VTA). Figure from [14]

GLP-1 also has a significant effect on the liver when it comes to metabolism. The liver stores glucose reserves in the form of glycogen, which is just many connected glucose molecules. For the liver in particular, insulin increases uptake of glucose as well as the process of glycogen synthesis (storing that excess glucose), and decreases gluconeogenesis (making more glucose – the body doesn’t need to synthesize more since the insulin signal is saying “hey, check it out! We just got a windfall of glucose!”). Glucagon induces breakdown of glycogen into glucose to increase glucose levels in the blood stream. Through GLP-1’s interactions with insulin and glucagon, we can maintain balanced levels of glucose in our blood stream and have more energy for our cells. Since GLP-1RA drugs mimic GLP-1, they are currently FDA approved to treat Type II Diabetes, a disease where blood glucose balance is out of whack, as well as obesity (although the mechanism of action for GLP-1RAs against obesity is not as clear, the drugs do help patients feel fuller after meals). Since the turn of the century, several different GLP-1RAs have been brought to the market, but many have been discontinued due to toxicity or poor market performance (Figure 2).  

Figure 2: Timeline of GLP-1RA development and discontinuation. [7-13]

GLP-1RAs aren’t only used for diabetes and obesity – they can also treat additional conditions, including substance use disorder (SUD). According to the CDC, in 2021 there were 106,699 drug overdose deaths in the United States.3 SUD poses a significant health risk and has led to many deaths, particularly when involving opioids; opioid deaths make up over 70% of overdose fatalities.4 Although there are already some medications to treat different substance use disorders, overdose deaths remain a problem. For example, methadone and buprenorphine treat opioid use disorder (OUD), but due to limited access and opioid stigmatization, opioid overdoses remain a problem.

Fortunately, there is evidence that GLP-1RAs, like Ozempic®, can treat SUD. Many animal studies have found that GLP-1RAs cause reduction of preference, intake, and seeking behaviors with alcohol,16-18,21 nicotine,22-23 cocaine,19-20 amphetamine,20,24 and opioids.25-27 These animal studies have taught scientists that finding the optimum dose is key for favorable results. The research also emphasized that with both acute and chronic GLP-1RA treatment, addiction behaviors can be mediated particularly in more vulnerable populations.  Moreover, GLP-1RAs were found to reduce the three roads to relapse: cue-, drug-, and stress-induced seeking behaviors. Cue-induced seeking is when a location or other familiar sight puts someone into withdrawal and causes them to seek a drug. Drug-induced seeking is when someone takes a drug after not having it for a while and then is primed to seek more. Stress-induced seeking is when there is a stressor that makes someone go into withdrawal and seek drug to reduce their stress.   As for humans, observational studies have found that those taking GLP-1RAs for weight loss treatment have also noticed decreased desire for alcohol.32 Several randomized controlled GLP-1RA addiction studies have been or are being conducted in humans as well (Table 1).28-31 Excitingly, our institution, Penn State College of Medicine, ran clinical trial (NCT04199728) at the Caron Treatment Center and found significant reduction in cravings when using the GLP-1RA, Liraglutide, to treat OUD. They are currently extending the clinical trial to outpatient locations.

Table 1: Clinical Trials with GLP-1RA treatment for SUDs. [28-31]
NRT=Nicotine Replacement Therapy

In addition to weight loss, type 2 diabetes treatment, and SUD treatment, GLP-1RAs have been found to cause positive health outcomes in other parts of the body. These include: improved cardiovascular function;33-34 reduced COVID-related death in patients with type 2 diabetes;35 reduced anxiety and depression;36 reduced risk of prostate cancer;37 improved outcomes with neurodegenerative diseases;38,40 and reduced suicidal ideation.39 Now, while many of these improvements could correlate with GLP-1RAs effects on metabolism, there still needs to be more research to discover how GLP-1RAs are helping with these outcomes.

As with all medications, GLP-1RAs do have side effects. Common negative side effects associated with GLP-1RAs are GI distress, weight loss (if not intended), and irritation at the injection site (since most GLP-1RAs are administered as subcutaneous injections). GI distress is a big factor in why patients drop out of clinical trials utilizing GLP-1RAs. More serious side effects include acute gall bladder disease and renal impairment, among others. Thyroid cancer, acute pancreatitis, and suicidal behaviors/thoughts are also considered possible serious adverse side effects, though there are studies that have found that these are not the case.39,41-42 Overall, the reaction to GLP-1RAs depends on the individual taking it. GLP-1RAs like Ozempic have much promise in many realms of health care, particularly with metabolism and addiction, but there is still much work that needs to be done to understand how they work and why they have the effects they do.  Even though the full mechanism of action is unknown for GLP-1RAs, Ozempic and other GLP-1RAs remain in high demand for their demonstrated effects on weight loss, to the point that there are shortages nationwide. So, if you’ve seen Ozempic in the headlines and were wondering “hey, what’s that?” – we hope this article has provided some helpful information!

TL;DR

  • Ozempic® is a GLP-1RA, a class of drug which can have many clinical uses.
  • GLP-1RAs stimulate insulin release and lower blood glucose levels.
  • More work is needed to fully understand the mechanism of GLP-1RAs.

Reference

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