(Yes, it Sounds Like a Nursery Rhyme)
All of the anti-obesity medications on the market come with a list of potential side effects. This shouldn’t come as a huge surprise – it’s par for the course with all medications – we are messing with the body’s hormones – but side effects from GLP-1s can be intense – and can often cause patients to stop taking the mediations and swear to never try again. Which is tragic. With the right counseling and preparation, this can often be avoided.
Always, always, always: start low and go slow:
If patients are struggling with side effects, pause or extend the dose escalation phase duration. At Heartland Weight Loss, we rarely need to take patients up to high doses of medications. With the right counseling and a comprehensive treatment strategy, many patients achieve phenomenal results on low doses of medications.
Think practically – you don’t have to follow the instructions on the package insert or the website. If a patient experiences disruptive adverse effects (AEs) when moving up to a higher dose, go back on the lower one and stay on it for a few weeks. Then, try it again – if they are willing. In the case of persistent tolerability limitations, set a dose lower than the maximum one recommended by the studies as a maintenance dose.
You can always withhold treatment temporarily until the resolution of AEs and then resume treatment.
Although this list is primarily aimed at mitigating side effects from GLP-1 medications, the tips here can be applied to patients who may be experiencing similar side effects from other anti-obesity medications.
Gastrointestinal AEs:
GI AEs may lead to the temporary or permanent discontinuation of GLP-1 RA treatment. Patient education in terms of how to take and deal with satiety once GLP-1 RAs are started is crucial for ensuring treatment compliance.
GI AEs usually develop in 40–70% of treated patients, although they have sometimes been reported in up to 85%. They are usually transient, typically starting during the dose-escalation period and generally resolving shortly thereafter. In most cases, they are mild to moderate in severity. A recent report summarizing the results of several trials reported that the majority (99.5%) of documented GI AEs in people with obesity on GLP-1 RA treatment were non-serious. In case of persistence and/or remarkable severity, and where the patient presents with dizziness, confusion, and fatigue, standard procedures to clinically manage severe vomiting can be initiated. Rarely, intravenous rehydration may be necessary.
Nausea/Vomiting:
Warning patients about this is essential. Having them eat smaller, more frequent meals can help (although it’s not ideal advice for long-term weight loss, doing it transiently shouldn’t have a lasting impact). Hydration helps. Avoiding a lot of fatty foods at once definitely helps. It’s also typically dose-dependent. If patients are experiencing nausea, don’t titrate their dose up higher until it has passed – or they are completely comfortable living with their symptoms and willing to live with them if they worsen. You can certainly prescribe medications – but be careful putting them on Ondansetron if they are also struggling with constipation!
Avoid giving them dietary advice that contradicts the dietary recommendations you give them for healthy weight loss (such as drinking Sprite/Gatorade or eating cereal/toast) – mixed messages like this, especially during a time of physical overwhelm/uncertainty, can be devastating. They don’t have to forgo fruits and veggies in favor of ultra-processed junk because of nausea. Yes, it’s hard to digest raw veggies when nauseated, but cooked veggies are a different story. If patients are significantly restricting food intake due to nausea (or any reason), they are at high risk of losing a lot of lean mass quickly, which can put them at high risk of developing sarcopenia, which can be devastating for long-term health.
Often, the nausea is caused by or exacerbated by one of the major mechanisms of action: delayed gastric emptying. Although at Heartland Weight Loss, we rarely take this approach, you could try prescribing Metoclopramide to expedite gastric emptying. I’m not a big fan of treating side effects with medications that also carry a high risk of side effects and prefer to decrease the dose of the culprit causing the side effects, but everyone does things differently. I have no idea if speeding up gastric emptying would reduce the effectiveness of the GLP-1 on weight loss. If you go there, let me know what you find out.
Bowel Irregularities:
Changes in bowel habits are common when patients start taking any AOM. Some people get constipation, others get diarrhea. It’s difficult to tease out how much of this is a medication side effect and how much is due to changes in diet quality. When we change our diet quality, we usually experience an abrupt change in our gut flora.
We typically recommend a broad-spectrum probiotic when patients make dietary changes.
Non-nutritive sweeteners (even the “natural” ones) can cause significant issues with our gut flora and inflammation in the lining of our gut.
When attempting to lose weight, many people substitute their comfort foods with low-calorie or calorie-free alternatives, which are often full of sweeteners, emulsifiers, and all sorts of other chemicals that disrupt the fragile ecosystem that lives in our microbiome.
Diarrhea seems to be more common than constipation with GLP-1 medications, occurring in 5-25% of people. In contrast to nausea/vomiting, which typically occurs immediately, diarrhea often presents a few weeks after treatment is initiated and often only lasts a few days
Constipation occurs in about 4-12% of patients and also tends to have a delayed onset. Symptoms persist for a median duration of 47 days in people with obesity.
Secondary to the feeling of gastric fullness while taking these medications, patients tend to reduce water intake, which may predispose them to this AE. Patients should be advised to increase their mobility, and intake of water and fiber, as well as to consider the use of stool softeners as needed.
Dyspepsia:
This side effect is often associated with changes in our gut flora and/or delayed gastric emptying. Treat this the same way you would treat it in someone not taking a GLP-1. Advise them to restrict food for a few hours before lying down (good advice for everyone – not just those with symptoms!), to stay away from high-fat meals or highly acidic foods (such as citrus or red sauce), and eat slowly.
A lot of patients liken the AEs they experience when starting GLP-1 medications to the first few months of pregnancy. If you’ve ever counseled a patient through this process, use much of the same advice! I’ve had quite a few people tell me that strong smells trigger their nausea – similar to what we see in pregnant patients. Crazy.
Gallbladder Disease: Rapid weight loss, whether the result of anti-obesity mediations, bariatric surgical procedures, or significant caloric restriction promotes biliary lithogenicity. However, a direct action on biliary secretion and/or the modification of gallbladder motility can’t be ruled out. A comprehensive review encompassing 30 trials focusing on GLP-1 RA safety in people with T2D reported cholelithiasis in less than 1% of patients in the majority of cohorts. Ursodeoxycholic acid may be administered to patients with a history of cholelithiasis.
Elevations in lipase and amylase:
Although higher circulating levels of lipase and amylase have been reported in patients on GLP-1 RA therapy in many trials, the increases were rarely higher than three or five-fold the upper limit of normal, respectively. These returned to normal levels after medication was withdrawn and were poor predictors of acute pancreatitis. Acute pancreatitis has been reported by less than 1% of patients treated with GLP-1 medications and many of the cases were reported in subjects with a previous history of pancreatitis or gallbladder disease. Caution must be exercised in patients with these antecedents. Screening for elevations in pancreatic enzymes is not recommended, although if nausea and vomiting persist despite conservative management or are severe, pancreatitis should be ruled out.
Here is a helpful article with more information (if you need it):
False Hypoglycemia:
I hate this name, but I want to distinguish it from true hypoglycemia. GLP-1s rarely cause hypoglycemia in someone who is not taking another medication that can cause hypoglycemia (like insulin or a sulfonylurea). It’s really rare. More often than not, when you check blood glucose levels in people complaining of feeling “hypoglycemic”, their blood glucose level is perfectly normal. What these people are typically experiencing is the body’s response to having a normal glucose level and an abnormally elevated insulin level.
It’s a beautiful description of insulin resistance – before they progress to having full-blown type 2 diabetes. When someone has early insulin resistance and they spike their glucose abnormally high (by eating something high-glycemic, containing a lot of sugar or simple carbohydrates), they get a compensatory, abnormally high elevation in their insulin level. Which quickly brings their serum glucose down into the “safe” range. But, because their insulin is still elevated (consistent with insulin resistance), their body struggles to access the stored glucose and sends panic signals to the brain to get the person to ingest more food – which is perceived as both acute physical hunger (being “hangry”) and an increase in foraging behavior (having “cravings”).
Although ruling out true hypoglycemia isn’t a terrible idea, having patients track their symptoms relative to their food intake can often provide evidence that this is happening. Dietary modifications designed to reduce or eliminate spikes of insulin and insulin resistance are the optimal treatment for this symptom.
Injection site reactions:
This happens with every injectable medication from time to time. Putting a liquid into a space not designed to hold that liquid causes an inflammatory reaction – which often results in redness and/or itching for a short time. If the reaction is severe, with hives, blistering, or skin breakdown, it may indicate an allergic reaction to something in the solution and the medication should be discontinued.
Rotating injection sites regularly can be beneficial. Pinching the area, elevating it from the surrounding tissue, then putting a cold compress on it before injecting may also help. Following up with the cold compress to reduce swelling after injecting is also a good idea. Some people report less irritation when injecting in the abdomen vs the thigh and vice versa. No idea why, but it can’t hurt to have them try various locations.
This is completely anecdotal, but having the patient remove the medication from the refrigerator for 30-40 minutes before injecting it may also help by raising the temperature of the solution a bit closer to the body temperature.
For severe reactions, consider switching to a different medication altogether.
Headache:
Headache is a common reaction to a lot of medications. There is no known mechanism of action to explain why GLP-1 medications may cause headaches, but it happens more when compared to placebo, so it’s real. I imagine a lot of it is due to dehydration. Due to a sensation of fullness while taking these medications, patients often unconsciously or subconsciously restrict fluid intake along with food intake. Adequate hydration is an easy fix for headaches if they are the result of restriction. As long as they don’t have contraindications to OTC pain relievers, they can take these – but again, it’s always best to address the cause of the side effects before adding on another layer of medication. If patients restrict their intake of coffee or soda, they may develop headaches as they undergo caffeine withdrawal. A more gradual withdrawal may be indicated – or simply reassurance that the symptoms related to withdrawal are transient and self-limited.
Fatigue:
This is a difficult one. Almost everyone complains of being tired at least some of the time. Whether this is related to an AOM is debatable. People restricting food and/or water intake often feel tired due to low fuel availability. People sleeping poorly due to nausea and/or lower GI issues often feel tired. People undergoing an intensive lifestyle intervention often feel tired from an increased cognitive load. Digging into the causes of this symptom is key – then use that information to advise them about safe and effective ways to increase energy.
Dizziness:
Similar to fatigue, this is a vague complaint. There is no mechanism of action that we know of that increases a person’s risk of vertigo while taking these medications – and we all know that people use the word “dizzy” to refer to a whole host of symptoms. If a person is truly experiencing vertigo – regardless of whether they are taking a GLP-1 or not, you should do the workup. If they are feeling shaky and tired and calling it “dizziness” – it may be false hypoglycemia. It may be dehydration. It may be severe caloric restriction. You will have to dig into the symptoms a bit further. I don’t need to tell you how to do that!
Best of luck!