The discussion around weight loss these past five years has been supercharged by the increasingly widescale popularity of glucagon-like peptide-1 (GLP-1) agonist medications as safe, reliable, effective solutions to the obesity epidemic.
GLP-1 is a natural gut hormone produced by cells that line one’s intestines. This hormone is secreted in response to eating specific foods like sugars, protein, short chain fatty acids, fibre and so on.
An ‘agonist’ in medicine, is a drug whose function has a similar effect as the original, natural hormone it has been engineered to copy.
So, while GLP-1 agonists as a class have been mainly used by diabetics over the past 20 years, a significant side effect of these drugs – weight-loss – has popularized their modern use, increasing the demand for GLP-1 agonists by non-diabetics.
What Organs Are Affected By GLP-1 Hormones?
GLP-1 has multiple, effects on multiple organs in the body including, but not limited to:
- Brain: appetite regulation
- Cardiovascular: decreased blood pressure
- Liver: reduced glucose production
- Gut: slowed gastric emptying
- Pancreas: stabilized blood glucose by increasing insulin production and suppressing glucagon secretion
- Immune system: decreased inflammation
- Kidneys: increased diuresis
- Fat cells: increased fat cell breakdown and reduced plasma lipids
- Muscle: increased blood flow to muscle and increased glucose uptake
Despite its many benefits, the problem with natural GLP-1 is that half of it is removed from the body within two minutes after being broken down by an enzyme called DPP-4, limiting the duration of its positive effects.
GLP-1 agonists can dodge the DPP-4 enzyme, possessing a half-life between five to seven days – in keeping with the typical seven day dosing interval that applies to several GLP-1 agonists.
This extended duration of action confers several prolonged benefits through:
- Reduced depression, anxiety and substance use
- Improved overall health markers (lower HbA1c, blood glucose, etc.)
- Decreased risk of cardiac disease
- Better outcomes after cardiac surgery
- Decreased inflammatory response
- Diminished severity of gynaecological conditions such as infertility, endometriosis and polyendocrine metabolic ovarian syndrome (PMOS) – previously known as polycystic ovarian syndrome (PCOS)
- Rapid/significant and persistent weight loss
What are the names and effects of these GLP-1 medications?
Publicly available GLP-1 agonists in South Africa go by several trade/drug names: Ozempic™/Wegovy™ (semaglutide), Saxenda™/Victoza™ (liraglutide), Trulicity™ (dulaglutide) and Mounjaro™ (tirzepatide).
Mounjaro™, the most recently released of this class, has been found to have a pronounced effect on weight loss as it has a dual role as a GIP (glucose independent insulinotropic polypeptide) receptor agonist – over and above its role as a GLP-1 agonist.
Using GLP-1 agonists
These medications are generally started at their lowest dose and increased gradually according to one’s response.
Rapid increments in dose volume have been associated with a higher risk of gastrointestinal side effects such as nausea, diarrhoea, constipation, bloating, gallstones, etc.
Accessing GLP-1 agonists in South Africa (S.A.) can be difficult due to:
- They need a doctor’s prescription: GLP-1’s are designated as S4 medications on the S.A. drug scheduling status
- Limited supply: all GLP-1 agonists are imported to S.A. in limited quantities. Their growing popularity keeps them in high public demand.
- Prohibitive price tag: costing between ZAR 1 500.00 to ZAR 5 000.00 a month, GLP-1 agonists are easily unaffordable to the average South African
- Off-label use: registration of GLP-1 agonists in south Africa has seen only a handful being registered for weight loss management (Ozempic™, Wegovy™ and Mounjaro™ as at the time of writing this article)
- Lack of medical aid cover: schemes are increasingly demanding proof of existing cardiovascular disease to authorize funding for these medications; obesity, despite being recognized as a disease, is not documented as a Prescribed Minimum Benefit, therefore will not be covered by schemes as a chronic drug
What are the negative side effects of GLP-1 agonists?
While GLP-1 agonists look to be the latest ‘wonderdrug’, their use has unfortunately been found to cause:
- Hair loss
- Nausea/vomiting
- Constipation/diarrhoea/bloating
- Low vitamin B levels
- Anaemia
- Iron deficiency
- Folate deficiency
- A theoretically increased the risk of developing certain cancers (colorectal, thyroid)
- Loss of muscle mass
- Decreased bone density
- Bone/joint instability
- Increased fatigue and decreased strength and endurance
More About Orthopaedic risks
Weight loss reduces the load on joints. However, the muscle loss associated with GLP-1 agonist use may simultaneously weaken the body’s ability to dissipate forces across joints and connective tissues due to the loss of muscle as a shock absorber.
A reduced muscle mass may also weaken tendons and decrease elasticity. This increases the risk of tendon irritation or injury.
The weakness and instability, worsens wear and tear on joints increasing the risk of falls and fractures in susceptible individuals.
Sarcopenia (loss of muscle mass) decreases the loading of bones, resulting in osteopaenia (decreased bone mineral density). These factors together increase one’s fall, dislocation and/or fracture risk.
Emerging areas of research
- Rebound weight gain: The STEP-1 trial showed that up to 40% of weight lost is regained within the first year of stopping GLP-1 agonists. The long term costs, limited practicality and incomplete long-term data are concerning to many. Long-term microdosing with oral alternatives are under investigation to combat this.
- Over 22% of patients on GLP-1’s develop nutritional deficiencies within a year of starting the medications. Balanced meals and supplements must be considered.
- Baseline blood tests: can be instructive and guide treatment where needed. These inclide Liver function tests, a full blood count, inflammatory markers, a lipid profile, thyroid function tests, vitamin B levels, iron studies, folate levels, etc to evaluate one’s risk prior to commencing GLP-1 agonists. Preventative supplements may need to be consumed regularly to prevent complications associated with various deficiencies.
- Anaesthetic risk: the risk of aspiration is increased due to a delayed gastric emptying time. This may lead to theatre cancellations and other adverse events. If one is planning surgery, it is imperative to mention the use of GLP-1 agonists to one’s treating medical team. Surgeons are increasingly reluctant to conduct surgery on individuals presently on GLP-1 agonists, owing to the risk of low blood sugar surrounding the time of surgery.
- Cancer: colorectal and thyroid cancers have been shown in animal studies to be more likely in users of GLP-1 agonists in at risk individuals those with a positive family or personal history of these cancers)
- Failure: Data shows that 10% of the population are resistant to GLP-1 agonists, meaning that trialling this class of medication may prove frustrating for some individuals. Alternatively, for others, the side effect profile may be so impactful that they have no means of taking the medications in the long run without constantly feeling severely ill.
In summary
-
Weight loss is a lifelong journey that demands long-term commitment and several lifestyle changes.
Rebound weight gain is a real risk, mandating the need for sustained changes that include healthy meal planning and a sustained exercise programme.
The emerging nature of research on GLP-1 agonists as weight-loss drugs demands a multidisciplinary approach.
Strategies to manage the medication’s side effects, such as dividing one’s meal in half, chewing slowly, pausing before starting on the second half of one’s meal are all ways to avoid nausea. Avoiding spicy and fatty foods also helps. Their supervised care can address/investigate sudden plateaus in loss.
A custom exercise programme should include progressive resistance training and loading exercises to maintain and/or rebuild muscle mass and bone density. This programme should be structured and progressive – ideally guided by a physical therapist, who would monitor training loads when returning to activity/sport.
Rebound weight gain upon cessation of GLP-1 agonists remains a persistent issue,
Maintenance microdoses to prevent rebound weight gain mat have a role in suppressing ‘food noise’.
Lastly, beware of fake GLP-1 agonists circulating in S.A. through informal channels.
This content is for educational purposes only and does not constitute medical advice.
Dr Anne Maina
Specialist Orthopaedic surgeon
MBBCh (Wits), FC Orth (SA), MMed Ortho (Wits)
References:
- Wilding JPH et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine.
- Wolfe RR (2006). The underappreciated role of muscle in health and disease. American Journal of Clinical Nutrition.
- Phillips SM (2014). A brief review of critical processes in exercise-induced muscular hypertrophy. Sports Medicine.
- American College of Sports Medicine (ACSM). Guidelines for Exercise Testing and Prescription.
