GLP-1 Drugs: Disrupting the Status Quo in Weight Loss Medicine

While the COVID-19 pandemic has been declared over by the WHO, the obesity pandemic seems to be advancing further, probably fuelled by the consequences of lockdowns. However, is there a chance that the COVID-19 legacy of the combined efforts of pharma and public health can now be marshalled to tackle obesity? And, what role might new ‘blockbuster’ drugs play in this fight?

Overweight and obesity affect almost 60% of adults and nearly one in three children in the European Region, according to a 2022 WHO report. It has been nearly 30 years since the WHO declared obesity as a global epidemic. During this time, it has become widely accepted that obesity can be considered a disease, and might be amenable to pharmacological treatment. This disease is accompanied by a host of comorbidities, including metabolic syndrome, diabetes, cardiovascular disease, osteoarthritis, and even cancer. 

While lifestyle modification remains the first line of obesity management, most guidelines strongly recommend medications if the first line fails. And here is where the blockbusters get underway.

GLP-1 receptor agonists

For decades, weight loss drugs have been used to treat severe obesity, but many of the earlier ones were withdrawn due to unmanageable side effects. Some also require a strict low-fat diet, such as old-generation drug orlistat, which reduces fat absorption. Appetite-reducing drugs, such as phentermine and diethylpropion, risk addiction and are thus only suitable for short-term use.

This is why GLP-1 (glucagon-like peptide-1) agonists, which facilitate significant weight loss and are suitable for long-term use, have gained so much attention. These drugs are used for weight management as an adjunct to increased physical activity and a reduced calorie intake, but do not require a strict diet.

These drugs mimic hormones which reduce appetite and enhance fullness by targeting the gut-brain weight regulation system. Glucagon-like peptide 1 (GLP-1) agonists, as the name suggests, activate GLP-1 receptors that help curb appetite and food intake. They boost insulin production to decrease blood sugar and signal the brain to limit food intake. They also slow food movement in the gastrointestinal tract to enhance fullness and reduce overeating.

GIP (gastric inhibitory polypeptide) is a glucose-dependent insulinotropic polypeptide that facilitates the release of insulin, while mediating appetite and eating behaviour. And glucagon is a hormone that reduces appetite and modulates lipid metabolism. The current evidence about tirzepatide and results from phase 2 studies of retatrutide suggests that the more substances the drug mimics, the stronger the effect.

The below table summarises the current GLP-1 RAs (including combinations) on the market. Due to the evidence of off-label use, we have included those that are currently only indicated for type 2 diabetes mellitus (T2DM).

Are these new drugs really that good?

Studies show that Novo Nordisk's semaglutide and Lilly’s tirzepatide can decrease body weight, on average, by roughly 15%, or approximately 34 pounds, after 68 weeks, and by an average of 22.5%, or about 52 pounds, in 72 weeks, respectively. Notably, these results cannot be compared directly due to the absence of head-to-head comparisons, but they clearly outshine those from older weight loss drugs.

But it's not just about weight loss. Researchers cautiously suggest these medicines might also benefit the heart. Notably, Piccini et al. have found that the discontinuation of GLP-1 RA treatment was associated with a higher risk of major cardiovascular events. Clinical guidelines recommend that individual risk of ischemic or heart failure complications should even guide the choice of treatment for diabetes. Moreover, Dr. Shaman and his colleagues have shown last year that GLP-1 agonists might help prevent diabetic kidney disease. Obesity and diabetes can be so tightly intertwined that all these findings might be projected (with caution) onto weight management. This is where a difficult question arises.

What are we treating, diabetes or obesity?

Does it really come down to that choice? See for yourself. The shortage of GLP-1 agonists, fuelled by celebrities promoting the “magic” drugs, is expected to continue into 2024. With patients struggling with an uneven supply of chronic treatment for their diabetes, messages like, “lose weight and reduce your risk of cardiovascular disease along the way”, might seem unethical.

Another potential stumbling block is that long-term weight management relies on diet and lifestyle changes. Should we be depleting the supplies of effective drugs for diabetics for what might be temporary relief for someone without strong weight-management habits? Wouldn’t it be better to wait until both the shortages are resolved and we receive more data on the long-term efficacy of GLP-1 agonists in obesity, especially in terms of improved risks of comorbidities?

Finally, while semaglutide received NHS approval recently, all other GLP-1 agonists are off-label for weight management in the UK. For tirzepatide, convincing British authorities of its effectiveness may take time, as indicated by the latest NICE statement. The authorities seem to be taking precautions and waiting for more comprehensive evidence. Some HCPs seem to have taken the same path and are avoiding prescribing the new drugs, especially off-label, for weight loss. This issue has even led to the development of online guides to help patients persuade doctors to prescribe new treatments.

In the face of a GLP-1 agonist shortage, we mustn't let their appeal as weight-loss solutions overshadow the immediate needs of diabetic patients. This could be ethically problematic, as it becomes a case of triaging which patients are more ‘deserving’. Moreover, thorough research must guide their application, ensuring supply stability and well-informed decision making. Essentially, the challenge is to prioritise patient needs and scientific evidence over trend and conjecture.

Compliance issues

In this context, there are at least two major drawbacks to the use of anti-obesity drugs. Firstly, they are administered by injection, and patient compliance depends on the type of device and needle size (the narrower the better).

Secondly, GLP-1 agonists come in different doses and in the formulations for once-daily and once-weekly injections. Several studies have shown that once-weekly injections not only improve compliance but also enhance the cost-effectiveness.

The prospect for improved compliance is promising as more research is performed on oral GLP-1 therapies for weight reduction. 

It all comes back to risk-benefit ratio

Beyond the potential cardiovascular and renal benefits associated with GLP-1 agonists, the positive evidence continues to accumulate. Meanwhile, as Dr. Fatima Cody Stanford pointed out, losing weight too quickly — more than 10 pounds a month — can increase the risk of gallstones. Also, physicians want more information about how much lean body mass people lose while taking the drug.

And if there weren’t enough factors to consider, Dr Klausen and her colleagues published preclinical data indicating GLP‐1 receptor agonists could help battle alcohol addiction by decreasing the rewarding/reinforcing effects of alcohol and activating additional mechanisms.

We mustn’t overlook the narrative that such drugs create. Are these drugs mirroring society's pursuit of unrealistic beauty standards? What signal are we sending people with overweight or obesity issues – especially younger people – when we pathologize obesity and then provide a quick-fix solution?

Could these drugs present a long-sought solution to major health challenges? Or will real-world evidence, combined with a social contempt for what these drugs might represent, sound the death knell for these ‘miracle’ treatments? Only time will tell and we will be watching this closely.

References:

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