The use of GLP-1 agonist drugs—particularly for weight loss—are trending in a huge way. According to a new report,1 GLP-1s were the best-selling drug class in 2024, with approximately $50 billion in annual sales, and forecasted to surpass $100 billion by 2029 with an astounding compound annual growth rate of 19.2 percent. Certainly, anyone who attended SupplySide West in Las Vegas, NV in October of 2024 would have been hard pressed to have missed the plethora of nutraceuticals claiming to be GLP-1 stimulants—but more on that later. In any case, the effectiveness of GLP-1 agonist drugs for weight loss is associated with some common adverse effects which can, at least in part, be mitigated by the concurrent use of select nutraceuticals.
Overview of GLP-1 Agonist Drugs
A common GLP-1 agonist drug is semaglutide (Ozempic). It operates as a GLP-1 receptor agonist, sharing a remarkable 94 percent structural homology with human GLP. Semaglutide delivers its benefits in lowering blood glucose levels and promoting weight loss through the activation of GLP-1 receptors primarily located in the gastrointestinal tract, pancreas and brain. This involves enhancing glucose-dependent insulin secretion, providing a physiological response to elevated blood glucose levels after a meal. Simultaneously, it slows gastric emptying, which is a primary mechanism by which it delivers its well-known benefit of reducing appetite. Complementary mechanisms include increasing pancreatic β-cell proliferation and reduces glucagon release which also contribute to an overall reduction in appetite. In addition, semaglutide’s interaction with GLP-1 receptors in the hypothalamus may mitigate sensations of hunger, alleviate food cravings and enhance the feelings of satiety. Semaglutide is also considered a “long-acting” GLP-1 receptor agonist, alongside other GLP-1 agonist drugs.2
Adverse & Severe Adverse Effects of GLP-1 Agonist Drugs
The use of GLP-1 agonist drugs may result in some adverse effects, severe adverse effects, and other undesirable effects that impact any time of rapid weight loss due to caloric restriction.
Adverse Effects
There are some well-established and common gastrointestinal side-effects associated with the use of GLP-1 agonist drugs. These include nausea, vomiting, diarrhea and constipation. These adverse effects can persist for several days, and may result in dehydration, which if severe may lead to other serious health complications.3
Nausea is the most common adverse effect reported with GLP-1 agonists with up to 50 percent of patients affected. Most patients have mild to moderate episodes of nausea, which seem to be dose-dependent and tend to diminish with ongoing treatment—although some patients continue to experience some degree of nausea.4 Likewise, the prevalence rate of constipation is around 30 percent.5
Ozempic Skin/Ozempic Face/Ozempic Butt
So called “Ozempic skin,” “Ozempic face” or “Ozempic butt” is loose, sagging skin on the face or buttocks that occurs because of rapid weight loss. To be clear, this isn’t an adverse effect specific to Ozempic or any GLP-1 agonist drug. It may occur in any scenario resulting in rapid weight loss. Essentially, with the weight loss that occurred, the skin has less tissue to cover which makes the skin seem saggy. It is more common in middle-aged and older adults.
Loss of Lean Mass
Weight loss, achieved through a calorie-reduced diet, which may or may not involve the use of GLP-1 agonist drugs, decreases both fat and lean body mass. Lean body mass is everything except fat, including bones, muscles, organs, blood and skin. However, for all practical purposes, the loss of lean body mass in this context is primarily muscle with some bone density. In persons with normal weight, the contribution of fat-free mass loss often exceeds 35 percent of total weight loss, and weight regain promotes relatively more fat gain. In persons who are overweight or obese, lean mass contributes only ~20–30 percent to total weight loss.6 It should be noted that a 10 percent weight loss can result in a 1-2 percent loss of bone mineral density (BMD). However, the amount of bone loss varies by population and skeletal site.7
Severe Adverse Effects
A more severe adverse effects associated with the use of GLP-1 agonist drugs is pancreatitis. This was shown in a study of more than 4,700 patients using GLP-1agonist drugs compared to 654 patients using bupropion-naltrexone, a different type of medication used for managing obesity. Results were that incidence of biliary disease, i.e., conditions that effect the gallbladder/bile ducts, (per 1,000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide (another GLP-1 agonist), and 12.6 for bupropion-naltrexone and 4.6, 7.9 and 1.0, respectively, for pancreatitis. The use of GLP-1 agonists compared with bupropion-naltrexone was associated with increased risk of pancreatitis, bowel obstruction, and gastroparesis (a condition that slows or prevents the stomach from emptying its contents into the small intestine), but not biliary disease.8
Nutraceutical Compensation
There are some nutraceuticals which may help compensate for some of the adverse effects associated with the use of GLP-1 agonist drugs. These include the following as indicated below.
Gastrointestinal Adverse Effects
As previously noted, the most common adverse of GLP-1 agonist drug use is nausea. So, what can be done to help mitigate this symptom? In a word, ginger. A study9 published in the journal Clinical Diabetes suggested the use of ginger as an antinausea supplement is worth trying. This makes sense when considering that there are several studies in which ginger extract has been effectively used to reduce nausea. This includes studies in nausea associated with medication use,10-15 the nausea of pregnancy,16-18 nausea in some disease states,19,20 nausea associated with surgery,21,22 and nausea associated with motion sickness.23
As another common adverse effect of GLP-1 agonist drug use, constipation can be addressed using fiber supplements. While there are many to choose from, the use of acacia gum is a good option. Acacia gum (also known as gum arabic, arabic gum, gum acacia, acacia, Senegal gum and Indian gum24), is derived from the hardened sap of acacia tree species, and a source of dietary fiber. A single-blind, controlled study25 demonstrated that 10 g/day and 15 g/day for 10 days, resulted in significantly increased concentrations of Bifidobacteria, Lactobacilli and total lactic acid bacteria groups were significantly increased with acacia gum at the dose of 10 g/d compared to control—attesting to acacia gum’s prebiotic properties. The effect was also significant at the dose of 15 g/d. In addition, the number of stools per week was increased with acacia gum (10 and 15 g/day) and daily stool weight was higher during acacia gum consumption. This effect is of interest for people suffering from constipation, including those using a GLP-1 agonist. Another double-blind clinical study26 also found that 10 g/day acacia gum likewise helped relieve constipation compared to placebo.
Ozempic Skin/Face/Butt Adverse Effects
Perhaps the best advice to avoid this type of sagging skin is to lose no more than 1-2 lb per week. The next best piece of advice is to make sure strength training is part of your approach to weight loss so you can build muscle while losing fat. From the standpoint of nutraceuticals, I recommend considering collagen.
Collagen is the main structural protein found in the skin and other connective tissues. It is an ideal nutraceutical for combating saggy skin. Consider that bovine-sourced collagen peptides have been shown27 to support and stimulate the body’s own collagen production, increasing pro-collagen production by 65 percent, as well as increase production of the critical skin protein elastin by 18 percent. Likewise, studies28-31 have demonstrated that it has significantly reduced wrinkles, improved skin elasticity and moisture, reduced cellulite and increased hair thickness.
Lean Mass Loss
Consume pea protein, as well as creatine monohydrate, to support muscle growth. In a randomized, comparator-controlled, parallel clinical trial,32 randomized to pea protein (PPr) or whey protein (WPr) in combination with a weekly resistance training program for 84 days. Results were that the participants supplemented with PPr had a 16.1 percent improvement in in whole-body muscle strength following 84 days of supplementation (p = 0.01), while those taking WPr had an improvement of 11.1 percent (p = 0.06). Eighty-four days of PPr supplementation resulted in improvements in strength and muscle mass comparable to WPr when combined with a resistance training program in a population of healthy sedentary adults. Multiple studies33,34 have also demonstrated the satiating properties of pea protein, which resulted in people reducing their food intake.
Creatine serves as an anabolic signal for muscle growth, acting as the chemical messenger that links increased muscle activity with the production of new muscle tissue.35,36 The most used and studied supplemental form of creatine is creatine monohydrate. In addition to athletic and exercise improvement, research has shown that creatine supplementation may enhance post-exercise recovery, promotes injury prevention, thermoregulation, rehabilitation and neuroprotection.37
To address the bone density aspect of lean mass loss, consider the use of vitamin D2 and vitamin K2 as MK-7 and MK-4. Vitamin D has long been known to help the body absorb and retain calcium and phosphorus and, as such, is critical for building bone. Vitamin D3 is better than vitamin D2 for this purpose since vitamin D2 potency is less than one third that of vitamin D30F.38 Multiple studies have demonstrated that vitamin D3 and calcium can decrease postmenopausal bone loss, help prevent osteoporosis and decrease the risk of fractures 145F39 146F40 147F41 148F42 149F43 150F44 151F45 152F46 153F.47 Other research has demonstrated that vitamin D with calcium or vitamin D alone improved bone mineral density compared with no therapy 124F48 125F.49 Likewise, a large clinical trial 138F50,51 found that supplementing with a high dose of vitamin D3 for two years helped reduce declines in in bone mineral density.
In the September 2024 issue of Vitamin Retailer, I wrote about the bone health benefits of vitamin K2 as MK-7 and MK-4. To reiterate, in a three year, double-blind, placebo-controlled trial,52 244 healthy postmenopausal women received 180 mcg/day of MK-7 or a placebo for three years. The results were that MK-7 decreased age-related decline in bone mineral content and bone mineral density, and favorably affected bone strength and decreased loss in vertebral height. Also, postmenopausal women with osteopenia (bone softening) also demonstrated a preservation of bone structure with 375 mcg/day MK-7.53 Vitamin K2 as MK-7 is available in synthetic form, as well as in both natto (soy) and chickpea-derived forms for those who prefer a soy-free option (e.g., K2Go by Nutraland USA).
Research has also shown that MK-4 also has significant research to support its role in bone health. In fact, it could be argued that it has more research for this purpose than MK-7. It should also be noted that the doses used of MK-4 are higher (although safe) than MK-7. For example, in one randomized, double-blind, placebo-controlled trial,54 1.5 mg/day of MK-4 for six to 12 months in postmenopausal women improved carboxylation of VKDPs (associated with bone health) and helped maintain bone mineral density. Similar results were seen in another study55 with 600 mcg/MK-4. When 5 mg/day MK-4 was used there was a significant improvement in carboxylation of VKDPs, with no additional benefit compared to 45 mg/day MK-4.56
In addition, there is a synergistic relationship between vitamin K and vitamin D. A two-year randomized study57 found that the combined administration of vitamin D3 and vitamin K2 (as MK-4), was effective in increasing the bone mineral density in postmenopausal women with osteoporosis. Another study58 in women with estrogen deficiency found that MK-4 combined with vitamin D3 partially prevented bone loss caused by estrogen deficiency.
Nutraceuticals Claiming to be GLP-1 Stimulants
Now let’s take a couple of minutes to consider all those nutraceuticals claiming to be GLP-1 stimulants. In September of 2024, a good friend and colleague of mine, Dr. Jacqueline Jacques, spoke at a UNPA (United Natural Products Alliance) meeting about peptides, including GLP-1. She gave such a fantastic presentation that I asked her for a quote on this topic to use in this article. Here’s what she had to say:
“GLP-1 receptor agonist drugs are specifically engineered to have significant advantages over the GLP-1 that your body naturally makes. Some of these advantages include being much stronger than natural GLP-1, having a stronger binding affinity at receptor sites that GLP1 targets, having a long half-life (meaning they stay around a long time—two hours to five days), and being engineered to resist breakdown by DPP-4 enzymes (the peptide degrading enzymes that break down GLP-1 and similar compounds).
“So, when you hear someone say their supplement stimulates GLP-1 release or increases GLP-1, that is not the same thing and does not make them “nature’s Ozempic.” For a start, many common foods are great stimulators of GLP-1. For example, avocado has a known positive benefit of increasing GLP-1 and at least one study showing one half an avocado can decrease postprandial hunger for several hours.59 But really the list is long and includes high fiber foods, high fat foods, high protein foods, bitter foods, and fermented foods. The body produces GLP-1 in response to all kinds of food intake, but it has a very short duration of action because it is rapidly degraded by DPP-4 enzymes. Natural GLP-1 is broken down very rapidly, with a half-life of only one to two minutes. Does this mean there is no value in products claiming to increase GLP-1? I think the real question is can they also demonstrate significant weight loss in a human clinical trial? Perhaps time will tell.”
To elaborate on her last point, from my perspective it is less about whether a nutraceutical works as a GLP-1 stimulant or agonist, and more about if it actually demonstrates significant weight loss.
Black Ginger Extract
As an example, in a recent episode of my Vitamin Professor podcast (brought to you by VRM Media), I interviewed the brilliant Dr. Tim Ziegenfuss about the effects of black ginger extract (check it out if you haven’t already seen it). During the podcast, Dr. Z talked about how the polymethoxyflavones in black ginger extract helped promote the reduction of abdominal fat (both visceral and subcutaneous) in human studies.60,61 For example, one of the studies showed the following fat reduction (the second had similar results). (See chart).
Dr. Z also talked about a new study for abdominal fat loss he’s conducting using a black ginger extract with a high standardization of polymethoxyflavones (ACTIZ!NG from Nutraland USA). Of course, black ginger extract is only one of many possible nutraceuticals with good human clinical research supporting weight reduction or—more importantly—fat reduction.
Conclusion
Unquestionably, GLP-1 agonist drugs are trending, and that trend shows no sign of slowing down anytime soon. For many people, these medications have made a big difference in promoting meaningful weight loss. However, GLP-1 agonist drugs are associated with some common adverse effects. In part, these can be mitigated by the concurrent use of select nutraceuticals. Also, some nutraceuticals may also help promote fat loss.VR
Gene Bruno, MS, MHS, Professor Emeritus of Nutraceutical Science, is a writer, educator and a nutraceutical scientist with more than 45 years of experience educating natural product retailers and health care professionals and formulating natural products for dozens of dietary supplement companies. He has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. Bruno also hosts “The Vitamin Professor Podcast” brought to you by VRM Media. He can be reached at eugenejbruno@gmail.com.
