GLP-1 Agonists for Weight Loss- where are we now?

Through ongoing use and post-marketing experience, GLP-1 agonists have become better understood, with notable additional metabolic and cardiovascular benefits. This has culminated in the official “licensing” of some GLP-1 agonists as registered medications for weight loss. In parallel, obesity has started to be viewed as a chronic metabolic disease with possible severe consequences, no longer just the “stigmatised” condition resulting from a “lack of willpower,” as sometimes portrayed in the past. It has become clear that obesity needs to be treated as a chronic medical condition, just as high blood pressure, diabetes and coronary heart disease need to be treated, usually long-term.

What exactly are GLP-1 agonists?

GLP-1, which is an “incretin” hormone made mainly in the small bowel, binds to GLP-1 receptors, which are spread throughout the body, including in the intestine, pancreas and even the brain. The “GLP-1 agonists” are synthetically manufactured drugs which bind to the GLP-1 receptor so have similar actions to naturally occurring GLP-1.

GLP-1 acts as follows:

• Triggers insulin release from the pancreas, to regulate blood sugar
• Blocks glucagon secretion: glucagon is a natural hormone which acts to release glucose into the bloodstream
• Increases glucose uptake into muscles
• Slows stomach emptying: Slower digestion means you stay full for longer, and your body releases sugar into the bloodstream more slowly
• Affects the area in your brain that processes hunger (the hypothalamus), making you feel full more quickly

So, where are we now, in 2025, with obesity and GLP-1 agonist medications?

Obesity, defined as body mass index of > 30 kg/m2, has reached epidemic proportions and more than half the world’s population is projected to have overweight or obesity by the year 2035. High BMI accounts for millions of deaths globally, mainly because of associated cardiovascular diseases. South Africa has a high obesity rate, contributing towards chronic ill-health and premature death.

South Africa has very recently seen the “landmark” launch of semaglutide (also originally known by the brand name Ozempic) as a drug for weight loss, with the same molecule made by the same company (Novo Nordisk) now being customised in doses suitable for obesity and branded as “Wegovy.” Wegovy comes as a weekly subcutaneous injection, with a dose escalation programme adapted for each patient. Liraglutide (Saxenda) is an alternative GLP-1 agonist made by Novo Nordisk, available as a daily injection, licensed for weight loss by the Food and Drug Administration in the USA. Several other molecules/companies are seeking licensing approval for obesity, noticeably tirzepatide (Mounjaro by Eli Lilly), a combined GLP-1 and GIP (Glucose-dependent Insulinotropic Polypeptide) agonist, both of which stimulate insulin secretion.

Most of the GLP-1 agonists are available in the subcutaneous injectable form (injections under the skin with a tiny needle, a device like an insulin syringe), though scientists are working hard on releasing an oral form for obesity too.

With obesity now being viewed as a potentially life-long metabolic disease with potentially severe consequences, it is also being viewed as a disease likely needing life-long management, possibly even with medications in addition to lifestyle changes, to prevent the yoyo effect of regaining weight once the medication has been stopped or diet discontinued. This is important for patients to understand when they are considering embarking on a course of GLP-1 agonists for weight loss- it may be an ongoing treatment, similar to “blood pressure” medication for example. Cost and side effects therefore need serious consideration, and possible alternative weight loss approaches need to be discussed. However, when considering “cost” of treatment, the potential extended beneficial effects of the GLP-1 inhibitors need to be acknowledged, which could lead to the long-term cost savings of improved metabolic and cardiovascular health.

Whether medications are used or not, it remains imperative that the approach to weight control is multi-modal, including dietary control and exercise with muscle maintenance as part of the weight loss plan.

Let’s look a bit more closely at benefits and potential risks of GLP-1 agonists as weight loss drugs:

Benefits of GLP-1 Agonists:

1. Lowering in blood glucose
2. Weight loss- expect loss of 4-5% of starting body weight after 2 months, 8% after the 4^th month and up to 17% of starting body weight after 18 months.
3. Reduced risk of heart disease and significantly reduced overall risk for cardiovascular events including heart attacks, strokes and death. In the landmark “Select” study, Wegovy reduced the risk of major cardiovascular events (MACE) by 20%. This is through weight loss as well as direct drug effects.
4. Lowering in blood pressure
5. Improvement in lipid disorders
6. Improvement in fatty liver disease
7. Delayed progression of diabetic nephropathy (diabetes related kidney disease)
8. They are neuroprotective – may reduce progression rate of neurodegenerative diseases such as Alzheimer’s and Parkinsons diseases.
9. May slow down progression of joint diseases such as osteoarthritis and rheumatoid arthritis, because of anti-inflammatory effect and weight loss.

Risks/ disadvantages of GLP-1 agonists:

1. Nausea and vomiting (far less likely when starting on a very low dose and titrating up slowly)
2. Diarrhoea
3. Dizziness and tiredness
4. Mild tachycardia (increased heart rate)
5. Headaches
6. Temporary itchiness /redness around injection sites
7. Dry mouth/reduced salivary secretions
8. Low blood sugar

Rare but more serious side effects:

1. Pancreatitis
2. More serious gut side effects because of stagnated gut movement
3. Medullary thyroid cancer
4. Sudden kidney injury (usually because of reduced volume intake or vomiting)
5. Worsening of diabetic retinopathy (diabetes related eye disease)
6. Allergic reactions
7. Gallbladder or biliary disease
8. Depression and suicidal ideation
9. Aspiration (food or liquid getting into lungs) during anaesthesia as the stomach empties more slowly- ideally the medication should be stopped for 2-4 weeks prior to elective surgery.

Generally, risks and side effects are reduced by starting with small doses and increasing slowly, and by making sure the patient is drinking sufficient fluids.

For whom should GLP-1 agonists be considered?

The FDA and the SAHPRA have approved the use of semaglutide (Wegovy) to help weight loss under the following circumstances:

1. Obesity, with body mass index ³ 30
2. Overweight (BMI 25-30) WITH other chronic health conditions, if losing weight can help manage the coexisting conditions (e.g. heart disease, diabetes, high blood pressure, high cholesterol.)

Contra-indications (circumstances under which the drug should NOT be used) include:

1. Pregnancy and breastfeeding
2. Hypersensitivity reactions to any ingredients in the medication
3. Severe gut disease e.g. Crohn’s/Ulcerative Colitis
4. Personal or family history of thyroid cancer or multiple endocrine neoplasia type 2 (“family cancer clusters”)
5. History of pancreatitis

Summary and Reality Check:

GLP-1 agonists are not a “quick and permanent cure” for overweight and obesity. They are not suitable for people who are not significantly overweight but would like to “shed a few kilograms.” They will always need to be combined with dietary modification (protein-rich, nutrient-dense diet), exercise (including cardio and weight training), behaviour modification, stress management, adequate hydration and adequate sleep. Enrolling the help of a dietitian and biokineticist together with regular doctor check-ups will be extremely useful.

However, when obesity is leading to severe metabolic complications, then using GLP-1 agonists as a PART of your management strategy may, in fact, be life-changing and even life-saving. Their therapeutic benefits are widespread, and as more “sustainable” forms of the medications are developed, such as good oral formulations, their use is likely to become even more widespread.

Fit4Life with SSISA

Think Fit4Life. Think The Sports Science Institute of South Africa.