Why we examine the effects of medications used in obesity beyond affecting your body weight?
Glucagon-like peptide 1 (GLP-1) was discovered in the 1980s. A GLP-1 receptor agonist ( GLP-1 RA), or hormonal agent that mimics the function GLP-1 was found in the Gila monster venom in the 1990s called exendin-4. This led to the use and approval of exenatide for type 2 diabetes. The reason these drugs have received so much acclaim is because of their effects in improving glucose control in diabetes, weight regulation, cardiovascular, and metabolic benefits. Some of several agents available include dulaglutide, semaglutide, and tirzepatide. There is a lot of press about obesity medications, with them advertised as the magic cure , but have we stopped to focus on the risks involved with the use of medications? All medications have risks attached along with the much publicized benefits. In this section we will delve deeper into the risk involved with GLP 1 agonists.
Documented side effects associated with these agents:
Gastrointestinal side effects
Pathophysiology:
GLP-1 RA affects the gastrointestinal tract by affecting motility by affecting the gastric pacemaker cells. This is more pronounced in diabetics who already have effects of the diabetes affecting the autonomic nervous system causing gastroparesis. This effect which is tied into benefits of early satiety and fullness and therefore decreased food intake and therefore weight control, can also cause other effects as follows:
Gastric food retention and increased risk of aspiration particularly from endoscopic procedures and surgeries. Unfortunately halting the drug prior to the procedure for 1 week, did not improve the food retention and aspiration risk associated with them . There was a 4.5 times as much Intestinal obstruction risk with hospitalization, associated with the use of GLP-1 RAs.
Hepatobiliary side effects
Pathophysiology:
The LEADER trial ( liraglutide effect and action in diabetes-evaluation of cardiovascular outcome results) reported a gallstone disease rate of 3.1% compared to 1.9% in placebo. This may be secondary to the fact that weight loss is associated with cholilithiasis or gall stones.
Weight reduction causes cholesterol to be saturated in the gallbladder to cause gallstone formation. GLP-1 also decreases the mobility of the gallbladder therefore decreasing or delaying gallbladder emptying. GLP-1 also causes proliferation of the cholangiocytes and increases the likelihood of duct obstruction.
Data from the trial reported a consistent increase in the following rates of incidence of disease among people on the medication. Liraglutide was found to have higher risk when compared to dulaglutide:
Complicated gallbladder stones
Uncomplicated gallbladder stones
Biliary obstruction
Cholecystitis with or without gallbladder stones
Pancreatic side effects
Pathophysiology:
Database analysis from 2004-2009 showed a 6 fold increase in pancreatitis with the use of DPP-4 Inhibitor sitagliptin and GLP-1 RA exanatide. There was an observed incidence of pancreatic cancer in patients who used these medications.
A recent evaluation of FAERS (FDA adverse event reporting system) from 2004 to 2020 showed a significant association between GLP-1RA use and the incidence of malignant or cancerous pancreatic tumors.
Many RCTs fail to demonstrate this association—this may be connected with their short duration compared to long term studies.
GLP-1 RA were associated with a 3 fold increase in pancreatic enzymes when compared to controls.
Rat models when treated with exanetide exhibited acinar-to-ductal metaplasia and ductal hyperplasia which may represent precursors to cancerous development.
Mental health side effects
Pathophysiology:
Mental health disease is an epidemic in today's society. It is important to note the GLP-1 receptors are present in different areas of the brain that include the hippocampus, amygdala and hypothalamus, therefore effects on mood may be central to our understanding of their mental health effects.
GLP-1 receptors also interact with neurotransmitters like serotonin, dopamine, and glutamate, that are central for mood regulation.
Suicidal ideation and depression needs to be monitored among patients who are on these medication. There was some association of suicidal ideation with liraglutide and semaglutide.
Ocular side effects
Pathophysiology:
The worsening of diabetic retinopathy among patients on GLP-1 RA, may be attributed to osmotic pressure changes rather than direct toxic effect on the retina.
Moreover the GLP-1 RA may cause upregulation of the VEGF( Vascular endothelial growth factor), which could promote angiogenesis or new blood vessel growth that could lead to retinal complications.
GLP-1 RA have a variety of beneficial effects, however their long term effects on the eye need to be understood. While examining the SUSTAIN trial with semaglutide, patients receiving the medication for more than 104 weeks had an increased risk of complications of already existing diabetic retinopathy with other complications that included vitreous hemorrhage, and blindness that required intervention.
The LEADER trial with liraglutide also showed a higher rate of retinopathy events than placebo.
This was also seen in the REWIND trial with dulaglutide, which resulted in interventions like vitrectomy, anti-vascular endothelial growth factor therapy and photocoagulation.
A meta-analysis of 13 random control trials revealed that GLP-1 RA which include semaglutide, liraglutide and dulaglutide are associated with a 23% increased risk of worsening diabetic retinopathy in diabetic patients with Type 2 diabetes.
The pathophysiology may involve increased diabetic retinopathy complications associated with deterioration in retinopathy secondary to the swift rapid glucose control.
NAION or Non-arteritic anterior ischemic optic neuropathy leading to visual loss was seen in users of semaglutide with an incidence of 4- 7 per 1000 person years in type 2 diabetic on the medication for 36 months. These results were not replicated, so it is important to observe with caution individuals who are on these medications.
It is important to note that GLP-1RA also offers direct neuro-protective effects that offer protection to the nervous system that includes the prevention of retinal neuro-degeneration. The ongoing FOCUS trial will give us more information about the effects of GLP-1 RA on eye health, particularly in patients with diabetes.
Effects on cancer:
There has been a study on the ongoing association on the incidence of malignant tumors in people treated with GLP-1 RAs. This includes breast, thyroid, biliary cancers. This outlines the importance of continuing to monitor patients on these medications for complications. The association still needs further clinical trials to confirm a solid link.
In a nut shell, these medications need more evaluation to determine the long term side effects. They have a host of benefits that have helped many people, however close observation of these side effects and intense patient education is needed before placing them on the medication. I believe knowledge is power, and it is vital for everyone to make an informed decision with respect to their health and treatment choices. As always, I wish you keep your health and nutrition in center focus and stay connected with your health care provider and live long and strong!
