Semaglutide, the GLP-1 better known by its brand name Ozempic, has revolutionized the fight against obesity. Unfortunately, its popularity has fueled a marketing trend that promotes certain weight-loss products as “natural Ozempic” alternatives. In reality, these supplements are primarily sources of soluble fiber that promote satiety or plant extracts that slow digestion and improve insulin sensitivity.
Popular examples include:
- Psyllium – The husk of Plantago seeds, psyllium is rich in viscous soluble fibers that form gels, relieve constipation, and increase feelings of fullness.
- Glucomannan – A soluble fiber derived from Amorphophallus konjac, glucomannan forms gels that support bowel movements and promote satiety.
- Berberine – A compound found in plants such as European barberry, berberine activates the AMPK enzyme, which helps regulate metabolism and improve insulin sensitivity.
Equating these supplements with semaglutide is both misleading and irresponsible. Fiber supplements create mechanical satiety by expanding in the stomach. Berberine modulates metabolism and enhances insulin sensitivity. Semaglutide, on the other hand, acts hormonally, regulating blood glucose, appetite, and digestion.
The outcomes clearly reflect these differences. Some studies using glucomannan have shown approximately 1 kg of weight loss by the end of treatment, while studies using berberine have shown around 2 kg. In contrast, studies on semaglutide report an average weight loss of 8 kg. Of course, these findings stem from distinct research contexts, characterized by varying designs, sample sizes, and durations. However, these supplements play a limited role in weight loss and cannot compare to approved obesity medications. The “natural Ozempic” label is a marketing gimmick.
Still, given growing public interest, it’s important to clarify what these supplements can actually offer and how fundamentally different they are from anti-obesity drugs. To understand why semaglutide has attracted so much attention, it’s helpful to explore the history of anti-obesity medications.
Pre-Semaglutide Strategies
In the 17th century, Swiss physician and anatomist Théophile Bonet published a treatise describing several strategies he had encountered for treating obesity. One striking account reads:
“Chiapinius Vitellius, Master-in-Camp, a middle-aged man, grew so fat that he was forced to support his belly with a sash that went around his neck. Realizing his condition, he abstained from wine and drank vinegar for the rest of his life; in doing so, he lost 87 pounds in weight (the equivalent of 39.5 kg).”
Other examples follow the same anecdotal pattern, ranging from the use of purgatives to curious concoctions, including a formula made with tartar, cinnamon, ginger, and sugar.
Fortunately, these rudimentary approaches gave way as scientific understanding of physiology, pharmacology, and related disciplines progressed.
In 1893, thyroid hormone therapy emerged as the first rational pharmacological treatment for obesity, based on the action of thyroid hormones in increasing metabolism. Around the same time, French factory workers exposed to dinitrophenol (DNP) began to experience significant weight loss. Stanford researchers confirmed DNP’s efficacy in animals in 1931, but human trials soon revealed severe side effects due to its narrow therapeutic window. Although participants lost an average of 7.8 kg over 88 days, reports of death, neuropathy, and blindness led the FDA to ban DNP in 1938.
Meanwhile, amphetamine, synthesized in 1887 but recognized for its stimulant effects only in 1929 by Gordon Alles, showed promise in obesity treatment by suppressing appetite, enhancing well-being, and increasing activity levels. However, concerns about dependence and cardiovascular risks emerged quickly. By 1937, amphetamines were widely abused, prompting their classification as controlled substances.
In 1940, “Rainbow Pills” combined amphetamines, laxatives, diuretics, and sedatives to suppress appetite and promote weight loss. However, multiple deaths between 1967 and 1968 prompted a U.S. Senate investigation, which led to stricter regulations on weight-loss medications. Other high-profile obesity drugs met similar fates. Fenfluramine, developed in the 1960s and structurally related to amphetamine, was widely prescribed despite early reports of pulmonary hypertension — two cases in 1981, rising to 12 by 1993. Often combined with phentermine in the popular Fen-Phen combination, it reached 4 million users in the U.S. by 1995. However, heart valve abnormalities were observed in up to 30% of users, prompting the global withdrawal of both fenfluramine and dexfenfluramine in 1997.
This history illustrates a persistent pattern in obesity pharmacotherapy: promising drugs that ultimately proved unsafe. Among the few that have withstood regulatory scrutiny and remain in use, the mechanisms vary widely, from blocking fat absorption during digestion to targeting neurotransmitters involved in appetite regulation.
The real breakthrough was the introduction of semaglutide, developed by the pharmaceutical company Novo Nordisk as a treatment for diabetes; its impact on weight was a fortuitous side effect.
The Semaglutide Revolution
As detailed in an article published in Frontiers of Endocrinology, successful clinical trials with liraglutide, a diabetes medication that mimics the hormone GLP-1, which promotes satiety, reduces appetite, and slows calorie absorption, sparked growing interest in similar therapies. However, its requirement for daily injections posed adherence challenges, leading to the development of longer-acting GLP-1 analogues, such as semaglutide, designed for weekly administration.
Researchers overcame several challenges, including the risk of allergic reactions and the need to ensure prolonged drug activity. The first human trial results were published in 2021 in The New England Journal of Medicine, evaluating the efficacy and safety of semaglutide compared to a placebo when used in combination with lifestyle interventions.
This 68-week, randomized, double-blind, placebo-controlled trial was conducted across 129 centers in 16 countries and enrolled 1,961 obese or overweight adults who had not achieved weight loss through previous dietary efforts. Of these, 1,306 received semaglutide and 655 received a placebo. The trial had a high completion rate, with 94.3% of participants finishing the study.
By week 68, the semaglutide group showed:
- A 14.9% reduction in initial body weight (–15.3 kg), compared to 2.4% (–2.6 kg) in the placebo group
- A decrease of 13.53 cm in waist circumference
- A reduction of 5.54 units in BMI
- Improvements in blood pressure
Side effects occurred at similar rates in both groups and were primarily mild to moderate gastrointestinal symptoms. These included nausea, diarrhea, vomiting, and constipation.
It’s worth noting that the study was funded by Novo Nordisk, and several authors disclosed ties to the company, as employees, advisory board members, or speakers receiving honoraria.
A recent systematic review and meta-analysis published in The Lancet evaluated randomized trials through June 2024 involving FDA and European Medicine Agency (EMA) approved drugs. This included tirzepatide, a dual GLP-1/GIP receptor agonist. While all the drugs studied reduced weight, tirzepatide showed the most significant effect, with an average loss of 11.69 kg, followed by semaglutide at 8.48 kg, and liraglutide at 4.18 kg.
Despite limitations such as outcome heterogeneity and potential confounders, these findings represent a significant advancement. Before the advent of semaglutide and tirzepatide, most weight-loss medications produced average reductions of 2.19–5.67 kg. Now, achieving a weight loss of more than 10 kg is a realistic and clinically achievable goal.
And what about those supplements?
Starting with psyllium, the most insightful study I found was published in 2020 in Critical Reviews in Food Science and Nutrition.
This systematic review and dose–response meta-analysis is based on 22 randomized clinical trials published between 1983 and 2018, involving 1,458 participants aged 18 to 80, most of whom were overweight or obese. Doses ranged from 1.7 to 15 g/day, with intervention durations from two to 48 weeks.
The study concluded that psyllium had no significant effect on body weight, BMI, or waist circumference. It’s essential to consider the key limitations noted by the authors. These include high heterogeneity in dosage, duration, and participant characteristics; lack of adjustment for confounders; and the use of active comparators instead of placebos in some trials.
A 2020 study published in Obesity Medicine conducted a systematic review and meta-analysis of six randomized controlled trials of glucomannan published between 1984 and 2015, involving 255 participants. Doses ranged from 1.24 to 3.99 g/day, with interventions lasting between 5 and 12 weeks.
The analysis revealed that glucomannan intake led to a significant reduction in body weight, with an average difference of 0.96 kg compared to the control group. However, conflicting reports on efficacy persist, likely due to variations in dosage, participant characteristics, sample sizes, study durations, and methodological quality. Additionally, external factors such as dietary patterns and lifestyle were not taken into account.
Relevant evidence for berberine comes from a systematic review and meta-analysis published in Clinical Nutrition ESPEN. This study comprised 12 randomized trials involving 1,040 participants, with doses ranging from 300 to 1,500 mg per day and treatment periods lasting from 1 to 24 months. Five studies reported outcomes on weight and waist circumference, showing average reductions of 2.07 kg and 1.08 cm, respectively. Eight studies reported a mean decrease in BMI of 0.47 kg/m².
Proposed mechanisms included modulation of adipogenesis, increased expression of thermogenic genes in both white and brown adipose tissue [1], and alterations in gut microbiota, which may have contributed to insulin resistance and inflammation. The authors concluded that berberine supplementation was associated with significant reductions in body weight, BMI, and waist circumference, suggesting potential metabolic benefits. However, the study’s limitations, particularly the high heterogeneity in participant health status, dosage, and intervention duration, significantly impact the interpretation of its findings. Small sample sizes and a high or unclear risk of bias in several trials further weaken the evidence.
While berberine’s average weight loss (2.07 kg) exceeds that of glucomannan (0.96 kg) and psyllium (non-significant), it still falls far short of semaglutide’s average (8.48 kg).
In this context, labels like “natural Ozempic” are little more than marketing strategies designed to capitalize on the success of a proven drug by promoting products with inconsistent scientific support. Should you avoid these supplements? Not necessarily. But when it comes to weight loss, they are unlikely to deliver meaningful results. Any modest benefits will likely, if not entirely, rely on combining their use with a calorie-restricted diet and increased physical activity.
[1] Unlike white adipose tissue, brown adipose tissue is known for its thermogenic effect, which results from the high expression and activity of uncoupling protein-1.
Sources: An Historical Review of Steps and Missteps in the Discovery of Anti-Obesity Drugs. Endotext.
Safety and effects of anti-obesity medications on weight loss, cardiometabolic, and psychological outcomes in people living with overweight or obesity: a systematic review and meta-analysis. eClinicalMedicine. DOI: 10.1016/j.eclinm.2024.103020.
