💊 Weight-Loss Medicines : What's available, how well do they work, and what are the risks? ⚖️💉

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

How strong is the evidence? ⭐ = a summary of many studies (systematic review or meta-analysis); 🔹 = a single study; 🐭 = animal or laboratory research only.

⚡ The short version

✅ Today's weight-loss medicines work but is not risk free. The newer injections, such as semaglutide (Wegovy®) and tirzepatide (Zepbound®, Mounjaro®), lead to average weight losses of roughly 15–20% in trials, far more than older medicines (1, 2).

🥗 They are not a replacement for healthy eating and activity. Medicines work best alongside nutrition, physical activity and behavioural support, and guidelines recommend always combining them (3).

🔁 Think long term before you start. About half of people stop GLP-1 medicines within the first year (4), and about 60% of the weight lost returns within a year of stopping (5). Part of the weight lost is muscle and bone density can fall too, so losing and then regaining weight may leave some people, especially older adults, weaker than before with less metabolically active muscle. Protein and strength training are essential (6, 7).

❤️ Benefits go beyond the scale: in large trials, semaglutide and tirzepatide improved blood sugar, blood pressure and blood fats, reduced heart attacks and strokes in high-risk people, and protected the kidneys (8–10).

🤢 Side effects are common, mainly nausea, vomiting, diarrhoea and constipation. Rarer concerns include muscle and bone loss, a possible small risk of an eye condition called NAION, and problems with anaesthesia because food stays in the stomach longer (6, 7, 11, 12).

🚫 These medicines are not for everyone, should never be used during pregnancy, and should only be used under medical supervision. Illegal "research-grade" and copycat products are a real danger (13, 14).

🧬 For rare genetic forms of obesity, targeted medicines such as setmelanotide and leptin replacement can correct the underlying cause.

🧐 Why weight-loss medicines matter

Obesity is now widely recognised as a chronic disease with many causes: genes, hormones, metabolism and the environment we live in. The American Medical Association called it a disease in 2013, although some researchers argue that this framing puts too much focus on individuals and too little on prevention (15). Since then and especially since semaglutide was approved for weight loss in 2021, the use of weight-loss medicines has grown quickly (16).

😓 Why is losing weight with diet alone so hard? When you lose weight, your body fights back: you burn less energy than expected (17) and your hunger hormones shift in ways that make you hungrier, changes that can last for years (18). That's one reason many people regain weight.

🏥 Surgery is still the most effective treatment, but it is invasive, has lifelong nutritional effects and doesn't suit everyone (19). Interestingly, the new medicines haven't reduced the number of people choosing surgery (16).

🌍 Medicines can't fix the environment. They treat individuals but don't change the food systems, cities and social and economic inequalities that drive obesity, so prevention still matters (20).

👥 Who are these medicines for?

Weight-loss medicines are usually considered for adults with:

• a BMI of 30 or more (obesity), or
• a BMI of 27 or more plus a weight-related condition such as high blood pressure or type 2 diabetes,

and only when there are no medical reasons not to use them. Some are approved for teenagers under strict criteria.

🎯 Medicines are not the first step. They are added when lifestyle changes alone haven't been enough, and they work best, and help prevent weight regain, when healthy habits continue (3, 21).

💊 Pills or injections? 🔹 In a survey of 351 adults, most preferred a once-daily pill over a once-weekly injection; how a medicine is taken mattered more to them than anything else (22).

🗂️ The main types of weight-loss medicines

🧠 Appetite suppressants: older, short-term options

Medicines such as phentermine act on the brain's "fight-or-flight" chemical noradrenaline to reduce hunger and help you feel full sooner. They can produce meaningful weight loss, but:

• ⚠️ they can raise heart rate and blood pressure and cause sleeplessness, anxiety, dry mouth, nausea and constipation
• ⚠️ some carry a risk of misuse and dependence
• 📅 most are approved for short-term use only, and weight often returns when they're stopped unless habits have changed

🍽️ Because you may eat much less, it's important to keep meals balanced and nutrient-dense, drink enough water and eat enough fibre.

🫘 "Natural carb blockers": promising but unproven

Some plant extracts slow the digestion of starch, similar to the diabetes medicine acarbose. The best known is white kidney bean extract (Phaseolus vulgaris).

• ⭐ One review found no clear effect on body weight (23), while ⭐ a later one found a small benefit: about 1 kg more weight loss than with a placebo (24)
• Studies differ a lot in design and dose, and long-term safety data are lacking (25)

🎯 Takeaway: interesting, but not yet a reliable weight-loss tool.

🧈 Orlistat: the fat blocker

Orlistat (Xenical® on prescription, Alli® over the counter) blocks the enzymes that digest fat, so about 25–30% of the fat in a meal passes through unabsorbed (26).

• ⭐ It leads to modest weight loss and may improve triglycerides and waist size, but it also lowers HDL ("good") cholesterol (27)
• 🔹 In a two-year trial, it helped people lose weight and regain less (28)
• 💩 Side effects depend on how much fat you eat: oily spotting, urgent or frequent bowel movements and wind are common (28). Keeping fat to about 15 g per meal, spread through the day, helps
• 💊 It also reduces absorption of vitamins A, D, E and K, so a daily multivitamin taken at least two hours before or after orlistat is advised

🎯 Expect about 5–10% weight loss over a year when orlistat is combined with a reduced-energy diet and regular activity.

💉 GLP-1 medicines and tirzepatide

GLP-1 is a hormone your gut releases after eating. GLP-1 medicines copy it: they slow stomach emptying, make you feel full sooner, reduce appetite and help the body control blood sugar. They were first developed for type 2 diabetes, and people's weight loss was noticed as a "side effect". Higher doses of liraglutide (Saxenda®) and semaglutide (Wegovy®) are now approved for weight loss, and tirzepatide (Zepbound®), which copies two gut hormones (GLP-1 and GIP), is approved too.

🇿🇦 Growing interest in South Africa: a recent survey found that about 13% of South Africans are using or considering GLP-1 weight-loss medicines, although 63% had never heard of them (29).

🏋️ How well do they work?

⚠️ Not everyone responds equally. 🔹 A genetic study of nearly 28,000 users found that small differences in the genes for the GLP-1 and GIP receptors were linked to how much weight people lost and how likely they were to feel sick (33).

💪 What kind of weight is lost?

⭐ GLP-1 medicines mainly reduce fat (about 3.4 kg more than control), but also cause some loss of lean mass, which is mostly muscle and water (about 0.8 kg) (6). 🔹 In one large trial, up to about 40% of the weight lost was lean mass (34). 🔹 Bone density at the hip and spine also fell when the medicine was used without exercise (7). 🔹 A small study in humans and mice found muscle strength was largely preserved (35). 🔹 In a 24-week study, liraglutide and a calorie-restricted diet similarly reduced liver fat, belly fat and fat in the pancreas (36).

🥩 Takeaway: eat enough protein and do resistance (strength) exercise to protect your muscles while on these medicines.

🌱 Newer and upcoming medicines

• 🔹 CagriSema (semaglutide plus cagrilintide, an amylin-like hormone): about 20% weight loss over 68 weeks in a large trial, but side effects were very common (37)
• 🔹 Retatrutide ("triple G"), which copies three hormones, produced large weight losses in a phase 2 trial but is not yet approved anywhere (38)
• 💊 Orforglipron is a GLP-1 pill that can be taken with or without food and doesn't need refrigeration; in trials it led to about 12% weight loss (30)
• Ecnoglutide was approved in China in 2026 for diabetes and weight management (39)
• 🐭 Researchers are developing medicines that avoid the GLP-1 receptor altogether, which could mean less nausea; so far these have only been tested in mice and rats (Perez-Tilve et al., 2026)

❤️ Benefits beyond weight loss

🫀 Heart, blood sugar and kidneys

• ⭐ Semaglutide and tirzepatide reduce heart attacks, strokes and heart-related deaths in people at high risk, and improve blood sugar, blood pressure and liver fat (8, 9)
• ⭐ In people without obesity, GLP-1 medicines still lowered major heart events by about 19% (40)
• 🔹 In people with obesity and prediabetes, about 90% on tirzepatide returned to normal blood sugar, compared with 76% on semaglutide (41)
• 🔹 Oral semaglutide lowered heart-failure events in people with diabetes who already had heart failure, but not in those without it (42)
• 🔹 Combining data from three large trials (more than 30,000 people), semaglutide lowered the risk of serious kidney problems by 16–20% (10)

🌙 Other conditions

• 😴 Sleep apnoea: tirzepatide reduced sleep apnoea severity, with up to half of people going into remission, although CPAP machines remain more effective (43)
• 🩺 PCOS: liraglutide shows promise for weight, belly fat, blood sugar and possibly fertility, but more research is needed (44)
• 🍽️ Binge eating: ⭐ GLP-1 medicines modestly reduced binge eating and emotional eating, especially in people with binge eating disorder (45)
• 🙂 Quality of life: ⭐ semaglutide improved physical functioning and weight-related quality of life, but only modestly (46)
• 🏥 After weight-loss surgery: 🔹 in people who lost too little weight after bariatric surgery, semaglutide led to about 19% more weight loss than placebo (47)
• 👧 Children and teens: ⭐ GLP-1 medicines reduced BMI, waist size and blood sugar, with more stomach side effects (48). ⭐ A large review of 42 trials found that medicine combined with lifestyle treatment works far better than either on its own (49)
• 🎗️ Breast cancer: 🔹 women with breast cancer and obesity or diabetes who used GLP-1 medicines had better survival and less recurrence, but this type of study can't prove cause and effect (50)

🛒 Changes in behaviour

🔹 People who started GLP-1 medicines shifted their shopping towards foods with less sugar, saturated fat and ultra-processed ingredients, and more protein (51). GLP-1 medicines also act on the brain's reward system, which may reduce alcohol use, gambling and impulsive behaviour (52). 🔹 In people with depression, oral semaglutide improved motivation (53).

🤢 Side effects and safety concerns

Common side effects

🤢 Stomach problems are by far the most common: nausea, vomiting, diarrhoea and constipation (54). 🔹 In over 410,000 Reddit posts, 43.5% of semaglutide and tirzepatide users mentioned side effects, mostly nausea, tiredness and vomiting (55). Other possible effects include tiredness, dehydration and gallstones (more likely with rapid weight loss).

Less common but important

🤰 Pregnancy

🚫 Do not use these medicines during pregnancy. Animal studies raised concerns about fetal growth, although human data so far haven't shown a clear increase in birth defects (64). 🔹 Stopping well before pregnancy appears safest: women who stopped close to conception had a 53% higher risk of gestational diabetes (65).

🔁 What happens when you stop?

⚠️ The warning in short: stopping is common, most of the weight tends to come back, and part of what was lost was muscle (and some bone density). It is not yet clear whether the regained weight is mainly fat: early evidence suggests it comes back in roughly the same mix of fat and lean tissue as it was lost (66), and on average people keep about a quarter of their weight loss (5). But for older adults and people with low muscle mass or weak bones, a cycle of losing and regaining weight could still leave them weaker and frailer than before. Protect yourself by eating enough protein, doing strength training throughout treatment, and planning with your doctor, before you start, what will happen if you stop.

• 🔹 In Denmark, about half of people stopped semaglutide within a year, more often younger people, men and those in lower-income areas (4)
• ⭐ After stopping, about 60% of the lost weight returns within a year and about 75% in the long run (5)
• 🔹 A computer model showed weight loss naturally plateaus after about two years on treatment, as appetite gradually catches up (67)
• 🔹 Within a year of stopping, about 1 in 5 people restarted their original medicine and about a third tried another treatment (68)
• 🔹 A small study suggested that taking doses less often after reaching a plateau may help maintain weight loss (69)
• 🏃 Exercise is underused but important for keeping weight off and protecting muscle (70)

🌿 Off-label, herbal and traditional products

💊 Off-label medicines: some medicines approved for other conditions, such as metformin (diabetes), topiramate (epilepsy) and bupropion (depression and smoking), are sometimes prescribed for weight loss. Their effects are usually modest and they need careful monitoring.

🌱 Herbal products such as green tea extract, Garcinia cambogia and bitter orange are often marketed as "natural" alternatives, but:

• ⚠️ most have only small effects at best
• ⚠️ some are risky: bitter orange has been linked to heart problems, and ephedra was banned in many countries after heart attacks, strokes and deaths
• ⚠️ high-dose green tea extract may harm the liver

🔹 A traditional Unani herbal remedy (Safoof-e-Muhazzil) performed similarly to orlistat in one study (71), but larger, well-designed trials are needed.

⚰️ Lessons from history: medicines that were withdrawn

Several weight-loss medicines were removed from the market because of serious harm:

• Fen-Phen (fenfluramine/dexfenfluramine): heart-valve damage and high blood pressure in the lungs
• Sibutramine: 🔹 a large trial showed more heart attacks and strokes in people with heart disease (72)
• Rimonabant: depression and suicidal thoughts
• Lorcaserin: increased cancer risk
• Ephedra: heart attacks, strokes and deaths
• 🪱 Early 20th century: "tapeworm diet" pills caused serious infections and even death

🎯 The lesson: long-term safety monitoring matters, even for medicines that seem to work well at first.

🧬 Precision medicine for rare genetic obesity

A small number of people have obesity caused by a single faulty gene that disrupts the brain's hunger-control system. They often have extreme hunger and rapid weight gain from early childhood.

• 💉 Leptin replacement (metreleptin) helps people born without the hormone leptin: it restores the feeling of fullness and leads to large weight loss
• 💉 Setmelanotide helps people with faults in the "POMC–MC4R" hunger pathway, reducing hunger and leading to more than 10% weight loss in many patients
• 🐭 In mice lacking MC4R, semaglutide, tirzepatide and retatrutide still led to large weight losses (73)

🧪 Takeaway: genetic testing is important for people with severe obesity that starts early in childhood.

⚠️ Fake, compounded and black-market products

• 🚨 In South Africa, a black market is selling unapproved medicines such as retatrutide, often labelled "research grade", through gyms and social media. They may be contaminated, mis-dosed or not sterile. SAHPRA advises anyone who bought them to stop using them and report the seller (14)
• 🧪 Compounded "copycat" tirzepatide mixed with vitamin B12 may contain impurities and have unreliable strength (74)
• 💻 Buying through online telehealth platforms has led to dosing errors, overdoses and poor follow-up (13, 75)

💰 Cost and access

These medicines are expensive, and access depends heavily on medical-aid or insurance cover. 🔹 In the US, employer health plans that covered GLP-1s saw much bigger increases in use than plans that didn't (76).

🥦 Can food boost your own GLP-1?

Your gut naturally makes GLP-1, and some habits may modestly increase it:

• 🌾 Fibre-rich foods (oats, legumes, whole grains) feed gut bacteria that make compounds that trigger GLP-1 release (77, 78)
• 🥚 Protein (eggs, dairy, legumes) promotes GLP-1 release and fullness (79, 80)
• 🏃 Physical activity may increase gut hormones that reduce appetite (81)

⚠️ These effects are much smaller than those of medicines, but they support appetite control and overall health.

🥗 If you use a weight-loss medicine, do it well

• 🥩 Eat enough protein and include strength training to protect muscle and bone (6, 7)
• 🍽️ Don't skip meals: smaller, more frequent, nutrient-dense meals are often better tolerated
• 💧 Drink enough water and eat enough fibre to manage constipation
• 🧪 Ask about checking iron, calcium, vitamin B12 and other vitamins, especially during long-term use
• 🩺 Tell your doctor, surgeon and dentist that you're using the medicine
• 🏪 Only use registered products from a pharmacy with a prescription, never "research-grade" or unregistered products
• 🔁 Plan for the long term: discuss with your doctor what happens if you stop, and keep up healthy habits

🚫 Who should not use these medicines?

🩺 Always talk to your doctor and a registered dietitian before starting, changing or stopping any weight-loss medicine.

🎯 The bottom line

✅ Modern weight-loss medicines, especially semaglutide and tirzepatide, are genuinely effective and bring benefits for the heart, blood sugar and kidneys.

🥗 They work best together with healthy eating, physical activity and behavioural support, never instead of them (3).

🔁 Stopping is common and weight tends to return, and muscle and bone lost during treatment don't rebuild by themselves, so plan for the long term, protect your muscles and bones, and consider cost and access before you start.

🤢 Side effects are common but usually manageable; rarer risks need to be weighed up individually.

🚨 Avoid unregistered, compounded or black-market products.

🧬 For rare genetic obesity, targeted precision medicines can address the root cause.

🌍 Medicines treat individuals, but preventing obesity still requires healthier food environments and less inequality (20).

💭 Questions to ask yourself

⚖️ Have I given lifestyle changes a real try and do I meet the criteria for a weight-loss medicine?

🎯 What are my goals? Weight loss, better blood sugar, heart health or feeling better day to day?

🔁 Am I prepared for long-term use and what's my plan for protecting my muscles and bones and keeping weight off if I need to stop?

💰 Can I afford the medicine over time, and does my medical aid cover it?

🥩 Am I eating enough protein and doing strength exercise to protect my muscles and bones?

🚫 Does anything in the "who should not" table apply to me and have I told all my health professionals I'm taking it?

Always seek guidance from your doctor and a registered dietitian for personalised advice on weight management and medicines.

💌 Love what you're reading? Share the knowledge! Forward this link to a friend who might also enjoy it. 📨

📚 References

Want to go deeper? Here are all the studies behind this summary. 🔍

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