In the late 19th Century, obesity was largely dismissed as a mere spectacle rather than a genuine medical concern. Figures like Miss Conley, infamously labelled the ‘fattest woman in the world’, and Daniel Lambert, who weighed an astonishing 335kg at his death in 1809, were objects of public curiosity rather than being considered as patients with a severe form of a common disease.
Their extreme cases captivated the public’s imagination, yet they were exploited for entertainment rather than managed medically. During this period, the prevailing view was that obesity was a visible manifestation of gluttony and sloth due to a lack of self-control. Obesity was thus considered a personal failure rather than a disease.
The history of obesity as a chronic disease
In 1904, Dr Leonard Williams suggested that obesity might not solely result from overeating and sedentary behaviour, but could also be linked to metabolic imbalances. This revolutionary idea challenged the simplistic view that weight gain was entirely within an individual’s control.
Williams recognised that the habit of overeating often formed in youth, during periods of high physical activity, and these habits could persist into adulthood, even as physical activity levels decreased. He also noted that drinking fluids with meals could increase appetite and accelerate the passage of food through the stomach, leading to greater food consumption.
Williams emphasised the importance of chewing food until it becomes fluid and tasteless as a natural method to reduce food intake. His approach to treating obesity focused on dietary modifications and increased physical activity, laying the groundwork for more structured interventions in the future.
In 1902, WM Bayliss and EH Starling published their discovery of secretin, a hormone released into the bloodstream by the small intestine when acidic stomach contents enter it. This hormone stimulates the secretion of digestive juices from the pancreas needed for food breakdown. This showed that pancreatic regulation involves the nervous system and chemical signals, allowing Bayliss and Starling to speculate that organs can communicate and coordinate their activities through blood-borne chemical messengers; a concept now fundamental to our understanding of endocrinology and human biology.
In 1958, Dr Daniel Cappon argued that obesity should not be defined solely by body weight, but by the pathological accumulation of adipose tissue. He emphasised that obesity was not just about how much someone weighed, but about the distribution and function of fat within the body. This perspective highlighted the inadequacy of using simple bodyweight measurements to define obesity.
In 1994, leptin was discovered, and in 1999, ghrelin was also shown to regulate hunger and fat storage. Leptin, produced by adipose tissue, signals the brain to reduce appetite when fat stores are sufficient, while ghrelin, made in the gastrointestinal tract, stimulates hunger.
These discoveries were pivotal in shifting the understanding of obesity from a matter of willpower to a complex endocrine disorder, and a turning point that began to focus on the intricate systems that regulate metabolism and body weight. It became clear that obesity was not simply a result of overeating, but involved a complex interplay of genetic, hormonal, and environmental factors. This realisation laid the groundwork for a more sophisticated approach to treating obesity; one that considered the underlying biological processes driving weight gain.
The birth of statins
Another disease that caused high rates of cardiovascular death, dyslipidaemia, was managed primarily through diet and exercise. However, in 1985, the work of Michael Brown and Joseph Goldstein was awarded the Nobel Prize for discovering the low-density lipoprotein (LDL) receptor and the HMG-CoA reductase pathway, which explained how cholesterol is synthesised and regulated in the liver. Their research led to the development of statins, a class of drugs that inhibit the HMG-CoA reductase enzyme in the liver, lowering LDL cholesterol levels and reducing the risk of cardiovascular death. Statins quickly became the gold standard for managing dyslipidaemia and preventing death, transforming the treatment landscape. The introduction of statins was a watershed moment, as it provided a highly effective pharmacological tool for managing a condition previously unsuccessfully treated with diet and exercise.
Despite their effectiveness, statins also highlighted the challenges of long-term therapy for chronic diseases. By the late 1990s, it became clear that while statins were highly effective in reducing cholesterol levels and preventing cardiovascular events, patient adherence was a significant issue. Recognising dyslipidaemia as a disease catalysed effective management. This shift paved the way for innovative strategies addressing the root causes of poor adherence.
By integrating patient-centred approaches and leveraging technology, we have developed personalised treatment plans and support systems that enhance patient engagement and adherence – resulting in patients living longer and with a better quality-of-life. This lesson is now relevant when treating obesity, where long-term adherence to therapy is equally critical for achieving sustained health benefits.
Pharmacological management of obesity
The story of how the treatment of dyslipidaemia was transformed is repeated for obesity treatment with glucagon-like peptide (GLP) receptor agonists. In the 1980s, the role of GLP-1 in glucose metabolism was discovered, particularly its ability to stimulate insulin secretion, inhibit glucagon release, and slow gastric emptying – fundamental mechanisms for managing type 2 diabetes and obesity. However, the native GLP-1 peptide was rapidly degraded in the body, necessitating the development of long-acting analogues.
In 2004, liraglutide was discovered as a longer-acting GLP-1 receptor agonist, allowing for once-daily dosing. Approved by the US Food and Drug Administration (FDA) in 2009 for type 2 diabetes, and later in 2014 for obesity, liraglutide significantly improved glycaemic control and promoted weight loss, marking a significant advance in obesity treatment.
Building on liraglutide’s success, semaglutide was developed as a once-weekly GLP-1 receptor agonist, offering greater convenience and efficacy. Approved in 2017 for diabetes and in 2019 for obesity, semaglutide enabled 15 per cent weight loss, which was unprecedented for obesity pharmacotherapies. The next leap came with tirzepatide, a dual GIP (gastric inhibitory polypeptide, also known as a glucose-dependent insulinotropic polypeptide), and GLP-1 receptor agonist, pushing weight loss to over 20 per cent.
These drugs also significantly improved obesity-related complications such as type 2 diabetes, hypertension, and dyslipidaemia. The turning point was in 2023, when, for the first time ever, a randomised control trial confirmed that treating the disease of obesity with semaglutide resulted in fewer cardiac deaths.
However, as with the introduction of statins, the widespread adoption of GLP-1 therapies faced significant hurdles. By 2024, adherence to these medications remained a challenge. The high cost of GLP-1 analogues also posed a substantial barrier to long-term use. Additionally, gastrointestinal side-effects such as nausea and vomiting, while generally mild, especially during the initial phase of treatment, contributed to the discontinuation of therapy for some patients.
Most importantly, neither patients nor doctors thought of obesity as a biological disease, and hence, taking lifelong medication made little sense to them. This was problematic because the full benefits of GLP-1 therapy only manifest with long-term usage. Early discontinuation prevents many patients from realising these long-term health improvements. This mirrored the challenges seen with statins, where the benefits of continuous use were clear, but patient adherence was the Achilles’ heel.
A complex and chronic disease
The evolution of obesity treatment reflects a broader shift in understanding the disease as complex and chronic, requiring long-term management. Treating obesity as a biological disease, much like dyslipidaemia, offers significant opportunities for improving patient outcomes. Just as statins became a lifelong therapy for those at risk of cardiovascular disease, GLP-1 analogues and other emerging obesity treatments will have to become integral components of long-term management strategies, focusing on sustained health improvements rather than short-term weight loss.
This approach requires a shift in how clinicians and patients view obesity. The goal must move beyond short-term weight loss to achieving health gain, sustained improvements in overall health metrics such as blood pressure, glucose levels, lipid profiles, and, most importantly, obesity complications prevention. Treating obesity as a chronic disease necessitates lifelong management strategies akin to the treatment of hypertension or diabetes. It also means that healthcare systems must adapt, ensuring that these treatments are accessible and that patients receive the ongoing support they need to adhere to long-term therapy.
The understanding of obesity has changed from lifestyle choices to recognising it as a biological disease. This marks a significant milestone in medical science, opening doors to more effective and compassionate patient care. The evolution from essential dietary advice to advanced hormonal therapies highlights the tremendous strides in treating obesity. This progress underscores the critical need for ongoing research, robust patient education, and the development of comprehensive, accessible treatment strategies to maximise the benefits of these advancements.
Conclusion
The journey of GLP-1 receptor agonists – from their initial research stages to their prominent role in managing obesity – mirrors the broader evolution in chronic disease treatment. By acknowledging obesity as a biological disease that demands continuous management rather than a one-time cure, the focus has shifted toward long-term health outcomes instead of merely achieving short-term weight loss. This approach aligns obesity management with the treatment models of other chronic diseases, such as asthma, hypertension, and diabetes. Obesity is thus no more or less unique than any other chronic disease, and all we need to do is put it in the same box and manage it the same way we do with other chronic diseases.
References available on request
